Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][Cl:7].[ClH:11].Cl.[CH2:13]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[ClH:7].[ClH:11].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][N:25]1[CH2:26][CH2:27][N:22]([CH2:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])[CH2:23][CH2:24]1
Reactant: O=C(CN1CCNCC1)c1ccccc1
Reactant: COc1cccc(CCl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cccc(CN2CCN(CC(=O)c3ccccc3)CC2)c1
Yield: 53.8 %

Procedure:
A mixture of 3-methoxybenzylchloride (0.5 g, 2.15 mmol), N-phenacyl piperazine dihydrochloride (0.6 g, 2.15 mmol) and K2CO3 (1.04 g, 7.52 mmol) in 30 ml of acetone was treated according to general preparation 2 to give 0.46 g of compound (IV-25), yield 54%. M+ 324.
Reaction SMILES: [Mg].[CH2:2]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH2:11][CH3:12])[C:5]=1Br)[CH3:3].[C:14](OCC)(=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl>C1(C)C=CC=CC=1.BrC(Br)C.O1CCCC1>[CH2:2]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH2:11][CH3:12])[C:5]=1[C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:3]
Reactant: CCc1cc(C)cc(CC)c1Br
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(Br)Br
Agent: Cl
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1c(CC)cc(C)cc1CC
Temperature: 33 °C
Reaction time: 0.33 h
Yield: 118.4 %

Procedure:
To a 2 L volume four-necked flask, magnesium (cutting chip) (66.2 g), tetrahydrofuran (anhydrous) (494 g), and toluene (549 g) were added under a nitrogen atmosphere at room temperature. After starting to stir the mixture, dibromoethane (26.9 g) was added dropwise over 10 minutes at about 20° C., and then the internal temperature was raised to 33° C. The resulting mixture was stirred at 30° C. for 20 minutes. 2,6-diethyl-4-methylbromobenzene (10-a) (549.0 g) was added dropwise thereto at 40° C. over 1 hour. The resulting mixture was stirred at 50° C. for 51 hours, and diethyl oxalate (389.1 g) dissolved in toluene (550.1 g) was added dropwise thereto at about 0° C. over 1 hour. The resulting mixture was stirred at about 5° C. for 1 hour. Then, to the mixture, 3.5 w/w % of hydrochloric acid (832 g) was added dropwise at the same temperature. Then the mixture was warmed to room temperature, and the organic layer was separated. The aqueous layer was extracted with toluene (548.3 g). The organic layers were combined, washed with water (1098 g) and concentrated under reduced pressure to give 710.8 g of ethyl 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetate (9-a).
Reaction SMILES: [CH2:1]([O:7][C:8]([C:10]1[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:14]([C:25]([OH:27])=[O:26])=[C:13]([CH3:28])[NH:12][C:11]=1[CH3:29])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH3:6].[CH2:30](O)[CH:31]=[CH:32][CH:33]=[CH:34][CH3:35].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClC(Cl)C>[N+:22]([C:18]1[CH:17]=[C:16]([CH:15]2[C:10]([C:8]([O:7][CH2:1][CH:2]=[CH:3][CH:4]=[CH:5][CH3:6])=[O:9])=[C:11]([CH3:29])[NH:12][C:13]([CH3:28])=[C:14]2[C:25]([O:27][CH2:30][CH:31]=[CH:32][CH:33]=[CH:34][CH3:35])=[O:26])[CH:21]=[CH:20][CH:19]=1)([O-:24])=[O:23]
Reactant: CC=CC=CCO
Reactant: CC=CC=CCOC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Product: CC=CC=CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC=CC=CC)C1c1cccc([N+](=O)[O-])c1
Yield: 89.5 %

Procedure:
398 mg (1 mM) of 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2,4-hexadienyl)ester, 108 mg (1.1 mM) of 2,4-hexadien-1-ol, 227 mg (1.1 mM) of dicyclohexylcarbodiimide and 134 mg (1.1 mM) of 4-dimethylaminopyridine were dissolved in 20 ml of dichloroethane, and refluxed for 2 hours. Insoluble matters were filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and 428 mg (89.4%) of bis(2,4-hexadienyl) 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate was obtained (yield 89.4%).
Reaction SMILES: C(OC([NH:11][C:12]12[CH2:19][CH2:18][C:15]([C:20]([NH:22][CH:23]3[CH2:28][CH2:27][C:26]([F:30])([F:29])[CH2:25][CH2:24]3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=O)C1C=CC=CC=1.[H][H]>O1CCCC1.[C].[Pd]>[NH2:11][C:12]12[CH2:19][CH2:18][C:15]([C:20]([NH:22][CH:23]3[CH2:28][CH2:27][C:26]([F:29])([F:30])[CH2:25][CH2:24]3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2
Reactant: [H][H]
Reactant: O=C(NC12CCC(C(=O)NC3CCC(F)(F)CC3)(CC1)CC2)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: NC12CCC(C(=O)NC3CCC(F)(F)CC3)(CC1)CC2
Yield: 101 %

Procedure:
4-Benzyloxycarbonylamino-N-(4,4-difluorocyclohexyl)bicyclo[2.2.2]octane-1-carboxamide (55.4 mg) was dissolved in tetrahydrofuran (6 mL). To this solution, 10% palladium carbon (20.0 mg) was added and the mixture was stirred at room temperature for 6 hours in a hydrogen atmosphere. The reaction mixture was filtered to remove the catalyst and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column (eluant:ethyl acetate:methanol=10:1) to give 4-amino-N-(4,4-difluorocyclohexyl)bicyclo[2.2.2]octane-1-carboxamide (38.1 mg) as a white solid.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].CO.C([O:8][C:9]([C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[C:20]([Cl:22])[C:19]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:18][C:17]=2[O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:13][N:12]=1)=O)C>C(O)C>[CH2:1]([NH:3][C:9]([C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[C:20]([Cl:22])[C:19]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:18][C:17]=2[O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:13][N:12]=1)=[O:8])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Reactant: CCN
Solvent: CCO
Solvent: CO
Product: CCNC(=O)c1cc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Temperature: 80 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
A solution of ethylamine in methanol solution (2.0M; 40 mL; 80 mmol) was added to a stirred suspension of 5-(2,4-bis-benzyloxy-5-chlorophenyl)-isoxazole-3-carboxylic acid ethyl ester (4.40 g; 9.51 mmol) in absolute ethanol (50 ml). The reaction mixture was heated to 80° C. (oil-bath temperature) for five hours. The reaction mixture was allowed to cool to ambient temperature and left to stand overnight. A colourless solid product formed and the reaction mixture was further cooled in an ice-water bath, filtered and washed with cold ethanol (2×20 ml). The colourless product was dried in vacuo to afford 5-(2,4-bis-benzyloxy-5-chlorophenyl)-isoxazole-3-carboxylic acid ethylamide 3.42 g (78%) LCMS: [M+H]+ 465, 463 (37Cl; 35Cl). 1H NMR (400 MHz, CDCl3) δ 1.25 (t, 3H), 3.48 (m, 2H), 5.10 (s, 2H), 5.2 (s, 2H), 6.59 (s, 1H), 6.83 (brt, 1H), 7.08 (s, 1H), 7.30-7.41 (m, 10H), 7.97 (s, 1H).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.[I:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:22]([CH3:23])=[CH:21][C:20](=[O:24])[C:19]([C:25]([OH:27])=[O:26])=[N:18]2)=[CH:13][CH:12]=1>CCCCCC>[I:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:22]([CH3:23])=[CH:21][C:20](=[O:24])[C:19]([C:25]([O:27][CH2:1][CH2:2][CH2:3][CH3:4])=[O:26])=[N:18]2)=[CH:13][CH:12]=1
Reactant: CCCCO
Reactant: Cc1cc(=O)c(C(=O)O)nn1-c1ccc(I)cc1
Solvent: O=S(Cl)Cl
Solvent: CCCCCC
Product: CCCCOC(=O)c1nn(-c2ccc(I)cc2)c(C)cc1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 52 %

Procedure:
To 50 ml of n-butanol, cooled to -5° C., there is added dropwise 2.62 g (0.022 mol) of thionyl chloride. The solution is stirred at 0° C. for 15 minutes and to it there is added 7.12 g (0.02 mol) of 1-(4-iodophenyl)-1,4-dihydro-4-oxo-6-methylpyridazine-3-carboxylic acid. (See Example 3) The suspension formed is stirred at room temperature for 3 days and to it there is added 150 ml of hexane. The suspension is stirred at room temperature for 2 days and is vacuum filtered. The filter cake (HCl salt of the desired product) is air dried and slurried in 150 ml of water for 3 hrs. The suspension is vacuum filtered to afford 4.25 g (52% yield) of product, mp 137°-137° C.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][C:11]=1[N+:20]([O-:22])=[O:21].C[N+]1([O-])CC[O:27]CC1.[OH2:31]>O1CCCC1.O=[Os](=O)(=O)=O>[OH:31][C@@H:5]1[C@H:6]([OH:27])[C@@H:1]2[CH2:7][C@H:4]1[CH2:3][CH:2]2[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][C:11]=1[N+:20]([O-:22])=[O:21]
Reactant: O
Reactant: NS(=O)(=O)c1ccc(OCC2C[C@H]3C=C[C@@H]2C3)c([N+](=O)[O-])c1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(OCC2C[C@@H]3C[C@H]2[C@@H](O)[C@H]3O)c([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 201A (340 mg) in tetrahydrofuran (10 mL) and water (1 mL) was added N-methylmorpholine N-oxide (184 mg) and OsO4 (2.5% in 2-methyl-2-propanol) (1.05 mL). The reaction mixture was stirred overnight and purified by reverse phase HPLC to provide two isomers, which were temporarily assigned as EXAMPLE 203A and EXAMPLE 203B, respectively.
Reaction SMILES: [N:1]([CH:4]([CH3:19])[CH2:5][N:6]1[C:10]2=[CH:11][C:12]3[C:17]([CH2:16][CH:15]=[CH:14][C:13]=3[CH3:18])=[C:9]2[CH:8]=[N:7]1)=[N+]=[N-].[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24]>C(O)C.C(OCC)C.CO.[Pt]=O>[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24].[CH3:18][C:13]1[CH:14]=[CH:15][CH2:16][C:17]2[C:12]=1[CH:11]=[C:10]1[C:9]=2[CH:8]=[N:7][N:6]1[CH2:5][CH:4]([NH2:1])[CH3:19]
Reactant: CC1=C2C=c3c(cnn3CC(C)N=[N+]=[N-])=C2CC=C1
Agent: O=[Pt]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CCOCC
Solvent: CO
Product: CC1=C2C=c3c(cnn3CC(C)N)=C2CC=C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 86.6 %

Procedure:
1.38 g (5.45 mmol) of (RS)-1-(2-azido-propyl)-7-methyl-1,4-dihydro-indeno[2,1-c]pyrazole dissolved in 60 ml of anhydrous ethanol were hydrogenated over 140 mg of platinum oxide for 2 hours. The catalyst was subsequently filtered off, rinsed with ethanol and the solvent was removed in a vacuum. The colorless oil obtained was dissolved in 80 ml of anhydrous diethyl ether, filtered and treated while stirring with a solution of 633 mg (5.45 mmol) of fumaric acid in 10 ml of methanol. The mixture was stirred at room temperature for 15 hours and the white crystals were subsequently filtered off. 1.62 g (87%) of (RS)-2-(7-methyl-1,4-dihydroindeno[2,1-c]pyrazol-1-yl )-1-methyl-ethylamine fumarate (1:1) with m.p. 205° were obtained.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH:3]=[CH2:4].C1C2N[C:17]3[C:12](=CC=C[CH:16]=3)SC=2C=CC=1.[CH3:20][O-:21].[Mg+2].C[O-]>C(OC)(=O)C(C)=C>[C:20]([O:5][CH2:1][CH2:2][CH:3]=[CH2:4])(=[O:21])[C:17]([CH3:16])=[CH2:12]
Reactant: C=CCCO
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Reactant: C[O-]
Agent: C=C(C)C(=O)OC
Agent: [Mg+2]
Product: C=CCCOC(=O)C(=C)C
Temperature: 25 °C

Procedure:
To a 250 ml round-bottom flask, containing 3-buten-1-ol (24.7 g) and phenothiazine (0.1 g inhibitor), methyl methacrylate (80 ml) was added, followed by a methanolic solution of magnesium methoxide [prepared by dissolving magnesium metal (0.1 g) in anhydrous methanol (5 ml)]. The stirred mixture was slowly heated and methanol was distilled off (bp 64-70° C.) until the temperature at the distillation head rose to approximately 100° C. and the methyl methacrylate started to distill. The mixture was then cooled to room temperature and the solids were filtered off. The filtrate was fractionated under vacuum. Pure 3-butenyl methacrylate was collected at bp 63-66° C./30 mmHg. Yield: 22.5 g.
Reaction SMILES: O[CH2:2][CH:3]([N:8]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[NH2:17])[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[C:36](Cl)(=[O:40])/[CH:37]=[CH:38]/[CH3:39]>C(Cl)Cl>[C:36]([NH:17][C:11]1[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=1[CH2:9][N:8]([S:18]([C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)(=[O:19])=[O:20])[C:3](=[CH2:2])[C:4]([O:6][CH3:7])=[O:5])(=[O:40])/[CH:37]=[CH:38]/[CH3:39]
Reactant: C/C=C/C(=O)Cl
Reactant: COC(=O)C(CO)N(Cc1cc(C)ccc1N)S(=O)(=O)c1ccc(OC)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C(=O)OC)N(Cc1cc(C)ccc1NC(=O)/C=C/C)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 8 h

Procedure:
As described for Reference Examples 181 and 182, a mixture of 1.41 g (3.455 mmol) of methyl 3-hydroxy-2-[-(4-methoxybenzenesulfonyl)-(2-amino-5-methylbenzyl)amino]propionate, 1.75 g (17.3 mmol) of triethylamine and 0.809 ml of trans-crotonyl chloride in 15 ml of CH2Cl2 was stirred overnight to give 1.52 g of methyl 2-{[2-(trans-crotonylamino)-5-methylbenzyl]-(4-methoxybenzenesulfonyl) amino}acrylate as a brown oil; Mass spectrum (ES) 459.4 (M+H).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[C:14]([CH2:15][C:16](Cl)(Cl)Cl)=[C:13]2[C:8]([N:9]=[CH:10][C:11]([CH3:20])=[N:12]2)=[CH:7][CH:6]=1.S(=O)(=O)(O)[OH:22]>CO>[CH3:1][O:2][C:16](=[O:22])[CH2:15][C:14]1[C:5]([Cl:4])=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([CH3:20])[CH:10]=[N:9]2
Reactant: C[O-]
Reactant: Cc1cnc2ccc(Cl)c(CC(Cl)(Cl)Cl)c2n1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1c(Cl)ccc2ncc(C)nc12
Temperature: 70 °C
Yield: 46 %

Procedure:
NaOMe (5.4 M in MeOH, 8.3 ml, 44.71 mmol, 4.5 equiv) was added at room temperature to a solution of 7-chloro-2-methyl-8-(2,2,2-trichloro-ethyl)-quinoxaline (3.08 g, 9.94 mmol) in methanol (24 ml). The reaction mixture was heated to 70° C. for 3 hours. After cooling to 0° C., sulfuric acid (4.7 ml) dissolved in methanol (20 ml) was added, and the reaction mixture was heated to 70° C. for one hour. After cooling and dilution with EtOAc and H2O, the mixture was filtered and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via flash chromatography (gradient of hexane/EtOAc 100:0 to 70:30) to afford the title compound (1.14 g, 46%) as a solid. 1H NMR (400 MHz, CDCl3): δ=8.70 (s, 1H), 7.95 (d, J=9.1 Hz, 1H), 7.69 (d, J=9.1 Hz, 1H), 4.48 (s, 2H), 3.70 (s, 3H), 2.74 (s, 3H). MS (ES+): 251.1 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4].Br[CH2:23][CH2:24][N:25]1[C:33](=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]1=[O:35].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[NH3:11].[CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:23][CH2:24][N:25]4[C:26](=[O:35])[C:27]5[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:33]4=[O:34])[CH2:20][CH2:21]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(OC2CCNCC2)c2ncccc2c1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCc1cc(OC2CCN(CCN3C(=O)c4ccccc4C3=O)CC2)c2ncccc2c1
Product: N
Reaction time: 24 h

Procedure:
6-Butyl-8-(4-piperidinyloxy)quinoline (for example, as prepared for Intermediate 4) (2.44 g, 8.59 mmol) was stirred with 2-(2-bromoethyl)-1H-isoindole-1,3(2H)-dione (commercially available, for example, from Acros and/or Aldrich) (2.40 g, 9.4 mmol) and potassium carbonate (5.9 g, 43 mmol) in 2-butanone (75 ml) under nitrogen at 80° C. for 3 days. Further 2-(2-bromoethyl)-1H-isoindole-1,3(2H)-dione (2.4 g, 9.4 mmol) was added and the heating and stirring were continued for a further 24 h. More 2-(2-bromoethyl)-1H-isoindole-1,3(2H)-dione (1.2 g, 4.7 mmol) was added and the heating and stirring were continued for a further 24 h. The mixture was cooled and partitioned between water and DCM. The aqueous layer was extracted with more DCM (×2) and the combined organic layers were washed with water, dried (MgSO4) and evaporated to an oil. This oil was re-dissolved in DCM and loaded onto a column of silica gel (250 g) that had been preconditioned with DCM. The column was eluted with DCM, then DCM-ethanol-0.88 s.g. aqueous ammonia solution (200:8:1) to give the title compound (2.76 g, 6.03 mmol). LCMS RT=2.91 min, ES+ve m/z 458 [M+H]+.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]([CH2:16][C:17]([F:20])([F:19])[F:18])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[CH:10][CH:9]=2)=[O:5])C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1.C(N(C(C)C)C(C)C)C>CN(C)C=O.C(OCC)(=O)C>[OH:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:16][C:17]([F:18])([F:19])[F:20])[C:6]([C:4]([N:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1)=[O:5])=[CH:14]2
Reactant: CCOC(=O)c1cc2cc(O)ccc2n1CC(F)(F)F
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc2cc(O)ccc2n1CC(F)(F)F)N1CCOCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74 %

Procedure:
A mixture of 5-hydroxy-1-(2,2,2-trifluoro-ethyl)-1H-indole-2-carboxylic acid (intermediate 1, step c, 7.62 g, 1.0 eq.), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (12.8 g, 1.3 eq.), morpholine (3.36 mL, 1.3 eq.) and N-ethyldiisopropylamine (25.7 mL, 5 eq.) in dimethylformamide (85 mL) was stirred at room temperature for 24 h. The reaction mixture was diluted with ethyl acetate and washed with hydrochloric acid (1N), water and brine and dried over sodium sulfate, filtered and concentrated in vacuo. The precipitate was filtered, washed with ethyl acetate and dried in vacuo to yield 7.15 g (74%) of the desired product as off-white solid. MS (m/e): 329.5 (MH+, 100%).
Reaction SMILES: [CH:1](=O)[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[SH:11][CH2:12][CH2:13][C:14]([OH:16])=O.C(=O)([O-])[O-].[NH4+:21].[NH4+]>C1(C)C=CC=CC=1>[CH3:9][O:8][C:3]1[C:2]([CH:1]2[S:11][CH2:12][CH2:13][C:14](=[O:16])[NH:21]2)=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [NH4+]
Reactant: COc1ccccc1C=O
Reactant: O=C(O)CCS
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1ccccc1C1NC(=O)CCS1
Temperature: 110 °C
Yield: 84 %

Procedure:
A mixture of 13.6 g of o-anisaldehyde, 10.6 g of 3-mercaptopropionic acid and 6 g of ammonium carbonate in 250 ml of toluene was refluxed at 110° C. for 2 hours in a flask provided with a Dean-Stark apparatus while removing the distilled water. The crystals which separated out after leaving the reaction mixture for a night were collected by filtering and recrystallized from hot dimethylformamide to obtain the object, colourless prisms melting at 201.5° to 203° C. in an amount of 18.7 g corresponding to a yield of 84%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:27][N:28]([CH3:45])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=1>>[CH3:27][N:28]([CH2:29][C:30]1[CH:31]=[C:32]([C:2]2[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=3[CH3:24])=[O:15])[C:5]3[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=3[CH:10]=2)[CH:33]=[CH:34][CH:35]=1)[CH3:45]
Reactant: CN(C)Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cccc(CN(C)C)c3)cc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 120 °C

Procedure:
The title compound was prepared from 6-bromo-N-((1,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1-isopropyl-1H-indazole-4-carboxamide (500 mg, 1.14 mmol) and N,N-dimethyl(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine (300 mg, 1.14 mmol) in the same manner as described for example 73 wherein the contents were heated at 120° C. for 2 h. The product was collected as a pale red solid (120 mg, 21%). 1HNMR (CDCl3, 400 MHz): 1.568 (d, J=6.8 Hz, 6H), 2.12 (s, 3H), 2.41 (s, 8H), 2.55 (s, 3H), 3.67 (s, 2H), 4.614 (d, J=5.2 Hz, 2H), 4.899-4.834 (m, 1H), 5.90 (s, 1H), 7.326-7.308 (m, 1H), 7.408-7.368 (m, 3H), 7.558 (d, J=7.6 Hz, 1H), 7.639 (s, 1H), 7.699 (s, 1H), 11.193 (brs, 1H). LCMS (ES+) m/z: 486.31.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[Cl:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>>[Cl:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4](=[O:19])[CH2:3][C:2]2([CH3:20])[CH3:1]
Reactant: OB(O)c1cccc(Cl)c1Cl
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Product: CC1(C)CC(=O)c2ccc(-c3cccc(Cl)c3Cl)cc21

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 2,3-dichlorophenyl boronic acid according to the procedure described in example 21. MS (ES) m/z 305.1; HRMS: calcd for C17H14Cl2O+H+, 305.04944; found (ESI, [M+H]+), 305.0504.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][C:5]([CH3:11])(S(C)(=O)=O)[CH3:6].[F:13][C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=2)[CH:17]=[CH:16][C:15]=1[C:27]([OH:33])([CH3:32])[CH2:28][C:29](=[NH:31])[NH2:30].C(=O)([O-])O.[Na+]>O1CCCC1.O>[F:13][C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=2)[CH:17]=[CH:16][C:15]=1[C:27]([OH:33])([CH3:32])[CH2:28][C:29]1[NH:30][CH:2]=[C:3]([CH:4]=[C:5]([CH3:11])[CH3:6])[N:31]=1
Reactant: CC(O)(CC(=N)N)c1ccc(-c2ccc(F)cn2)cc1F
Reactant: CC(C)(CC(=O)CBr)S(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)=Cc1c[nH]c(CC(C)(O)c2ccc(-c3ccc(F)cn3)cc2F)n1

Procedure:
Step C In a quartz tube, 1-bromo-4-methyl-4-(methylsulfonyl)pentan-2-one (26 mg, 0.10 mmol), the di(trifluoroacetate) salt of (±)-3-[2-fluoro-4-(5-fluoropyridin-2-yl)phenyl]-3-hydroxybutanimidamide (105 mg, 0.202 mmol), and sodium hydrogen carbonate (53 mg, 0.63 mmol) were suspended in a mixture of tetrahydrofuran (1.5 mL) and water (0.5 mL). After being irradiated by microwave (120° C., 10 min), the reaction mixture was purified by reversed-phase high performance liquid chromatography to afford the di(trifluoroacetate) salt of the title compound. (M+H) found 370.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH2:17])([C:14](O)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:19]>C(Cl)Cl.Cl>[ClH:19].[ClH:19].[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH2:17])([C:14]([Cl:19])=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: NC1(C(=O)O)CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: ClCCl
Product: NC1(C(=O)Cl)CCN(Cc2ccccc2)CC1

Procedure:
HCl is passed into a suspension of 10 g of finely powdered 1-benzyl-4-amino-4-piperidinecarboxylic acid in 111 ml of CH2Cl2 at 0° C. for 1 hour. 26 g of PCl5 in 200 ml of CH2Cl2 are added in several portions to this mixture, with vigorous stirring and while passing in further HCl. After the mixture has been stirred at 0° C. for 4 hours, the reaction product is filtered off with suction over a glass frit, with exclusion of moisture, and washed thoroughly with petroleum ether (60°-80° C.) and CH2Cl2. The crude product thus obtained is used in the next reaction stage without further purification.