Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[Cl:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:30]1[CH2:29][CH2:28][N:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([Cl:20])[CH:22]=3)[CH2:32][CH2:31]1)=[O:19])=[N:5]2
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(Cl)ccc2nc1OC
Product: COc1nc2ccc(Cl)cc2nc1NC(=O)N1CCN(c2cccc(Cl)c2)CC1
Yield: 85 %

Procedure:
Ethyl N-(6-chloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound (yield, 85%). 1H NMR (300 MHz, CDCl3): δ 3.22-3.32 (m, 4H), 3.73-3.77 (m, 3H), 4.11-4.14 (m, 4H), 6.78-6.90 (m, 3H), 7.19-7.44 (m, 4H), 7.64-7.80 (m, 1H).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26])[CH:19]=[CH:18]3)=[N:8][CH:9]=1)=[S:3].Br[CH2:31][C:32](=O)[CH2:33][CH3:34]>C(O)C>[CH2:33]([C:32]1[N:1]=[C:2]([C:4]2[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26])[CH:19]=[CH:18]4)=[N:8][CH:9]=2)[S:3][CH:31]=1)[CH3:34]
Reactant: CCC(=O)CBr
Reactant: COC(=O)C(C)n1ccc2cc(OCCCOc3ccc(C(N)=S)cn3)ccc21
Solvent: CCO
Product: CCc1csc(-c2ccc(OCCCOc3ccc4c(ccn4C(C)C(=O)OC)c3)nc2)n1
Temperature: 80 °C
Yield: 98.4 %

Procedure:
A mixture of methyl 2-[5-(3-{[5-(aminocarbonothioyl)-2-pyridinyl]oxy}propoxy)-1H-indol-1-yl]propanoate (Example 68, 0.1 g, 0.24 mmol) and 1-bromo-2-butanone (0.05 g, 0.29 mmol) in ethanol (8.90 mL) was heated under argon at 80° C. for 3 h. The resulting mixture was concentrated. The title compound (0.11 g, 98%) was isolated by column chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD2Cl2) δ 8.69 (dd, 1H), 8.13 (dd, 1H), 7.25-7.10 (m, 3H), 6.90-6.81 (m, 3H), 6.47 (d, 1H), 5.12 (qt, 1H), 4.58 (t, 2H), 4.20 (t, 2H), 3.71 (s, 3H), 2.85 (qt, 2H), 2.36-2.24 (m, 2H), 1.82 (d, 3H), 1.35 (t, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11](=S)[S-:12].C([NH+](CC)CC)C.ClC(OCC)=O.C(Cl)(Cl)Cl.C(Cl)Cl>C(N(CC)CC)C>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[N:10]=[C:11]=[S:12]
Reactant: Fc1ccc(NC(=S)[S-])c(F)c1F
Agent: CCOC(=O)Cl
Agent: CC[NH+](CC)CC
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Fc1ccc(N=C=S)c(F)c1F

Procedure:
That is, first 2,3,4-trifluoroaniline (V) is reacted with carbon disulfide in the presence of triethylamine to produce triethylammonium N-(2,3,4-trifluorophenyl)dithiocarbamate (VI). Then the compound (VI) is reacted with ethyl chloroformate in an organic solvent such as chloroform or methylene chloride in the presence of triethylamine to give 2,3,4-trifluorophenylisothiocyanate (VII). The compound (VII) is then reacted with di(lower alkyl) malonate sodium salt, which is prepared from di(lower alkyl) malonate and sodium hydride, in an organic solvent such as tetrahydrofuran or dioxane to give di(lower alkyl) [(2,3,4-trifluoroanilino)(mercapto)methylene]malonate sodium salt (VIII). The compound (VIII) is then reacted with 1-acetoxy-3-halogenoacetone in an organic solvent such as N,N-dimethylformamide, dimethylsulfoxide or acetonitrile to give di(lower alkyl) [(2,3,4-trifluoroanilino)(3-acetoxy-2-oxopropylthio)methylene]malonate (IX). The compound (IX) is then reacted with sulfuric acid to give di(lower alkyl) [3-(2,3,4-trifluorophenyl)-4-hydroxymethyl-2-thiazolidene]malonate (X). The compound (X) is then reacted with sodium hydride in an organic solvent such as dioxane, tetrahydrofuran or N,N-dimethylformamide to give di(lower alkyl) (6,7-difluoro-1H,4H-thiazolo[4,3-c][1,4]benzoxazin-1-ylidene)malonate (XI).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:3][CH2:2]1>C(OCC)(=O)C>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC1=CCOCC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1CCOCC1
Reaction time: 18 h
Yield: 100.3 %

Procedure:
A mixture of 15.0 and 16.0 (3 g, 17.6 mmol) from Preparative Example 10 was dissolved in 20 mL of ethyl acetate containing 1.0 g of 10% paladium on carbon. This mixture was stirred for 18 hours under an atmosphere of hydrogen. The catalyst was filtered and the filtrate was concentrated under vacuum giving 3.04 g of the title product as a colorless oil.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:11]1[C:19]2[C:14](=[CH:15][N:16]=[CH:17][CH:18]=2)[N:13]([CH2:20][C:21]([OH:23])=O)[N:12]=1)(=[O:10])[NH2:9].FC(F)(F)C(O)=O.[Cl:31][C:32]1[C:33]([F:49])=[C:34]([C@H:38]([NH:40][C:41]([C@@H:43]2[CH2:48][C@@H:47]3[C@@H:45]([CH2:46]3)[NH:44]2)=[O:42])[CH3:39])[CH:35]=[CH:36][CH:37]=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>CN(C=O)C>[Cl:31][C:32]1[C:33]([F:49])=[C:34]([C@H:38]([NH:40][C:41]([C@@H:43]2[CH2:48][C@@H:47]3[C@@H:45]([CH2:46]3)[N:44]2[C:21](=[O:23])[CH2:20][N:13]2[C:14]3=[CH:15][N:16]=[CH:17][CH:18]=[C:19]3[C:11]([C:8]([NH2:9])=[O:10])=[N:12]2)=[O:42])[CH3:39])[CH:35]=[CH:36][CH:37]=1
Reactant: C[C@@H](NC(=O)[C@@H]1C[C@H]2C[C@H]2N1)c1cccc(Cl)c1F
Reactant: NC(=O)c1nn(CC(=O)O)c2cnccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)[C@@H]1C[C@H]2C[C@H]2N1C(=O)Cn1nc(C(N)=O)c2ccncc21)c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (3-carbamoyl-pyrazolo[3,4-c]pyridin-1-yl)-acetic acid trifluoroacetate salt (2.65 g, 7.94 mmol, prepared as described in Scheme A26) in DMF (30 mL) were added successively (1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid, [(R)-1-(3-chloro-2-fluoro-phenyl)-ethyl]-amide trifluoroacetate salt (3.00 g, 7.56 mmol), HBTU (3.44 g, 9.07 mmol) and DIPEA (5.28 mL, 30.2 mmol). The reaction mixture was stirred at RT for 16 h and then was concentrated under vacuum. The residual oil was partitioned between CH2Cl2 and a sat. aq. NaHCO3 solution. A solid precipitated from the resulting emulsion and was filtered off, washed with water and dried under vacuum. The solid was suspended in a mixture of water (150 mL) and MeOH (3 mL), stirred for 1 h at RT, filtered, washed with water and finally dried under vacuum to give the title material as a white powder. MS (LC/MS): 485 [M+H]+; tR (HPLC conditions c): 3.54 min.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH:15]([CH2:17][CH3:18])[CH3:16].[OH-].[K+]>CC(C)=O.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH:15]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)([CH2:17][CH3:18])[CH3:16]
Reactant: CCC(C)Br
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(C)n1c2ccccc2c2ccccc21
Reaction time: 10 h

Procedure:
25 g (0.15 mol) of carbazole and 33 g (0.24 mol) 2-bromo-butane were dissolved in 250 ml acetone. 14 g (40 mmol) tetrabutylammonium hydrogen sulfate was added, followed by the addition of 18.6 g (0.285 mol) potassium hydroxide (88%). The reaction mixture was refluxed for 10 hours. After 10 hours, an additional 4 g (30 mmol) 2-bromo-butane and 2 g (31 mmol) potassium hydroxide (88%) were added and the reaction was allowed to continue at reflux temperature for 16 hours. The precipitated salts were removed by filtration and the solvent was evaporated under reduced pressure. The residue was redissolved in 200 ml methyl tert.butyl ether and extracted with 100 ml 1M Na2CO3 and 100 ml water. The organic fraction was isolated, dried over MgSO4 and evaporated under reduced pressure. N-sec.butyl-carbazole was isolated by preparative column chromatography on a Prochrom LC80 column, using Kromasil Si60 10 μm and n. hexane/methylene chloride 93/7 as eluent. 8.7 g (26%) of N-sec.butyl carbazole was isolated.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].S(Cl)(Cl)=O.Cl.[CH3:28][N:29]1[C:37]2[C:32](=[CH:33][C:34]([Cl:38])=[CH:35][CH:36]=2)[C:31]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[Cl:45])=[C:30]1[CH2:46][NH2:47].C(=O)(O)[O-].[Na+]>CN(C)P(=O)(N(C)C)N(C)C.CCOCC.C(N(CC)CC)C>[CH3:28][N:29]1[C:37]2[C:32](=[CH:33][C:34]([Cl:38])=[CH:35][CH:36]=2)[C:31]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[Cl:45])=[C:30]1[CH2:46][NH:47][C:20](=[O:22])[C@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: Cn1c(CN)c(-c2ccccc2Cl)c2cc(Cl)ccc21
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: Cn1c(CNC(=O)[C@H](Cc2ccccc2)NC(=O)OCc2ccccc2)c(-c2ccccc2Cl)c2cc(Cl)ccc21
Reaction time: 8 h
Yield: 53.6 %

Procedure:
To a solution of N-carbobenzoxy-phenylalanine (3 g) in hexamethylphosphoric triamide (16 ml), thionyl chloride (1.2 g) is added dropwise at -6° to -2° C. in 5 minutes, and the resultant mixture is stirred at -6° to -8° C. for 10 minutes. To the mixture, a suspension of 1-methyl-2-aminomethyl-3-o-chlorophenyl-5-chloroindole hydrochloride (3.52 g) in ether (15 ml) previously treated with triethylamine is added, and the resultant mixture is allowed to stand at room temperature overnight. The reaction mixture is neutralized with an aqueous sodium bicarbonate solution and shaken with ether. The organic layer is dried and evaporated to remove the ether. The residue is crystallized from ether to give 1-methyl-2-(Nα -carbobenzoxy-phenylalanylaminomethyl)-3-o-chlorophenyl-5-chloroindole (3.15 g). This substance is recrystallized from ethyl acetate to give needles melting at 174° to 176° C. The yield is 54%. UV: λmaxEtOH 232, 285 mμ (log ε=4.88, 3.28).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]2[O:12][CH:13]=[C:14]([CH2:16]O)[N:15]=2)[CH:8]=[C:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[OH:22])([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:24].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>ClCCl>[C:1]([C:5]1[CH:10]=[C:9]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][Br:24])[N:15]=2)[CH:8]=[C:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[OH:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(-c2nc(CO)co2)cc(C(C)(C)C)c1O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)c1cc(-c2nc(CBr)co2)cc(C(C)(C)C)c1O
Temperature: 0 °C

Procedure:
The compound of Example 351 (4.70 mmol) is dissolved in dichloromethane (30 ml). After adding CBr4 (2.02 g; 6.10 mmol), the reaction medium is cooled down to 0° C. PPh3 (1.48 g; 5.63 mmol) is added by fractions then the mixture is left to return to ambient temperature. The reaction medium is then poured into ice-cold water before being extracted with dichloromethane. The organic phase is washed with salt water before being dried over magnesium sulphate, filtered and concentrated under vacuum. The crude oil obtained is sufficiently pure to be used directly in the following stage.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.[NH2:18][N:19]1[CH2:24][C:23]([CH3:25])=[N:22][NH:21][C:20]1=[O:26].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-].CN(C=O)C>O>[CH3:25][C:23]1[CH2:24][N:19]([NH:18][C:15]([C:12]2[CH:13]=[N:14][C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:10][CH:11]=2)=[O:17])[C:20](=[O:26])[NH:21][N:22]=1
Reactant: COc1cccc(-c2ncc(C(=O)O)cn2)c1
Reactant: CC1=NNC(=O)N(N)C1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(-c2ncc(C(=O)NN3CC(C)=NNC3=O)cn2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 64.3 %

Procedure:
A mixture of 2-(3-methoxy-phenyl)-pyrimidine-5-carboxylic acid (135 mg, 0.58 mmol), 4-amino-6-methyl-4,5-dihydro-2H-[1,2,4]triazin-3-one (76 mg, 0.58 mmol), DMTMM (171 mg, 0.6 mmol) and DMF (3 mL) is stirred at rt for 2 days. Water (3 ml) is added, and the precipitated product is filtered, washed with water and dried to afford 2-(3-methoxy-phenyl)-pyrimidine-5-carboxylic acid (6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-amide (127 mg). MS: 341 (M+H); 1H NMR (DMSO-d6): δ 1.91 (s, 3H), 4.23 (s, 3H), 4.62 (s, 2H), 7.53 (m, 2H), 8.34 (m, 1H), 8.46 (s, 1H), 9.27 (s, 2H), 9.97 (s, 1H), 11.08 (s, 1H). IC50=174.5 nM.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:26])[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH:4]=1.C(N(CC)CC)C.Cl.Cl.[NH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41].CN(C)C=O>O>[CH3:26][N:17]([S:18]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)(=[O:19])=[O:20])[C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[NH:9][C:8]([C:6]1[S:7][C:3]([CH2:2][NH:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:4][N:5]=1)=[CH:16]2
Reactant: CN(c1cccc2cc(-c3ncc(CCl)s3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CCOC(=O)CCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCNCc1cnc(-c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of N-{2-[5-(chloromethyl)-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (424 mg), triethylamine (693 μL), ethyl 4-aminobutanoate dihydrochloride (335 mg) and N,N-dimethylformamide (5 ml) was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give ethyl 4-{[(2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazol-5-yl)methyl]amino}butanoate as a crude product from a fraction eluted with ethyl acetate. A mixture of this product, methanol (2 ml), 1N aqueous sodium hydroxide solution (4 ml) and tetrahydrofuran (4 ml) was stirred at 45° C. for 20 hr. The mixture was neutralized with 1N aqueous hydrochloric acid solution, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (49 mg, yield 10%) as colorless crystals from a fraction eluted with ethyl acetate. MS 473 (M+1).
Reaction SMILES: [C:1]([C:5]1[C:6]([O:16][CH3:17])=[C:7]2[C:12](=[C:13]([Cl:15])[CH:14]=1)[NH:11][CH2:10][CH2:9][CH2:8]2)([O:3]C)=[O:2].[OH-].[Na+]>CO>[C:1]([C:5]1[C:6]([O:16][CH3:17])=[C:7]2[C:12](=[C:13]([Cl:15])[CH:14]=1)[NH:11][CH2:10][CH2:9][CH2:8]2)([OH:3])=[O:2]
Reactant: COC(=O)c1cc(Cl)c2c(c1OC)CCCN2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1c(C(=O)O)cc(Cl)c2c1CCCN2
Temperature: 0 °C

Procedure:
A mixture of the compound of step 5 above (1.1 g), 10% aqueous NaOH (20 ml) and MeOH (40 ml) is stirred under reflux for 30 minutes. The MeOH is evaporated and the aqueous residue partitioned with CHCl3. The mixture is stirred vigorously, cooled to 0° C. and treated with 10% HCl (28 mls). The aqueous layer is separated and the organic layer is dried and evaporated. The residue is crystallized from ether affording the desired product, M.P. 129°-132° C.
Reaction SMILES: [F:1][CH:2]([F:34])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:12]=[N:13][C:14](/[CH:17]=[CH:18]/[C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)[N:23]=[CH:22]4)=[CH:15][CH:16]=2)=[CH:6][CH:5]=1>C(OCC)(=O)C.[Pd]>[F:34][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:12]=[N:13][C:14]([CH2:17][CH2:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)[N:23]=[CH:22]4)=[CH:15][CH:16]=2)=[CH:6][CH:5]=1
Reactant: FC(F)Oc1ccc(Nc2ccc(/C=C/c3ccc4c(cnn4C4CCCCO4)c3)nn2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: FC(F)Oc1ccc(Nc2ccc(CCc3ccc4c(cnn4C4CCCCO4)c3)nn2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
To a solution of (E)-N-(4-(difluoromethoxy)phenyl)-6-(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)vinyl)pyridazin-3-amine (0.14 g, 0.302 mmol) in ethyl acetate (5 mL) was added Pd—C (0.064 g, 0.604 mmol and the reaction mixture was stirred at room temperature under H2 for 3 h. The reaction mixture was filtered through pad of celite, washed with ethyl acetate, and the filtrate was concentrated to give N-(4-(difluoromethoxy)phenyl)-6-(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethyl)pyridazin-3-amine as a yellow solid (0.13 g, 80%). LCMS (ES-API), m/z 466.6 (M+H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.[F:23][C:24](=[CH2:28])[C:25](Cl)=[O:26]>C(OCC)C>[F:23][C:24](=[CH2:28])[C:25]([O:8][C:3]([C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)([C:2]([F:1])([F:14])[F:15])[C:4]([F:7])([F:6])[F:5])=[O:26]
Reactant: C=C(F)C(=O)Cl
Reactant: OC(c1ccco1)(C(F)(F)F)C(F)(F)F
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=C(F)C(=O)OC(c1ccco1)(C(F)(F)F)C(F)(F)F
Temperature: 20 °C
Reaction time: 4 h
Yield: 61.1 %

Procedure:
A solution of 20 g (0.085 mol) of hexafluoro-2-(2-furyl)-2-propanol and 8.65 g (0.085 mol) of triethylamine in 25 ml of dry diethyl ether was added dropwise with stirring at a temperature of 20° C. to a solution of 9.8 g (0.09 mol) of α-fluoroacryloyl chloride (obtained according to Example 4) in 25 ml of dry diethyl ether in the course of 30 minutes. The reaction mixture was then stirred at a temperature of 20° C. for a further 4 hours. The resulting solid was filtered off. The filtrate was distilled under reduced pressure after addition of 0.005 g of hydroquinone monomethyl ether. 15.9 g (61 percent of theory) of hexafluoro-2-(2-furyl)-2-propyl α-fluoroacrylate having a boiling point of 55° to 57° C. (under 8 mbar) were obtained.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([C@@H:14]3[CH2:16][C@H:15]3[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]1>C(O)(CC)C>[Br:1][C:2]1[C:3]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:25]2)=[C:4]2[C:10]([NH:11][C:12]([C@@H:14]3[CH2:16][C@H:15]3[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)[C@@H]1C[C@H]1c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCC(C)O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)[C@@H]4C[C@H]4c4ccccc4)c23)C1
Yield: 48.3 %

Procedure:
trans-N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-phenylcyclopropanecarboxamide (500 mg, 1.34 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (1338 mg, 6.68 mmol) in s-BuOH (5 mL) were heated to 135° C. in a sealed tube for 24 hours. After cooling down, the residue was concentrated and purified by reverse phase chromatography (SP4, 25M, water/ACN 80/20→0/100, 30 CV) to yield tert-butyl (R)-1-(5-bromo-3-(trans-2-phenylcyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (359 mg, 48.5% yield) as a solid.
Reaction SMILES: [CH2:1]([N:7]([CH2:21][CH2:22]OS(C1C=CC(C)=CC=1)(=O)=O)[S:8]([C:11]1[C:12]2[CH:13]=[CH:14][N:15]=[CH:16][C:17]=2[CH:18]=[CH:19][CH:20]=1)(=[O:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH3:34]>C(O)C>[NH2:34][CH2:22][CH2:21][N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[S:8]([C:11]1[C:12]2[CH:13]=[CH:14][N:15]=[CH:16][C:17]=2[CH:18]=[CH:19][CH:20]=1)(=[O:10])=[O:9]
Reactant: CCCCCCN(CCOS(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1cccc2cnccc12
Reactant: N
Solvent: CCO
Product: CCCCCCN(CCN)S(=O)(=O)c1cccc2cnccc12
Temperature: 90 °C

Procedure:
To 2.34 g of the thus obtained N-hexyl-N-(2-p-toluenesulfonyloxyethyl)-5-isoquinolinesulfonamide was added 40 ml of an ethanol solution containing 4 g of ammonia, and the mixture was heated at 90° C. for 48 hours in a pressure vessel. Then, the solvent was removed under reduced pressure to obtain a residue. The residue thus obtained was subjected to purification by silica gel column chromatography (Wacogel C-200, 100 g; solvent: a 3% methanol solution in chloroform) to obtain 1.34 g of N-hexyl-N-(2-aminoethyl)-5-isoquinolinesulfonamide [Compound (4)]. Compound (4) was analyzed to give the following data.
Reaction SMILES: [H-].[Na+].Cl.Cl[C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1.[OH:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][Si](C(C)(C)C)(C)C.O>CS(C)=O>[OH:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1
Reactant: Clc1cccc2nccn12
Reactant: CC(C)(C)[Si](C)(C)OCCCCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: OCCCCOc1cccc2nccn12
Reaction time: 0.25 h

Procedure:
In a nitrogen stream, 8.0 g (200 mmol) of 60% oily sodium hydride was added to a solution of 18.90 g (100 mmol) of 5-chloroimidazo[1,2-a]pyridine hydrochloride in 200 ml of dimethyl sulfoxide at 0° C., followed by stirring for 15 minutes. To this mixture, 20.44 g (100 mmol) of 4-hydroxy-1-t-butyldimethylsiloxybutane was added, followed by stirring room temperature for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to yield 3.73 g (11.6%, orange oily substance) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:12]=[C:11]([CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[CH3:21]I.[H-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:12]=[C:11]([C:13]([CH3:21])([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[CH:10]=[CH:9][N:8]=2)=[CH:19][CH:20]=1
Reactant: CI
Reactant: COC(=O)C(C)c1ccnc(Oc2ccc(Cl)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)c1ccnc(Oc2ccc(Cl)cc2)c1
Reaction time: 0.5 h

Procedure:
Methyl 2-(2-p-chlorophenoxy-4-pyridyl)propionate (3.13 g) is treated with methyl iodide in the presence of 50% sodium hydride in anhydrous tetrahydrofuran in a nitrogen atmosphere at room temperature for 1 hour and then at 40°C for 30 minutes, whereby methyl 2-(2-p-chlorophenoxy-4-pyridyl)isobutyrate (2.59 g) is obtained as crystals melting at 92° to 92.5°C. Then, this substance is treated with a mixture of 20% aqueous potassium hydroxide and 95% ethanol with refluxing for 10 minutes, whereby 2-(2-p-chlorophenoxy-4-pyridyl)isobutyric acid (2.35 g) is obtained as crystals melting at 135° to 136°C.