Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=[O:4].[BH4-].[Na+].[NH4+].[Cl-]>CO>[F:1][C:2]([F:15])([F:16])[CH:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:9][CH:10]=1)[OH:4]
Reactant: O=C(c1ccc(C(F)(F)F)cc1)C(F)(F)F
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: OC(c1ccc(C(F)(F)F)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.1 %

Procedure:
In a 50 mL two-neck flask, 2,2,2-trifluoro-1-[4-(trifluoromethyl)phenyl]ethanone (2.0 g, 8.3 mmol) was dissolved in methanol (8 mL) and sodium borohydride (0.31 g, 8.3 mmol) was added carefully in portions with ice-bath cooling. The resultant colourless solution was stirred at RT for 2 hours and monitored by TLC. Upon the disappearance of all starting material, 5 mL of an aqueous saturated NH4Cl solution was slowly added to the reaction mixture with additional stirring for 10 min. The later was extracted 3 times with 20 mL of EtOAc and the organic fractions were combined and washed with 10 mL of brine, dried over Na2SO4, and filtered. The solvent was removed under reduced pressure to give 2,2,2-trifluoro-1-[4-(trifluoromethyl)phenyl]ethanol (2.13 g, quantitative) as a colourless oil which was used with no further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13](Cl)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:36]([O:43][CH2:44][C@@H:45]1[O:50][CH2:49][CH2:48][N:47]([C:51]2[CH:56]=[CH:55][CH:54]=[C:53](B3OC(C)(C)C(C)(C)O3)[CH:52]=2)[CH2:46]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[OH-].[Na+]>COCCOC.C(Cl)Cl.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13]([C:55]4[CH:54]=[CH:53][CH:52]=[C:51]([N:47]5[CH2:48][CH2:49][O:50][C@@H:45]([CH2:44][O:43][CH2:36][C:37]6[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=6)[CH2:46]5)[CH:56]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2cccc(N3CCO[C@@H](COCc4ccccc4)C3)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(Cl)nc43)cc2)CCC1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(-c5cccc(N6CCO[C@@H](COCc7ccccc7)C6)c5)nc43)cc2)CCC1
Temperature: 160 °C
Yield: 42.3 %

Procedure:
A mixture of tert-butyl (1-{4-[2-(2-aminopyridin-3-yl)-5-chloro-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutyl)carbamate (50.0 mg, 0.101 mmol), (2R)-2-[(benzyloxy)methyl]-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]morpholine (83.4 mg, 0.204 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (7.21 mg, 0.0102 mmol), and 2M NaOH aq. (0.150 mL, 0.310) in DME (2 mL) was heated at 160° C. for 2 hours under microwave irradiation. After cooling to room temperature, the mixture was diluted with DCM and filtered through a Celite pad. The combined filtrate and washings were concentrated. The residue was purified by silica gel column chromatography (CHCl3/MeOH=98:2) and PTLC (CHCl3/MeOH=9:1) to afford desired product (31.5 mg, 41.9%) as pale yellow foam.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.[H][H]>C(OCC)(=O)C.CN(C)C=O.C(N(CC)CC)C.[OH-].[Pd+2].[OH-]>[CH3:16][O:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[O:17][CH3:18])[N:8]=[CH:7][CH:6]=[C:5]2[O:4][C:3]1[CH:19]=[CH:20][C:21]([NH2:23])=[CH:22][C:2]=1[F:1]
Reactant: [H][H]
Reactant: COc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2cc1OC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC

Procedure:
4-Chloro-6,7-dimethoxyquinazoline (10.23 g) and 2-fluoro-4-nitrophenol (14.37 g) were suspended in monochlorobenzene (100 ml), and the suspension was heated under reflux overnight. The solvent was removed by distillation under the reduced pressure, and the residue was washed with toluene, was filtered, and was dried. The crystal thus obtained was then suspended in an aqueous sodium hydroxide solution, and the suspension was filtered, followed by drying to give 4-(3-fluoro-4-nitrophenoxy)-6,7-dimethoxyquinoline (14.2 g, yield 90%). 4-(2-Fluoro-4-nitrophenoxy)-6,7-dimethoxy-quinoline (4.57 g) was dissolved in ethyl acetate/N,N-dimethylformamide/triethylamine (100 ml/100 ml/20 ml) to prepare a solution. Palladium hydroxide (1.2 g) was added to the solution, and the mixture was stirred in a hydrogen atmosphere at room temperature overnight. After filtration through Celite, the solvent was removed by distillation under the reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure to quantitatively give 4.27 g of the title compound.
Reaction SMILES: [CH3:1][CH:2]([O:12][C:13](=[O:32])[C:14]1[C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:17]([O:28][CH3:29])=[CH:16][C:15]=1[O:30][CH3:31])[CH2:3][CH2:4][C:5](=[O:11])[CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].[Cl-].[Li+].[CH:35]([Sn](CCCC)(CCCC)CCCC)=[CH2:36].O>CN(C)C=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>[CH3:1][CH:2]([O:12][C:13](=[O:32])[C:14]1[C:19]([CH:35]=[CH2:36])=[CH:18][C:17]([O:28][CH3:29])=[CH:16][C:15]=1[O:30][CH3:31])[CH2:3][CH2:4][C:5](=[O:11])[CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: C=CCCCC(=O)CCC(C)OC(=O)c1c(OC)cc(OC)cc1OS(=O)(=O)C(F)(F)F
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCCCC(=O)CCC(C)OC(=O)c1c(C=C)cc(OC)cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.1 %

Procedure:
A mixture of 2,4-dimethoxy-6-trifluoromethanesulfonyloxy-benzoic acid 1-methyl-4-oxo-non-8-enyl ester (0.041 g, 0.085 mmol), PdCl2(PPh3)2 (0.007 g, 0.01 mmol), lithium chloride (0.052 g, 1.2 mmol), and vinyltributyltin (50 μL, 0.17 mmol) in dimethylformamide (2 mL) was stirred at room temperature for 24 hours. After addition of water (10 mL), extraction, and chromatography afforded 2,4-dimethoxy-6-vinyl-benzoic acid 1-methyl-4-oxo-non-8-enyl ester as a clear oil (23 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][C:10]1[S:11][C:12]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:13]([C:15](=O)[NH2:16])[N:14]=1.Cl.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.N1C=CC=CC=1>[C:15]([C:13]1[N:14]=[C:10]([NH:9][CH3:8])[S:11][C:12]=1[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)#[N:16]
Reactant: CNc1nc(C(N)=O)c(-c2ccncc2)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: CNc1nc(C#N)c(-c2ccncc2)s1
Temperature: 0 °C
Reaction time: 6 h
Yield: 25.8 %

Procedure:
Trifluoroacetic acid (2.8 g) was dropwise added to a suspension of 2-methylamino-4-carbamoyl-5-(4-pyridyl)thiazole (2.1 g) and pyridine (2.8 g) in methylene chloride (60 ml) at 5° to 10° C. with stirring, which was continued under the same condition for 6 hours. The reaction mixture was poured into ice-water and the resultant mixture was acidified to pH 1.0 with 10% hydrochloric acid. The separated aqueous layer was adjusted to pH 7.5 with 20% potassium carbonate and extracted with ethyl acetate. The organic extract was washed with brine and dried over magnesium sulfate. The solvent was removed in vacuo to give a crystalline residue, which was recrystallized from a mixture of ethyl acetate and tetrahydrofuran to afford 4-cyano-2-methylamino-5-(4-pyridyl)thiazole (0.5 g). mp 192°-195° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([O:13]C)=[CH:8][CH:9]=2)[CH:4]=1.[Na]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10]([CH2:9][CH2:8][C:7](=[O:13])[CH2:6]2)=[CH:11][CH:12]=1
Reactant: COc1ccc2ccc(OC)cc2c1
Agent: [Na]
Product: COc1ccc2c(c1)CC(=O)CC2

Procedure:
2,7-dimethoxynaphthalene of formula XXV, ##STR36## is subjected to the action of sodium metal, in the heated state and in the presence of an anhydrous alcohol, to form 7-methoxy-1,2,3,4-tetrahydro-2-naphthalenone of formula XXVI, ##STR37## which is then reacted in the heated state in an alcoholic solvent with a hydroxylamine salt to form 7-methoxy-1,2,3,4-tetrahydro-2-naphthalenone oxime of formula XXVII, ##STR38## which is then subjected to a catalytic hydrogenation, in solution in an alcohol, in the presence of Raney nickel and ammonia, to form 2-amino-7-methoxy-1,2,3,4-tetrahydronaphthalene of formula XXVIII, ##STR39## which is condensed with acetic anhydride in acetic acid medium to form 2-acetamido-7-methoxy-1,2,3,4-tetrahydronaphthalene of formula XXIX, ##STR40## which is subjected to the action of boron tribromide, at room temperature in a halogenated organic solvent, to form 2-acetamido-7-hydroxy-1,2,3,4-tetrahydronaphthalene of formula XXX, ##STR41## which is then reacted with chloroacetonitrile, in the presence of boron trichloride and aluminum chloride, to form 2-acetamido-6-(2- chloro-1-oxoethyl)-7-hydroxy-1,2,3,4-tetrahydronaphthalene of formula XXXI, ##STR42## which is subjected to the action of triethylamine, in the heated state in a halogenated organic solvent, to form 7-acetamido-2,3,5,6,7,8-hexahydronaphtho[2,3-b]furan-3-one of formula XXXII, ##STR43## which is then
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12]C(OCC2C=CC=CC=2)=O)[C:7]1=[O:23])[CH3:5]>[Pd].CO>[NH2:12][C:8]1[C:7](=[O:23])[N:6]([CH:4]([CH3:5])[C:3]([O:2][CH3:1])=[O:24])[CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)C(C)n1cccc(NC(=O)OCc2ccccc2)c1=O
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(C)n1cccc(N)c1=O
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
A mixture of 2(S) methyl-2-[3-benzyloxycarbonylamino-1,2-dihydro-2-oxo-1-pyridyl)propionate (49a) (2.75 g, 8.33 mmol), methanol (100 ml), and 10% palladium on carbon (300 mg) was stirred under an atmosphere of hydrogen for 30 min. The mixture was filtered and concentrated to afford 1.63 g (100%) of a colorless solid: 1H NMR (d6-DMSO) δ 8.35 (1H, brs), 7.46 (1H, d), 7.22 (1H, d), 6.29 (1H, t), 5.22 (1H, q), 3.63 (3H, s), 1.55 (3H, d).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.Cl.[OH-:14].[K+]>>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([OH:14])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: [OH-]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [K+]
Product: COc1cc(O)ccc1[N+](=O)[O-]
Temperature: 90 °C

Procedure:
4-Fluoro-2-methoxynitrobenzene (4.68 g, 27.4 mmol) was suspended in a 5M potassium hydroxide solution (50 ml) and heated to 90° C. for 5 h. The red solution was cooled to room temperature and acidified to pH 6 with 1M HCl. The aqueous solution was extracted three times with ethyl acetate and the combined organics were washed with brine and dried over sodium sulfate. Removal of the solvent under reduced pressure, followed by purification by flash column chromatography (1:1 hexane/ethyl acetate) afforded the title compound as a yellow solid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:7]([NH2:8])=[C:6]([CH3:14])[CH:5]=1.[CH3:15]I.O>CN(C=O)C>[Br:3][C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:7]([NH:8][CH3:15])=[C:6]([CH3:14])[CH:5]=1
Reactant: CI
Reactant: Cc1cc(Br)cc([N+](=O)[O-])c1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CNc1c(C)cc(Br)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
3.80 g (86.6 mmol) sodium hydride (55%, suspension in mineral oil) were added batchwise to 20.0 g (86.6 mmol) 4-bromo-2-methyl-6-nitroaniline in 250 mL DMF with slight cooling and the mixture was stirred for 30 min. Then 5.40 mL (86.6 mmol) methyl iodide were slowly added dropwise, the cooling was stopped and the mixture was stirred overnight at RT. Then water was slowly added while the mixture was cooled and it was extracted several times with EtOAc. The organic phases were combined, dried on sodium sulphate, filtered and evaporated down i.vac. The residue was recrystallised from DIPE, cooled and the precipitate was suction filtered and dried.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=2[F:17])[C:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])([C:18]#[N:19])[CH:7]([CH2:28][C:29]([CH:32]2[CH2:34][CH2:33]2)([CH3:31])[CH3:30])[NH:6]1)=[O:4].[OH-].[Na+].CO.Cl>O1CCCC1>[Cl:16][C:12]1[C:11]([F:17])=[C:10]([CH:9]2[C:8]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[F:27])([C:18]#[N:19])[CH:7]([CH2:28][C:29]([CH:32]3[CH2:33][CH2:34]3)([CH3:31])[CH3:30])[NH:6][CH:5]2[C:3]([OH:4])=[O:2])[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)C1NC(CC(C)(C)C2CC2)C(C#N)(c2ccc(Cl)cc2F)C1c1cccc(Cl)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F)C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.5 %

Procedure:
To rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-cyclopropyl-2-methyl-propyl)-pyrrolidine-2-carboxylic acid methyl ester prepared in Example 99b (0.95 g, 1.87 mmol) in tetrahydrofuran (40 mL) was added an aqueous solution (20 mL) of NaOH (0.15 g, 3.7 mmol) and methanol (20 mL). The reaction mixture was stirred at room temperature for 18 h. The “pH” of the mixture was adjusted to 5 by aqueous HCl solution. The mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried over MgSO4, concentrated, and trituated with dichloromethane and hexanes to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-cyclopropyl-2-methyl-propyl)-pyrrolidine-2-carboxylic acid as a white solid (0.78 g, 80%)
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:6][C@H:5]([OH:7])[CH2:4]1.[N:8]1[CH:9]=[CH:10][N:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[C:12]=12.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[N:8]1[CH:9]=[CH:10][N:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:2][C@@H:3]3[CH2:6][C@H:5]([OH:7])[CH2:4]3)[C:12]=12
Reactant: N[C@H]1C[C@@H](O)C1
Reactant: O=Cc1cccn2ccnc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: O[C@H]1C[C@@H](NCc2cccn3ccnc23)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 104.3 %

Procedure:
To an emulsion of cis-3-aminocyclobutanol hydrochloride (1.254 g, 10.15 mmol) in DCM (15 mL) was added MeOH (60 mL), imidazo[1,2-a]pyridine-8-carbaldehyde (1.5 g, 10.26 mmol) and DIPEA (2 mL, 11.45 mmol) and the reaction mixture stirred at room temperature under nitrogen for 10 minutes. Sodium triacetoxyborohydride (5.4 g, 25.5 mmol) was then added and the reaction mixture stirred under nitrogen for 18 hours and then concentrated in vacuo. The residue was dissolved in DCM (200 mL), aqueous sodium hydroxide (2M, 200 mL) was added and the mixture was stirred at room temperature for 1 hour. The layers were separated and to the aqueous phase was added sodium hydroxide pellets (ca. 5 g) which was then extracted with 3:1 chloroform:isopropanol (2×500 mL). The combined organic extracts were dried using a hydrophobic frit, evaporated in vacuo and the residue was dissolved in DCM and purified on a silica cartridge (100 g) using a 0-25% methanol-DCM gradient over 60 min. The product containing fractions were combined and evaporated in vacuo to give the title compound as an orange oil (2.3 g).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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>[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3ccccc3F)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 55.8 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (60 mg, 0.10 mmol) was treated with (2-fluorophenyl)boronic acid (34 mg, 0.24 mmol), sodium carbonate (25 mg, 0.24 mmol) and bis(triphenylphosphine)palladium(II) dichloride (7 mg, 0.01 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 20%, hexane-ethyl acetate) to give 34 mg (56% yield) of the title compound. Purity 93%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH:5]1[O:10][CH2:9][CH2:8][N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1.[NH2:18][C:19]1[C:27]([Cl:28])=[CH:26][C:22]([C:23](O)=[O:24])=[C:21]([O:29][CH3:30])[CH:20]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[NH2:18][C:19]1[C:27]([Cl:28])=[CH:26][C:22]([C:23]([NH:1][CH2:2][CH2:3][CH2:4][CH:5]2[O:10][CH2:9][CH2:8][N:7]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:6]2)=[O:24])=[C:21]([O:29][CH3:30])[CH:20]=1
Reactant: NCCCC1CN(Cc2ccccc2)CCO1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1cc(N)c(Cl)cc1C(=O)NCCCC1CN(Cc2ccccc2)CCO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.9 %

Procedure:
To a mixture of 2-(3-aminopropyl)-4-benzylmorpholine (2.0 g), 4-amino-5-chloro-2-methoxybenzoic acid (1.7 g) and dichloromethane (40 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.8 g) is added, and the mixture is stirred at 25° C. for 4 hours. The reaction mixture is washed successively with water, 10% aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and evaporated under reduced pressure. The residue is dissolved in chloroform and chromatographed on silica gel. The eluate with chloroform is discarded, and the subsequent eluates with methanol-chloroform (1:9) are pooled and evaporated to give the title compound (2.5 g) as an oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][O:27][C:28]1[N:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:29]=1[C:30](O)=[O:31]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:30]([C:29]4[C:28]([O:27][CH3:26])=[N:36][C:35]([O:37][CH3:38])=[CH:34][CH:33]=4)=[O:31])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C(=O)O)c(OC)n1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C(=O)N2CCC(N3N=C(c4ccc(OC)c(OC)c4)C(C)(C)C3=O)CC2)c(OC)n1

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 2,6-dimethoxynicotinic acid as starting compounds. The crude product is purified by chromatography (silica gel and DCM/diethyl ether/methanol=7:3:2) to yield the title compound.
Reaction SMILES: [BH4-].[Na+].[CH3:3][CH:4]1[CH:9]([CH3:10])[C:8](=[O:11])[C:7]([CH3:12])=[C:6]([C:13](=[O:16])[CH2:14][CH3:15])[O:5]1>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[CH3:3][CH:4]1[CH:9]([CH3:10])[C:8](=[O:11])[C:7]([CH3:12])=[C:6]([CH:13]([OH:16])[CH2:14][CH3:15])[O:5]1
Reactant: CCC(=O)C1=C(C)C(=O)C(C)C(C)O1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(O)C1=C(C)C(=O)C(C)C(C)O1
Temperature: 40 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
After dissolving 6.8 g (0.05 moles) of zinc chloride in 120 ml of dehydrated tetrahydrofuran, 3.8 g (0.1 moles) of sodium borohydride were added to the solution. The mixture was agitated at 40° C. for 1 hour. After the mixture was cooled with ice, 9.8 g (0.05 moles) of 2,3-dihydro-2,3,5-trimethyl-6-(2-methyl-1-oxoethyl)-4H-pyran-4-one were dripped. After agitating the mixture for 3 hours, 8.7 g of 2,3-dihydro-2,3,5-trimethyl-6-(2-methyl-1-hydroxyethyl)-4H-pyran-4-one were obtained. The yield was 88%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](Cl)=[C:9]([NH:12][C:13](=[O:15])[CH3:14])[CH:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH3:24])[C:17]=2[F:25])[N:6]=1)=[O:4].[CH3:26][Sn](C)(C)C>C(#N)C.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>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH3:26])=[C:9]([NH:12][C:13](=[O:15])[CH3:14])[CH:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH3:24])[C:17]=2[F:25])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(NC(C)=O)c1Cl
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(NC(C)=O)c1C
Temperature: 110 °C
Yield: 88.6 %

Procedure:
4-Acetylamino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-pyridine-2-carboxylic acid methyl ester (500 mg, 1.29 mmol), tetramethyltin (924 mg, 5.17 mmol), bis(triphenylphosphine)palladium(II) dichloride (91 mg, 0.129 mmol), and tetrabutylammonium triphenyldifluorosilicate (1.395 g, 2.58 mmol) were combined in 2 mL of acetonitrile and heated in a CEM microwave reactor at 110° C. for 15 min. The resulting reaction mixture was filtered and concentrated. This intermediate product was purified by flash chromatography on silica gel (ethyl acetate/hexane gradient) to yield the title compound (419 mg, 88% yield). mp 182-184° C.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]([C:7]1[N:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[S:10][CH:11]=1)[CH2:5][NH2:6].Cl[CH2:17][C:18](OCC)=[O:19].Cl>C1(C)C=CC=CC=1.O.C(O)C>[F:13][C:12]([F:15])([F:14])[C:9]1[S:10][CH:11]=[C:7]([CH:4]2[O:3][CH2:17][C:18](=[O:19])[NH:6][CH2:5]2)[N:8]=1
Reactant: NCC(O)c1csc(C(F)(F)F)n1
Reactant: CCOC(=O)CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1COC(c2csc(C(F)(F)F)n2)CN1

Procedure:
0.3 g (0.0064 mol) of a dispersion of sodium hydride (50-55% in oil) is added in small portions to a stirred solution of 1 g (0.0047 mol) of 2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine in 15 ml of toluene at 30° C. After 1 hour a solution of 0.55 g (0.0045 mol) of ethyl chloroacetate in 2 ml of toluene is added dropwise. After 2 hours first 1 ml of ethanol and then 4 ml of water are added dropwise. The mixture is then acidified with hydrochloric acid and extracted several times with methylene chloride, and the extract is dried over sodium sulphate. The resulting product is purified on a silica gel column using ethyl acetate/methanol =1/1 as eluant and, after evaporation to dryness, digested with a little ether.