Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][CH:30]=1)[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:18]=[C:19]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])[CH:28]=[CH:29][CH:30]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(c1ccccc1)c1cccc(O)c1
Product: COc1cc2nccc(Oc3cccc(C(=O)c4ccccc4)c3)c2cc1OC
Temperature: 170 °C
Reaction time: 0.17 h
Yield: 65.3 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxyquinoline (112 mg) and commercially available 3-hydroxybenzophenone (297 mg) was stirred at 170° C. for 10 minutes, the reaction mixture was then purified by thin layer chromatography on silica gel eluting with hexane/acetone (2/1) to obtain 126 mg of the title compound (yield: 65%).
Reaction SMILES: [BH4-].[Li+].[N:3]1[C:4]([C:12](OCC)=[O:13])=[CH:5][N:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12.CO>O1CCCC1.O>[N:3]1[C:4]([CH2:12][OH:13])=[CH:5][N:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12
Reactant: CCOC(=O)c1cn2ccccc2n1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cn2ccccc2n1
Reaction time: 8 h
Yield: 7.8 %

Procedure:
3.68 g of lithium borohydride were added at room temperature to a solution of 9.17 g of ethyl imidazo[1,2-a]pyridine-2-carboxylate [described in J. Org. Chem., 30, 2403-2407 (1965)] in 200 ml of tetrahydrofuran, and then 20 ml of methanol were added dropwise to the mixture, which was then allowed to stand overnight at room temperature. At the end of this time, the reaction mixture was diluted with 10 ml of water and then concentrated by evaporation under reduced pressure. The concentrate was mixed with an aqueous solution of sodium chloride, after which it was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 5:1 by volume mixture of ethyl acetate and ethanol as the eluent. The product was then recrystallized from a mixture of ethyl acetate and hexane, to give 0.56 g of the title compound, melting at 126-128° C.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:7]2[N:21]=[CH:22][C:23]([C:24]#[N:25])=[C:6]12)=[O:4].[F:26][C:27]([F:42])([F:41])[C:28]1[CH:40]=[CH:39][CH:38]=[CH:37][C:29]=1[CH2:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[F:18][C:17]([F:20])([F:19])[C:13]1[CH:12]=[C:11]([C:8]2[N:7]3[N:21]=[CH:22][C:23]([C:24]#[N:25])=[C:6]3[N:5]([C:3](=[O:4])[CH2:2][N:34]3[CH2:33][CH2:32][N:31]([CH2:30][C:29]4[CH:37]=[CH:38][CH:39]=[CH:40][C:28]=4[C:27]([F:41])([F:42])[F:26])[CH2:36][CH2:35]3)[CH2:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1cnn2c1N(C(=O)CCl)CC=C2c1cccc(C(F)(F)F)c1
Reactant: FC(F)(F)c1ccccc1CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#Cc1cnn2c1N(C(=O)CN1CCN(Cc3ccccc3C(F)(F)F)CC1)CC=C2c1cccc(C(F)(F)F)c1
Yield: 52.6 %

Procedure:
A mixture of 7.4 g of 4-(chloroacetyl)-4,5-dihydro-7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile, 5.4 g of 2-trifluoromethylbenzyl piperazine and 2.4 g of sodium carbonate in 260 ml of toluene was reacted as described in Example 146, giving 6.1 g of the desired product, mp 169°-171° C.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([N+:8]([O-])=O)[CH:6]([CH3:11])[CH2:5][CH:4]=[CH:3]1.[H][H]>[Pd]>[CH3:11][CH:6]1[CH2:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH:7]1[NH2:8]
Reactant: [H][H]
Reactant: CC1C=CCC(C)C1[N+](=O)[O-]
Agent: [Pd]
Product: CC1CCCC(C)C1N

Procedure:
contacting said 3,5-dimethyl-4-nitro-cyclohexene with hydrogen at a temperature of about 0° C. to about 200° C. and a pressure of about 0 psig to about 1500 psig in the presence of a palladium catalyst to form 2,6-dimethylcyclohexyl amine; and
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:8][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19]
Reactant: C#C[Si](C)(C)C
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-bromo-4-fluoronitrobenzene (2 g, 9.1 mmol) in tetrahydrofuran (30 ml) was added triethylamine (1.9 ml, 13.6 mmol), trimethylsilylacetylene (1.9 ml, 13.6 mmol), triphenylphosphine (60 mg, 0.23 mmol) and dichlorobis(triphenylphosphine)palladium(II) (319 mg, 0.46 mmol). After stirring at room temperature for 20 minutes copper(I) iodide (17 mg, 0.09 mmol) was added and the mixture left to stir for 18 hours at room temperature. The reaction mixture was quenched into isohexane (150 ml) and filtered through a plug of silica using isohexane as eluent. The solvent was removed ex vacuo to leave (2-fluoro-5-nitrophenylethynyl)trimethylsilane as a brown solid: δH (360 MHz, CDCl3) 0.10 (9H, s), 7.02 (1H, dd, J 8 and 1), 7.97-8.02 (1H, m), 8.17 (1H, dd, J 6 and 3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:12]([C:14]1[C:15]2[N:16]([C:20]([CH3:23])=[N:21][N:22]=2)[N:17]=[CH:18][CH:19]=1)[CH3:13]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:12]([C:14]2[C:15]3[N:16]([C:20]([CH3:23])=[N:21][N:22]=3)[N:17]=[CH:18][CH:19]=2)[CH3:13])=[CH:4][CH:3]=1
Reactant: Cc1nnc2c(C(C)Br)ccnn12
Reactant: Oc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nnc2c(C(C)Oc3ccc(Cl)cc3)ccnn12
Reaction time: 1 h

Procedure:
p-Chlorophenol (0.25 g) was added to a suspension of sodium hydride (0.08 g) in anhydrous dimethylformamide (5 ml). The resultant mixture was stirred at room temperature for 30 minutes then 8-(1-bromoethyl)-3-methyl-1,2,4-triazolo[4,3-b]pyridazine (0.38 g), in dimethylformamide (20 ml), was added dropwise and the mixture stirred for 1 hour. The reaction mixture was concentrated to dryness and the residue dissolved in dichloromethane (50 ml). The solution was washed with 5% aqueous sodium hydroxide and then with water. The organic layer was separated and dried with sodium sulphate, filtered and concentrated to dryness. The white solid obtained was recrystallized from ethyl acetate:hexane to give 8-[1-(4-chlorophenoxy)ethyl]-3-methyl-1,2,4-triazolo[4,3-b]pyridazine. m.p. 158-160° C.
Reaction SMILES: C[N:2](/[CH:4]=[C:5](/[C:11](=O)[C:12]([CH3:15])([CH3:14])[CH3:13])\[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.Cl.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25]N)=[CH:21][C:20]=1[C:27]([F:30])([F:29])[F:28]>>[C:12]([C:11]1[N:25]([C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[C:20]([C:27]([F:30])([F:28])[F:29])[CH:21]=2)[N:2]=[CH:4][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])([CH3:15])([CH3:14])[CH3:13]
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)C(C)(C)C
Reactant: NNc1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Product: CCOC(=O)c1cnn(-c2ccc(Cl)c(C(F)(F)F)c2)c1C(C)(C)C

Procedure:
Ethyl 5-tert-butyl-1-(4-chloro-3-(trifluoromethyl)phenyl)-1H-pyrazole-4-carboxylate was prepared from (Z)-ethyl 2-((dimethylamino)methylene)-4,4-dimethyl-3-oxopentanoate (Intermediate#83) and (4-chloro-3-(trifluoromethyl)phenyl)hydrazine hydrochloride by the same process used for Intermediate#116.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][NH:7][CH:8]2[CH2:10][CH2:9]2)=[C:4]([CH3:13])[CH:3]=1.[CH2:14](I)[CH3:15].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.O>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][N:7]([CH:8]2[CH2:9][CH2:10]2)[CH2:14][CH3:15])=[C:4]([CH3:13])[CH:3]=1
Reactant: Cc1cc(Br)ccc1CNC1CC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCN(Cc1ccc(Br)cc1C)C1CC1
Temperature: 60 °C

Procedure:
A mixture of (4-bromo-2-methyl-benzyl)-cyclopropyl-amine (Intermediate 158, 600.0 mg, 2.49 mmols), ethyl iodide (1.56 g, 10.0 mmols), and K2CO3 (690.0 mg, 5.00 mmols) in 10 mL acetone was heated at 60° C. for 18 hours. The mixture was cooled to room temperature, diluted with H2O, and extracted with EtOAc. The combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The title compound was isolated by column chromatography (2.5% EtOAc-hexanes).
Reaction SMILES: [N:1]1([NH2:7])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH3:34])[C:15]2[O:21][C:20]3[C:22]([Cl:30])=[CH:23][C:24]([NH:26][CH2:27][CH2:28]Cl)=[CH:25][C:19]=3[CH2:18][S:17](=[O:32])(=[O:31])[C:16]=2[CH:33]=1)=[O:11].O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH3:34])[C:15]2[O:21][C:20]3[C:22]([Cl:30])=[CH:23][C:24]([NH:26][CH2:27][CH2:28][NH:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:25][C:19]=3[CH2:18][S:17](=[O:31])(=[O:32])[C:16]=2[CH:33]=1)=[O:11]
Reactant: NN1CCOCC1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCCl)cc(Cl)c1O2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCNN3CCOCC3)cc(Cl)c1O2
Temperature: 120 °C
Reaction time: 5.5 h

Procedure:
Morpholin-4-ylamine (0.1 mL, 1.16 mmol) and tetrabutylammonium iodide (0.075 g, 0.2 mmol) were sequentially added with stirring to a solution of the carboxylic acid of Example 56k (0.250 g, 0.59 mmol) in dry DMF (4 mL). The reaction mixture was then stirred at 120° C. for 5.5 h in an atmosphere of nitrogen. It was treated with cold water and the solid that precipitated was filtered, washed with water, and dried. The solid was treated with a methanolic HCl solution and refluxed at 70° C. for 3 h. The solution was concentrated and treated with an aqueous sodium bicarbonate solution. The solid that precipitated was filtered, washed with water, dried and purified using flash chromatography (silica gel, 2% methanol/chloroform) to obtain the title compound. Yield: 0.105 g, (36.45%). 1H NMR (DMSO-d6): δ 2.50-2.60 (m, 4H, 2CH2), 2.70 (s, 3H, CH3), 2.80 (t, 2H, CH2), 2.80 (t, 2H, CH2), 3.62-3.70 (m, 4H, 2CH2), 3.90 (s, 3H, OCH3), 5.20 (s, 2H, CH2), 6.20 (t, 1H, NH), 6.85 (s, 2H, 2Ar), 8.15 (s, 1H, Ar), 8.25 (s, 1H, Ar); MS: m/e (CI+) 496 (M+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([F:18])=[CH:13][CH:12]=2)(C)(C)C.FC(F)(F)C(O)=O.O>ClCCCl>[F:18][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([NH2:7])=[CH:17]2
Reactant: CC(C)(C)OC(=O)Nc1cnc2ccc(F)cc2c1
Solvent: O
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cnc2ccc(F)cc2c1

Procedure:
A solution of (6-fluoro-quinolin-3-yl)-carbamic acid tert-butyl ester (1.3 g, 4.95 mmol) in 1,2-dichloroethane (15 mL) was treated with trifluoroacetic acid (15 mL) and water (1 mL). The resultant solution was stirred at room temperature for 6 hours. The solvents were evaporated in vacuo, and the residue was triturated in diethyl ether. The solid was purified by flash chromatography using a gradient of 2 N ammonia in methanol (0% to 3%) in dichloromethane as the eluant, to give the product as a colorless solid, 0.47 g (59%). MS: m/z 162.9 (MH+).
Reaction SMILES: [Li]C(C)(C)C.Br[C:7]1[C:16]2[C:15]3[N:17]=[CH:18][CH:19]=[CH:20][C:14]=3[CH2:13][CH2:12][CH2:11][C:10]=2[NH:9][N:8]=1.[C:21](=[O:23])=[O:22]>CCCCC.C1COCC1>[C:7]1([C:21]([OH:23])=[O:22])[C:16]2[C:15]3[N:17]=[CH:18][CH:19]=[CH:20][C:14]=3[CH2:13][CH2:12][CH2:11][C:10]=2[NH:9][N:8]=1
Reactant: O=C=O
Reactant: Brc1n[nH]c2c1-c1ncccc1CCC2
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: O=C(O)c1n[nH]c2c1-c1ncccc1CCC2
Temperature: 25 °C

Procedure:
7.8 mL of 1.7 M of t-BuLi in pentane is added dropwise under argon to a stirred solution of 1-bromo-3,4,5,6-tetrahydro-2,3,10-triaza-benzo[e]azulene (1.4 g) in 75 mL of anhydrous THF at −78° C. After addition, dry carbon dioxide is bubbled into the mixture at the same temperature for 2 hours. The reaction mixture is allowed to warm to room temperature, quenched with 1N HCl solution, and diluted with water. The mixture is basified with 1N NaOH to pH 8-9, and then extracted with EtOAc. The aqueous layer is then acidified with HOAc to pH 4-5 and extracted with CH2Cl2 eight times. The combined extracts are washed with water, dried, and concentrated to give 3,4,5,6-tetrahydro-2,3,10-triaza-benzo[e]azulene-1-carboxylic acid as a tan solid. 1H NMR(DMSO): 1.95(m, 2H), 2.96(m, 2H), 3.07(t, 2H), 7.45(m,1H), 7.97(d,1H), 8.52(d, 2H). LR-MS: MW 229.23, Found: 230.2(M+1). Step 6: A mixture of 3,4,5,6-tetrahydro-2,3,10-triaza-benzo[e]azulene-1-carboxylic acid (80 mg), 1-(3-azetidin-1-yl-propyl)-1H-pyrazol-3-ylamine (68 mg), EDCI(85 mg) and DMAP(55 mg) in 10 mL of 1,2-dichloroethane is refluxed overnight, cooled and diluted with CH2Cl2. The mixture is washed with aqueous NaHCO3 solution, water, dried over Na2SO4 and concentrated under vacuum. Purification on a silica gel plate, eluting with 10% MeOH in CH2Cl2 yields 12 mg of 3,4,5,6-tetrahydro-2,3,10-triaza-benzo[e]azulene-1-carboxylic acid [1-(3-azetidin-1-yl-propyl)-1H-pyrazol-3-yl]-amide as a colorless foam. 1H NMR (CDCl3): 2.01-2.31(m, 6H), 2.67-2.92(m, 8H), 3.63(m, 2H), 4.17(t, 2H), 6.65(d, 1H), 7.23(m, 1H), 7.33(d, 1H), 7.65(d, 1H), 8.62(d, 1H), 14.13(bs, 1H). LR-MS: MW 391.48, Found: 392.2 (M+1).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:17]([CH:18]=O)[C:16]=1[OH:23]>>[F:14][C:15]1[C:16]([OH:23])=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1cccc(F)c1O
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: O=c1cc(N2CCN(Cc3cccc(F)c3O)CC2)nc[nH]1

Procedure:
6-[4-(3-Fluoro-2-hydroxy-benzyl)-piperazin-1-yl]-3H -pyrimidin-4-one was prepared using Procedure B from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 3-fluorosalicylaldehyde (available from Aldrich). 1H NMR (400 MHz, CDCl3) δ 2.62-2.66 (m, 4H), 3.58-3.65 (m, 4H), 3.79 (s, 2H), 5.40 (s, 1H), 6.71-6.76 (m, 2H), 6.99-7.03 (m, 1H), 7.84 (s, 1H), 11.85 (br s, 1H). Mass spectrum (ES) MH+=305.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:13]1([C:26]2[NH:27][C:28]3[C:33]([C:34]=2[CH3:35])=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:18][CH2:17][C:16]([N:23]([CH3:25])[CH3:24])([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:14]1.C(N(CC)CC)C.[CH:43]1([S:48](Cl)(=[O:50])=[O:49])[CH2:47][CH2:46][CH2:45][CH2:44]1.[OH-].[Na+]>ClCCl>[CH2:19]([C:16]1([N:23]([CH3:25])[CH3:24])[CH2:17][CH2:18][C:13]([C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH2:3][CH2:2][NH:1][S:48]([CH:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)(=[O:50])=[O:49])=[CH:11][CH:10]=[CH:9][CH:8]=3)([C:26]2[NH:27][C:28]3[C:33]([C:34]=2[CH3:35])=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:14][CH2:15]1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCC1(N(C)C)CCC(c2[nH]c3ccccc3c2C)(c2[nH]c3ccccc3c2CCN)CC1
Reactant: O=S(=O)(Cl)C1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC1(N(C)C)CCC(c2[nH]c3ccccc3c2C)(c2[nH]c3ccccc3c2CCNS(=O)(=O)C2CCCC2)CC1

Procedure:
4-(3-(2-aminoethyl)-1H-indol-2-yl)-1-butyl-N,N-dimethyl-4-(3-methyl-1H-indol-2-yl)cyclohexylamine (120 mg, 0.255 mmol, mixture of the two possible diastereoisomers in a ratio of approx. 30:70) mixed in dichloromethane (5 ml) with triethylamine (0.12 ml, 0.863 mmol) and cyclopentane sulphonyl chloride (65 mg, 0.385 mmol). After a reaction time of 24 h at 25° C. the reaction mixture was mixed with 1N sodium hydroxide solution (10 ml) and extracted with dichloromethane (3×15 ml). The combined organic phases were dried with Na2SO4 and then filtered. The volatile constituents of the filtrate were completely removed in a vacuum. The residue (yellow foam, 173 mg) was purified by column chromatography [silica gel 60 (25 g); ethyl acetate/methanol 4:1 (250 ml), methanol/30% ammonia 9:1 (100 ml)]. The product was obtained as a beige-coloured solid with a yield of 39 mg (25%) (melting point 111-115° C., AS 11227, mixture of the two possible diastereoisomers in a ratio of approx. 30:70).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20](Br)=[CH:21][N:22]=3)[N:19]=2)[CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:24])[N:7]([CH3:8])[CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([C:28]4[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=4)=[CH:21][N:22]=3)[N:19]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccncc1
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc3ncc(Br)n3n2)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc3ncc(-c4ccncc4)n3n2)C1
Temperature: 150 °C
Yield: 25.7 %

Procedure:
A mixture of [1-(3-bromo-imidazo[1,2-b]pyridazin-6-yl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (100 mg, 0.25 mmol), 4-pyridinylboronic acid (40 mg, 0.33 mmol), K2CO3 (104 mg, 0.75 mmol) and dichlorobis(triphenylphosphine)palladium(II) (8.8 mg, 0.013 mmol) in MeCN/water (3.2 ml/0.8 ml) was heated in a microwave at 150° C. for 15 min. The water layer was removed and the organic layer was diluted with MeCN and filtered. The filtrate was subjected to preparative HPLC to give the titled compound (25.3 mg). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.50-1.55 (m, 9H) 2.22-2.32 (m, 2H) 2.89 (s, 3H) 3.46-3.57 (m, 2H) 3.72-3.80 (m, 2H) 4.91 (t, J=7.61 Hz, 1H) 6.95 (d, J=9.92 Hz, 1H) 7.77 (d, J=9.70 Hz, 1H) 8.11 (s, 1H) 8.23-8.27 (m, 2H) 8.53-8.58 (m, 2H). LRMS (ESI) m/z 395.2 [(M+H)]+, calc'd for C21H26N6O2: 394.48.
Reaction SMILES: [Cl:1][CH:2]([CH:10]=[C:11]([Cl:13])[Cl:12])[C:3]([CH3:9])([CH3:8])[CH2:4][C:5](Cl)=[O:6].[O:14]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][OH:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1C=CC=CC=1>C1C=CC=CC=1.C(OCC)C>[Cl:1][CH:2]([C:3]([CH3:9])([CH3:8])[CH2:4][C:5]([O:25][CH2:24][C:23]1[CH:26]=[CH:27][CH:28]=[C:21]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:22]=1)=[O:6])[CH:10]=[C:11]([Cl:13])[Cl:12]
Reactant: CC(C)(CC(=O)Cl)C(Cl)C=C(Cl)Cl
Reactant: OCc1cccc(Oc2ccccc2)c1
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(C)(CC(=O)OCc1cccc(Oc2ccccc2)c1)C(Cl)C=C(Cl)Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
In 30 g of dry benzene were dissolved 2.6 g of 4,6,6,-trichloro-3,3-dimethyl-5-hexenoyl chloride and 2.0 g of 3-phenoxybenzyl alcohol were added to the solution. This was followed by the dropwise addition of 2.4 g of pyridine and the mixture was stirred at room temperature overnight. The reaction mixture was then diluted with diethyl ether, washed with dilute aqueous hydrogen chloride and water, dried over anhydrous magnesium sulfate and distilled to remove the low-boiling fraction. The residual viscous oil was purified by column chromatography. By the above procedure there were obtained 3.9 g of 3-phenoxybenzyl β-(1,3,3-trichloroallyl)isovalerate (3-phenoxybenzyl 4,6,6-trichloro-3,3-dimethyl-5-hexenoate, Compound [17]) the NMR spectrum and elemental analysis of which are given below [yield: 91%].
Reaction SMILES: I[C:2]1[O:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][C:14]=1[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O.O.C(OCC)(=O)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[O:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=2)=[CH:15][C:14]=1[CH3:22]
Reactant: Cc1cc(B(O)O)ccc1Cl
Reactant: CCOC(=O)c1coc(I)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1coc(-c2ccc(Cl)c(C)c2)n1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
385 mg (1.44 mmol) of the compound from Example 25A and 319 mg (1.87 mmol) of 4-chloro-3-methylphenylboronic acid are initially charged in 12.7 ml of dry N-methyl-2-pyrrolidone. 105 mg (0.14 mmol) of bis(diphenylphosphino)ferrocenepalladium(II) chloride, 0.33 ml water and 940 mg (2.88 mmol) of cesium carbonate are then added. The reaction mixture is stirred at 50° C. for 4 h. The mixture is then cooled to RT, and 20 ml of ethyl acetate and 10 ml of water are added. The aqueous phase is extracted twice with in each case 20 ml of ethyl acetate. The combined organic phases are washed once with 10 ml of sat. aqueous sodium chloride solution and dried over magnesium sulfate. After filtration, the solvent is removed on a rotary evaporator. The residue is purified by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([F:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH:4]=1.[C:22]1([N:28]2[CH:32]=[C:31]([C:33](O)=[O:34])[CH:30]=[N:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)CC)C>CN(C=O)C>[F:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:33]([C:31]3[CH:30]=[N:29][N:28]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:32]=3)=[O:34])=[CH:4][N:5]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[CH:10][CH:9]=1
Reactant: NCc1cn(-c2ccccc2F)c2cc(F)ccc2c1=O
Reactant: O=C(O)c1cnn(-c2ccccc2)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCc1cn(-c2ccccc2F)c2cc(F)ccc2c1=O)c1cnn(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
A mixture of 3-(aminomethyl)-7-fluoro-1-(2-fluorophenyl)quinolin-4(1H)-one (intermediate H) (50 mg, 0.175 mmol), 1-phenyl-1H-pyrazole-4-carboxylic acid (66 mg, 0.349 mmol), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrOP) (112 mg, 0.24 mmol), triethylamine (53 mg, 0.524 mmol), and DMF (3 mL) was stirred at room temperature overnight. The crude material was purified by flash chromatography (12 g silica gel eluting with 100% hexanes ramped to 70% ethyl acetate in hexanes). The product 1-phenyl-1H-pyrazole-4-carboxylic acid [7-fluoro-1-(2-fluoro-phenyl)-4-oxo-1,4-dihydro-quinolin-3-ylmethyl]-amide (46 mg, 58%) was obtained as an off-white solid. MS calcd. for C22H14ClF2N3O2 [(M+H)+] 426.1, obsd. 426.1.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1)[CH2:15][CH3:14])[CH3:21]
Reactant: O=c1ccc2ccc(O)cc2o1
Reactant: CCOC(=O)CCCBr
Product: CCOC(=O)C(CC)Oc1ccc2ccc(=O)oc2c1

Procedure:
Coumarin-7-oxybutyric acid N-hydroxysuccinimide ester was prepared by reacting 7-hydroxycoumarin with ethyl 4-bromobutyrate to form coumarin-7-oxybutyric acid ethyl ester. Next, the ethyl ester was reacted with acid to form coumarin-7-oxybutyric acid which was reacted with N-hydroxysuccinimide to form the N-hydroxysuccinimide ester in accordance with the Scheme 1 above.