Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B.[O:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.[C:7]([N:10]1[C:18]2[C:13](=CC(C=C)=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)(=[O:9])[CH3:8].O.O.C[N+]([O-])(C)C.Cl>O>[C:7]([N:10]1[C:18]2[C:13](=[CH:3][C:4]([CH2:5][CH2:6][OH:2])=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)(=[O:9])[CH3:8]
Reactant: C1CCOC1
Reactant: C=Cc1ccc2c(c1)CCN2C(C)=O
Agent: B
Agent: C[N+](C)(C)[O-]
Agent: Cl
Solvent: O
Product: CC(=O)N1CCc2cc(CCO)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
Borane-tetrahydrofuran complex (1.0M in THF, 20 ml, 20 mmol) was added dropwise to an ice cooled solution of 1-acetyl-2,3-dihydro-5-ethenyl-1H-indole (5.61 g, 30 mmol) in TEF (150 ml). The mixture was stirred at 0° C. for 30 minute then at room temperature for 1 hr. Trimethylamine N-oxide dihydrate (8.88 g, 80 mmol) was added and the mixture was heated under reflux for 3 hr, cooled and poured into water (400 ml) and aqueous HCl (6N, 10 ml). The mixture was extracted with dichloromethane (3×400 ml) and the combined organic fractions were dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate, to give the alcohol as a white solid (3.41 g, 55%).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:4].[CH3:22][S-:23].[Na+]>C(O)C.O.C(OCC)(=O)C>[CH3:22][S:23][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:4]
Reactant: C[S-]
Reactant: O=C(CBr)Nc1cccc(-c2cnc3ccccc3n2)c1
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CSCC(=O)Nc1cccc(-c2cnc3ccccc3n2)c1
Yield: 74.8 %

Procedure:
A slurry of 2-bromo-N-(3-(quinoxalin-2-yl)phenyl)acetamide (207 mg, 0.605 mmol) and sodium thiomethoxide (127 mg, 1.82 mmol) in ethanol (10 mL) was stirred at room temperature for 18 hrs. The reaction mixture was diluted with water (10 mL) and ethyl acetate (50 mL), the organic phase was separated, dried over sodium sulphate and evaporated in vacuo to afford 2-(methylthio)-N-(3-(quinoxalin-2-yl)phenyl)acetamide (140 mg, 75% yield). LCMS calculated for C17H15N3OS (M+H): 310.39. found 310. 1H-NMR (DMSO-d6, 400 Mhz) δH: 10.30 (1H, br.), 9.53 (1H, s), 8.53 (1H, m), 8.12-8.18 (2H, m), 8.05-8.08 (1H, m), 7.84-7.95 (3H, m), 7.55-7.60 (1H, m), 3.35 (2H, s), 2.22 (3H, s).
Reaction SMILES: [NH:1]([C:3]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[NH:13][CH:14]=[C:6]([C:7]=23)[CH2:5][N:4]=1)[NH2:2].[C:15](=O)(O)[O-].[Na+]>C(O)=O>[CH:11]1[C:12]2[C:3]3=[N:1][N:2]=[CH:15][N:4]3[CH2:5][C:6]3=[CH:14][NH:13][C:8]([C:7]=23)=[CH:9][CH:10]=1
Reactant: NNC1=NCc2c[nH]c3cccc1c23
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: c1cc2c3c(c[nH]c3c1)Cn1cnnc1-2
Temperature: 100 °C

Procedure:
5-Hydrazino-1,3-dihydropyrrolo[4,3,2-de]isoquinoline hydrofluoroborate (300 mg), described in Example 8, in formic acid (98%, 4 ml) is heated at 100°C for 2 hours. The mixture is then poured into a saturated sodium bicarbonate solution. The precipitate is collected to give the title compound, mp 248° - 249°C, nmr (DMSO-d6) δ 5.65 (2H), 7.3 (4H), 8.5 (1H), 11.3 (1H).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[CH2:4][NH:5][C@H:6]1[CH2:10][CH2:9][NH:8][CH2:7]1.Cl[C:17]1[N:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[CH2:4][NH:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:17]2[N:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=2)[CH2:7]1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: Clc1ccc(CN[C@H]2CCNC2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: FC(F)(F)c1ccnc(N2CC[C@H](NCc3ccc(Cl)cc3Cl)C2)n1
Yield: 65.9 %

Procedure:
Stir a mixture of (S)-(2,4-dichlorobenzyl)-pyrrolidin-3-ylamine (266 mg, 1 mmol), 2-chloro-4-(trifluoromethyl)-pyrimidine (365 mg, 2 mmol) and polymer supported potassium carbonate (626 mg, 2 mmol) at 80° C. overnight. Filter away the polymer and pour the filtered reaction mixture onto a SCX-2 column. Elute with methanol and then elute with 2 M ammonia in methanol. Concentrate to give a residue and chromatograph on silica gel to give the title compound (258 mg, 66%). Prepare the hydrochloride salt essentially as described in EXAMPLE 1 to give the hydrochloride salt of the title compound. 1H NMR (400 MHz, MeOH-d4) δ 8.39 (2H, m), 7.71 (1H, d, J=8.56 Hz), 7.68 (1H, d, J=1.71 Hz), 7.51 (1H, dd, J=8.31, 1.96 Hz), 4.46-4.55 (2H, m), 4.19-4.26 (1H, m), 4.09-4.14 (1H, m), 3.89-3.98 (2H, m), 3.73 (1H, m), 2.63-2.70 (1H, m), 2.39-2.48 (1H, m), MS (ES): m/z=391 [M+].
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][S:2]1(=[O:11])=[O:10].[CH3:12][NH2:13]>C1COCC1.C(OCC)(=O)C>[CH3:12][NH:13][S:2](=[O:11])(=[O:10])[O:1][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[OH:3]
Reactant: CN
Reactant: O=S1(=O)Oc2ccccc2O1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNS(=O)(=O)Oc1ccccc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1,3,2-benzodioxathiol 2,2-dioxide (300 mg) in THF (6 mL) was added methylamine (0.871 mL, 2 M THF solution) at room temperature, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (86 mg).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([F:12])=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O.[N:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[N+]=[N-].O>CO.C1(C)C(C)=CC=CC=1>[Cl:3][C:4]1[C:5]([F:12])=[C:6]2[C:9](=[CH:10][CH:11]=1)[NH:13][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:7]2
Reactant: O=Cc1cccc(Cl)c1F
Reactant: COC(=O)CN=[N+]=[N-]
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1C
Solvent: O
Product: COC(=O)c1cc2c(F)c(Cl)ccc2[nH]1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 5.6 %

Procedure:
Ethanol (100 ml) was added to sodium hydride (content: 60%, 4.7 g) at 0° C. under an argon atmosphere, and the mixture was stirred for 10 minutes. After 2-nitropropane (11 ml) was added to the reaction mixture to stir the mixture for 10 minutes, 1-(bromomethyl)-3-chloro-2-fluorobenzene (10 g) was added to stir the resultant mixture at room temperature for 3.5 hours. Precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was partitioned in diethyl ether and water, and an organic layer was successively washed with a 1N aqueous solution of sodium hydroxide, water and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatagraphy on silica gel (ethyl acetate:hexane=3:7) to obtain crude 3-chloro-2-fluorobenzaldehyde (5.5 g) as a pale yellow oil. Methanol (20 ml) was added to sodium hydride (content: 60%, 1.6 g) at 0° C. under an argon atmosphere, and the mixture was stirred for 10 minutes. The reaction mixture was cooled to −20° C., and the crude 3-chloro-2-fluorobenzaldehyde (5.5 g) and a solution of methyl 2-azidoacetate (5.0 g) in methanol (10 ml) were added within 20 minutes. The temperature of the reaction mixture was raised to 0° C., and after the mixture was stirred for 2.5 hours, water (40 ml) was added thereto. The reaction mixture was concentrated under reduced pressure, the residue was extracted with a mixed solvent of methylene chloride and ethyl acetate. The extract was washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by column chromatagraphy on silica gel (toluene:hexane=3:17) to obtain crude methyl 2-azido-3-[(3-chloro-2-fluoro)phenyl]acrylate (2.6 g). This product was dissolved in xylene (50 ml), and the solution was stirred at 130° C. to 140° C. for 3 hours. The reaction mixture was concentrated, and the resultant residue was purified by column chromatography on silica gel (methylene chloride) and then crystallized from diethyl ether-hexane to obtain the title compound (440 mg).
Reaction SMILES: [C:1]1([CH:7]=[CH:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O>C(OCC)(=O)C>[C:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCC=Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: OCCCc1ccccc1
Reaction time: 0.5 h
Yield: 95 %

Procedure:
67.1 mg (0.50 mmol) of 3-phenyl-2-propen-1-ol (34), 270 μL (15 mmol) of distilled water and stainless steel balls (50 pieces) were placed in the vessel of the planetary ball mill, which was then closed, and agitated by operating the planetary ball mill for 6 hours at 800 rpm (reversed every 30 minutes). After the lapse of 6 hours, 10 mL of ethyl acetate was added to the vessel of the ball mill to provide a solution containing the reaction mixture, which was then filtered with celite. The operation was repeated 5 times to provide a filtrate, which was then concentrated, thereby providing 64.7 mg (0.475 mmol) of 3-phenyl-1-propanol (35). The yield was 95%. The reaction is expressed by the following scheme.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:32]#[N:33])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH2:25][O:26][C:27]([F:30])([F:29])[F:28])[C:17]([O:19]C(C)(C)C)=[O:18])[C:10](=[O:31])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:32]#[N:33])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH2:25][O:26][C:27]([F:29])([F:30])[F:28])[C:17]([OH:19])=[O:18])[C:10](=[O:31])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CCOC(F)(F)F)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(CCOC(F)(F)F)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
384 mg (789 μmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-(trifluoromethoxy)butanoate (racemate) in 7.9 ml of dichloromethane and 2.28 ml (29.6 mmol) of TFA were reacted according to General Method 6A. Yield: 330 mg (96% of theory)
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:11])[C:5]([NH:7][N+:8]([O-:10])=[O:9])=[NH:6].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Cl)=[CH:15][N:14]=1>CN(C=O)C>[Cl:12][C:13]1[N:14]=[CH:15][C:16]([CH2:19][NH:6][C:5]([N:4]([CH3:11])[CH3:3])=[N:7][N+:8]([O-:10])=[O:9])=[CH:17][CH:18]=1
Reactant: CN(C)C(=N)N[N+](=O)[O-]
Reactant: ClCc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(=N[N+](=O)[O-])NCc1ccc(Cl)nc1
Reaction time: 0.17 h
Yield: 31.9 %

Procedure:
To a suspension of 0.44g of 60% sodium hydride (in mineral oil) in 10ml of DMF was added 1.32g of N,N-dimethyl-N'-nitroguanidine during 20 minutes at room temperature. After stirring for 10 minutes, 1.62g of 2-chloro-5-(chloromethyl)pyridine was added to the mixture in 5 minutes, and stirred for 2 hours at room temperature and for 4 hours in an oil bath of 60° C. After filtering insoluble materials off, the filtrate was concentrated. The resulting residue was purified by a column chromatography [developing solvent: dichloromethane-ethyl acetate (5:1-3:1)] to obtain 0.82g of 1-(6-chloro-3-pyridylmethyl)-3,3-dimethyl-2nitroguanidine (Compound No. 6).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23]([OH:25])=O)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[N:38]1C(C)=CC=C[C:39]=1C.CN.O1CCCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23](=[O:25])[NH:38][CH3:39])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Cc1cccc(C)n1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCC(=O)O)n2)cc1Cl
Agent: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)CCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.8 %

Procedure:
To a solution containing 3-{3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-propionic acid (prepared in example 9, 50 mg, 0.11 mmol) in methylene chloride (2 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (59 μL, 0.12 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (17 μL, 0.14 mmol) was added to the solution at 0° C. After 1 h, a 2.0 M solution of methylamine in tetrahydrofuran (59 μL, 0.11 mmol) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-methylcarbamoyl-ethyl)-1H-pyrazol-3-yl]-propionamide (11 mg, 21%) as a white solid: ESI-LRMS m/e calcd for C22H29ClN4O4S [M+] 480.2, found 481.4 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.09-1.20 (m, 2H, CH2), 1.46-1.96 (m, 8H, 4×CH2), 2.17-2.29 (m, 1H, CH), 2.62 (t, J=6.3 Hz, 2H, COCH2), 2.75 (d, J=4.9 Hz, 3H, CONCH3), 3.27 (s, 3H, SO2CH3), 3.55 (t, J=7.6 Hz, 1H, CH), 4.31 (t, J=6.3 Hz, 2H, NCH2), 5.48 (brm, 1H, NH), 6.58 (d, J=2.3 Hz, 1H, Ar), 7.30 (d, J=2.3 Hz, 1 H, Ar), 7.46 (dd, Jo=8.2, Jm=1.6 Hz. 1H, Ar), 7.60 (d, Jm=1.6 Hz, 1H, Ar), 7.88 (s, 1 H, NH), 8.09 (d, Jo=8.2 Hz, 1H, Ar).
Reaction SMILES: O.NN.[C:4]([C:8]1[CH:13]=[CH:12][C:11](/[C:14](/[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([O:35][CH3:36])[N:29]=2)=[CH:15]\[CH2:16][N:17]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:10][CH:9]=1)([CH3:7])([CH3:6])[CH3:5]>C(O)C.[Cl-].[Na+].O>[C:4]([C:8]1[CH:13]=[CH:12][C:11](/[C:14](/[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([O:35][CH3:36])[N:29]=2)=[CH:15]\[CH2:16][NH2:17])=[CH:10][CH:9]=1)([CH3:7])([CH3:5])[CH3:6]
Reactant: COc1nc(/C(=C/CN2C(=O)c3ccccc3C2=O)c2ccc(C(C)(C)C)cc2)ccc1Cl
Agent: NN
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1nc(/C(=C/CN)c2ccc(C(C)(C)C)cc2)ccc1Cl

Procedure:
Hydrazine monohydrate (13 μL) was added to a solution of 2-[(2E)-3-(4-tert-butylphenyl)-3-(5-chloro-6-methoxypyridin-2-yl)prop-2-en-1-yl]-1H-isoindole-1,3(2H)-dione (98 mg) in ethanol. Thereafter, the mixture was stirred with heating under reflux for three hours and then stirred at room temperature overnight. Brine was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure to give a crude product of (2E)-3-(4-tert-butylphenyl)-3-(5-chloro-6-methoxypyridin-2-yl)prop-2-en-1-amine.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:29]=[CH:30][CH:31]=3)[O:23][CH2:24][C:25]([O:27]C)=[O:26])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([N:7]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:10][C:9]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:29]=[CH:30][CH:31]=3)[O:23][CH2:24][C:25]([OH:27])=[O:26])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)COc1cccc(CCc2cc(-c3ccccc3)n(-c3ccccc3)n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)COc1cccc(CCc2cc(-c3ccccc3)n(-c3ccccc3)n2)c1
Yield: 84.1 %

Procedure:
A mixture of methyl [3-[2-(1,5-diphenyl-1H-pyrazol-3-yl)ethyl]phenoxy]acetate (3.50 g, 8.5 mmol), 5N NaOH solution (5 mL, 25 mmol) and methanol (70 mL) was heated to reflux on a steam bath for 15 minutes. The solvent was evaporated, the residue diluted with water and acidified with 2N HCl to pH=1. A white solid was filtered off and recrystallized from a mixture of hexanes and CH2Cl2 to give [3-[2-(1,5-diphenyl-1H-pyrazol-3-yl)ethyl]phenoxy]acetic acid (2.85 g, 84%), mp 125°-127° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[C@H:4]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=4)=[O:25])=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:37])[CH:5](C)C.Br[C:40]1C=C2C(CN(C(C)(C)C(OC)=O)C2=O)=CC=1.CC1(C)C(C)(C)OB(C2C=CC(NC(NC3C=CC=C(C(F)(F)F)C=3)=O)=CC=2)O1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:5][C:4]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:36])[F:35])[CH:28]=4)=[O:25])=[CH:21][CH:22]=3)=[CH:13][CH:14]=2)[C:9]1=[O:37])([CH3:40])[C:3]([O:2][CH3:1])=[O:38]
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)cc2C1=O
Reactant: COC(=O)C(C)(C)N1Cc2ccc(Br)cc2C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC1(C)OB(c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)OC1(C)C
Solvent: ClCCl
Product: COC(=O)C(C)(C)N1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)cc2C1=O

Procedure:
The compound of example 339 was prepared analogous to compound of example 330 by reaction of the compound of example 338, compound of example 327 and Pd(dppf)Cl2: CH2Cl2.
Reaction SMILES: CN1CCOCC1.[CH3:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:12]2[CH2:13][CH2:14][N:9]([CH3:8])[CH2:10][CH2:11]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CN1CCNCC1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CN1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Temperature: 0 °C

Procedure:
N-methylmorpholine (60 g, 65 mL, 0.6 mol) is dissolved in DCM (100 mL), to which 1-methylpiperazine (30.5 g, 0.3 mol) is added. The reaction is cooled to 0° C., after which a solution of 4-bromo-benzenesulfonyl chloride (75.8 g, 0.296 mol) in DCM (100 mL) is added dropwise. The reaction is allowed to warm to RT overnight. The reaction mixture is then concentrated and water (1 L) is added. The solids that are formed are filtered and the filtrate is extracted with EtOAc (500 mL). The organic layer is washed with saturated brine, dried over MgSO4, filtered and concentrated to afford 1-(4-bromo-benzenesulfonyl)-4-methyl-piperazine as a pale yellow solid: LC/MS 321.0 (M+1); 1H NMR (400 MHz, CDCl3) δ 2.3 (s, 3 H) 2.5 (m, 4 H) 3.0 (m, 4 H) 7.6 (dt, J=8.8, 2.0 Hz, 2 H) 7.7 (dt, J=8.8, 2.1 Hz, 2 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15]([C:17]2[N:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:16])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[C:26]([F:33])[CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:3]=[C:4]([NH:14][C:15]([C:17]3[N:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[O:16])[CH:5]=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[C:26]([F:33])[CH:25]=1
Reactant: O=C(Nc1cnc(OCC(F)(F)F)c(Br)c1)c1cccnn1
Reactant: OB(O)c1ccc(Cl)cc1F
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2F)c1)c1cccnn1

Procedure:
The title compound was synthesized in analogy to Example 39, using pyridazine-3-carboxylic acid[5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-amide (example 62 a) and B-(4-chloro-2-fluorophenyl)-boronic acid (CAN 160591-91-3) as starting materials; LC-MS (UV peak area/ESI) 98.7%, 427.0587 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][C:5]=1[C:13]1[NH:14][C:15](=[O:26])[C:16]2[N:21]([CH3:22])[N:20]=[C:19]([CH2:23][CH2:24][CH3:25])[C:17]=2[N:18]=1)[CH3:2].[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>ClCCl>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([N:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]2)=[O:9])=[CH:6][C:5]=1[C:13]1[NH:14][C:15](=[O:26])[C:16]2[N:21]([CH3:22])[N:20]=[C:19]([CH2:23][CH2:24][CH3:25])[C:17]=2[N:18]=1)[CH3:2]
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(C(=O)O)ccc3OCC)nc12
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(C(=O)N4CCN(C)CC4)ccc3OCC)nc12
Yield: 25.3 %

Procedure:
A solution of 4-ethoxy-3-(1-methyl-7-oxo-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-5-yl)benzoic acid (0.095 g, 0.00027 mol), 1-methylpiperazine (0.265 g, 0.00265 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.077 g, 0.0004 mol) and 1-hydroxybenzotriazole (0.054 g, 0.0004 mol) in dichloromethane (25 ml) was stirred at room temperature for 18 hours. The reaction solution was washed with water (25 ml), dried (MgSO4) and evaporated under vacuum, and then the resulting residue crystallised from ethyl acetate-hexane to give the title compound as colourless crystals (0.03 g, 25%), m.p. 196°-197° C. Found: C,63.12; H,6.81; H,18.96. C23H30N6O3 requires C,62.99; H,6.90; N,19.16%.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([O:6][CH3:7])=[O:5].N#N>CO>[OH:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: CCCCCCCCCCCC(=O)CC(=O)OC
Agent: N#N
Solvent: CO
Product: CCCCCCCCCCC[C@@H](O)CC(=O)OC
Temperature: 50 °C
Yield: 97.6 %

Procedure:
A slurry of methyl 3-oxotetradecanoate (29, 29.0 g, 113 mmol) in methanol (120 mL) was purged in a 300 mL high pressure reactor glass sleeve with N2 for 10 minutes. Dichloro-R-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl ruthenium (897 mg, 1.10 mmol) was added. The mixture was placed in a Parr 5500 series compact reactor. The reactor was charged with H2 (60 psi) and vented 3 times. The reactor was charged with H2 (60 psi) and stirred (1200 rpm) and heated to 50° C. for 20 h. The reactor was cooled to room temperature, and the resulting orange solution was concentrated in vacuo. The residue was purified by silica gel chromatography (120 g RediSep column, eluting with a gradient of 0% through 40% ethyl acetate/hexanes over 60 min, 85 mL/min) to provide product 30 (28.5 g, 97% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=2)[N:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Br.[F:48][C:49]([F:68])([F:67])[O:50][C:51]1[CH:52]=[C:53]([C:57]2[CH:66]=[CH:65][C:60]3[NH:61][C:62]([NH2:64])=[N:63][C:59]=3[CH:58]=2)[CH:54]=[CH:55][CH:56]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[F:68][C:49]([F:48])([F:67])[O:50][C:51]1[CH:52]=[C:53]([C:57]2[CH:66]=[CH:65][C:60]3[NH:61][C:62]([NH:64][C:11]([C:9]4[N:10]=[C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][N:6]5[CH:8]=4)=[O:13])=[N:63][C:59]=3[CH:58]=2)[CH:54]=[CH:55][CH:56]=1
Reactant: Nc1nc2cc(-c3cccc(OC(F)(F)F)c3)ccc2[nH]1
Reactant: O=C(O)c1cn2nc(Cl)ccc2n1
Agent: Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1nc2cc(-c3cccc(OC(F)(F)F)c3)ccc2[nH]1)c1cn2nc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.4 %

Procedure:
A mixture of 6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid (2.5 g), HBTU (4.41 g) and DIEA (4.0 mL) in DMF (20 mL) were stirred at room temperature for 10 minutes. To this reaction mixture was added 5-(3-trifluoromethoxy-phenyl)-1H-benzoimidazol-2-ylamine hydrobromide salt (3.78 g), and the mixture was heated at 80° C. for 30 minutes. After cooling the reaction mixture to room temperature, an aqueous sodium bicarbonate solution (200 mL) was added, and the mixture was stirred for 30 minutes. The mixture was then filtered, washed with water, dried, and purified on an 80 g pre-packaged silica gel column with a gradient of 0 to 10% 2M ammonia-methanol in DCM. 4.7 g of 6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-trifluoromethoxy-phenyl)-1H-benzoimidazol-2-yl]-amide was obtained. LCMS (m/z): 473.9. 1H NMR (400 MHz, DMSO-d6) δ 12.14 (2H, br. s.) 9.08 (1H, s) 8.35 (1H, d) 7.81 (1H, s) 7.73 (1H, d) 7.47-7.65 (5H, m) 7.34 (1H, d).