Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[CH:17][N:18]([CH3:20])[CH3:19])[C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1.N1C[CH2:26][O:25][CH2:24]C1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[CH:17][N:18]3[CH2:19][CH2:26][O:25][CH2:24][CH2:20]3)[C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=C1C(=O)N(c2cccc(Cl)c2)c2ccccc21
Reactant: C1COCCN1
Solvent: CCO
Product: O=C1C(=CN2CCOCC2)c2ccccc2N1c1cccc(Cl)c1
Reaction time: 18 h

Procedure:
Title product of Example A3 (0.3 g, 1.0 mmole), morpholine (0.45 ml, 5 mmole) and ethanol (10 ml) were combined and stirred 18 hours at 25°. Additional morpholine (2 ml) was added and the mixture refluxed 4 hours. The reaction mixture was evaporated in vacuo to an oil, chromatographed on silica gel (4.5 cm×18 cm) eluting with ethyl acetate, initially isolating purified title product as an oil which crystallized on standing under ether/pentane, 0.27 g; m.p. 130°-132.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])[NH2:7].C([O-])([O-])=O.[Na+].[Na+].[C:20]1([CH:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O.C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])[NH:7][C:27](=[O:28])[CH:26]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: Cc1cccc(C[C@H](N)C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(C[C@H](NC(=O)C(c2ccccc2)c2ccccc2)C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-methyl-L-phenylalanine (1.8 g, 10.06 mmol) and Na2CO3 (3.2 g, 3.0.18 mmol) in water (150 mL) is added a solution of diphenylacetyl chloride (2.32 g, 10.06 mmol) in THF (150 mL), and the resulting solution is stirred vigorously at room temperature overnight. The THF is then evaporated and the aqueous layer is diluted with 6% aqueous Na2CO3 (100 mL), and washed with Et2O (3×150 mL). The aqueous layer is then acidified to pH 1 with conc. HCl, and the resulting slurry is extracted with EtOAc (3×100 mL). The organic phase is then washed with water (2×100 mL) and brine (1×100 mL), dried over MgSO4 and evaporated to yield 3-methyl-N-(2,2-diphenylacetyl)-L-phenylalanine, as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([O:15]CC)=[O:14])=[N:9]2)=[CH:4][CH:3]=1.[Li+].[OH-].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([OH:15])=[O:14])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccn(-c2ccc(Cl)cc2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccn(-c2ccc(Cl)cc2)n1
Yield: 95.7 %

Procedure:
To a solution of ethyl 1-(4-chlorophenyl)pyrazole-3-carboxylate (250 mg, 1 mmol) in THF was added 3.0 mL of 1.0 M of LiOH (3.0 mmol). The resulting mixture was stirred at room temperature for 3 h at which time 1.0 M HCl was added to adjust the pH to 1.0. The organics were extracted with EtOAc (2×100 mL), dried over MgSO4, and concentrated under reduced pressure to give a white solid (213 mg, 96%), which was used for next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([I:9])=[CH:4][CH:3]=1.C1C(=O)N([Br:17])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>ClCCCl>[Br:17][CH2:8][C:6]1[C:5]([I:9])=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=1
Reactant: Cc1nc(Cl)ccc1I
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Product: Clc1ccc(I)c(CBr)n1
Temperature: 80 °C

Procedure:
To a stirred solution of 6-chloro-3-iodo-2-methyl-pyridine (20 g, 79 mmol, 1 eq) in 1,2-dichloroethane (200 mL) was added NBS (21.1 g, 118.6 mmol, 1.5 eq) followed by addition of AIBN (5.2 g, 31.6 mmol, 0.4 eq) at room temperature in dark. Resulting reaction mixture was heated at 80° C. for 16 hours. After maximum consumption of starting material, reaction mixture was cooled to room temperature and quenched with water (50 mL), extracted with DCM (3×50 mL). Combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to get dark brown semi solid (20 g, crude). Crude of title compound was used as such for next reaction. 1H NMR not clean. LC-MS: No ionization.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:15]([OH:16])=[C:14]([OH:17])[N:13]=[C:12]([C:18]3([CH3:32])[N:23]([CH3:24])[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]3)[N:11]=2)=[O:9])=[CH:4][CH:3]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:24][N:23]1[CH2:22][CH2:21][NH:20][CH2:19][C:18]1([C:12]1[N:11]=[C:10]([C:8]([NH:7][CH2:6][C:5]2[CH:33]=[CH:34][C:2]([F:1])=[CH:3][CH:4]=2)=[O:9])[C:15]([OH:16])=[C:14]([OH:17])[N:13]=1)[CH3:32]
Reactant: CN1CCN(C(=O)OC(C)(C)C)CC1(C)c1nc(O)c(O)c(C(=O)NCc2ccc(F)cc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCNCC1(C)c1nc(O)c(O)c(C(=O)NCc2ccc(F)cc2)n1

Procedure:
Crude material tert-butyl 3-(4-{[(4-fluorobenzyl)amino]carbonyl}-5,6-dihydroxypyrimdin-2-yl)-3,4-dimethylpiperazine-1-carboxylate (C-46) was stirred in DCM/TFA (1:1) for 1 hour. Evaporation of the solvent afforded the crude title compound (C47).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([N+:10]([O-])=O)[CH:7]=[CH:8][CH:9]=1.O>[Zn].CCOCC>[Br:3][C:4]1[CH:5]=[C:6]([NH:10][NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([Br:3])[CH:5]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(Br)c1
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: O
Solvent: CCOCC
Product: Brc1cccc(NNc2cccc(Br)c2)c1
Temperature: 60 °C
Yield: 79.5 %

Procedure:
To a stirred solution of 50% NaOH (3.6 mL, 45 mM) was added 3-bromonitrobenzene (15 g, 74 mM) and the resulting solution was heated to 60° C. Zinc dust (11 g, 170 mM) was added in portions in such a manner as to keep the reaction temperature below 80° C. After the addition was complete, 20% NaOH (22 mL, 113 mM) was added followed by water (37 mL). An additional portion of zinc dust (14 g, 220 mM) was then added in one portion. The resulting mixture was heated at 70° C. for 1 hour, cooled to room temperature, and poured into ether (200 mL). The liquid was decanted away from the solids and the solids were resuspended in ether and this procedure was repeated an additional three times. The organic layers were combined, dried over Na2SO4, and concentrated. Purification by flash column chromatography afforded the titled compound as a white solid (10.1 g, 79%). NMR (CDCl3): 6.99 (m, 6H), 6.76 (dd, J1 =1 Hz, J2 =8 Hz), 5.66 (br s, 2H). MS(CI): 341/343(M+1).
Reaction SMILES: CO.[C:3]([NH:11][C:12]1[CH:20]=[C:19]([CH:21]2[CH2:25][CH2:24][CH:23]=[CH:22]2)[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>[C].[Pd].C(OCC)(=O)C>[C:3]([NH:11][C:12]1[CH:20]=[C:19]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Nc1cc(C2C=CCC2)ccc1C(=O)O)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(Nc1cc(C2CCCC2)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
5.0 mg of 5% palladium-carbon was added to a mixed solution of 1.0 mL of methanol and 0.5 mL of ethyl acetate containing 25 mg of 2-(benzamido)-4-(2-cyclopenten-1-yl)benzoic acid and stirred at room temperature under hydrogen atmosphere for 7 hours and then at 40° C. for 8 hours and stirred at 45° C. for 15 hours. Insoluble were removed by filtration and the solvent was evaporated under reduced pressure. Methanol was added to the obtained residue and a solid substance was separated by filtration to obtain 16 mg of 2-(benzamido)-4-cyclopentyl benzoic acid as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([OH:13])=O)[C:7]([CH3:10])([CH3:9])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[CH3:35][N:36]1[CH2:41][CH2:40][N:39]([C:42]2[CH:47]=[CH:46][C:45]([CH2:48][N:49]([NH2:73])[CH2:50][C@H:51]([OH:72])[C@@H:52]([NH:60][C:61](=[O:71])[C@H:62]([CH:68]([CH3:70])[CH3:69])[NH:63][C:64]([O:66][CH3:67])=[O:65])[CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[CH:44][CH:43]=2)[CH2:38][CH2:37]1>CN(C=O)C.C(OCC)(=O)C.C(O)C>[CH3:35][N:36]1[CH2:41][CH2:40][N:39]([C:42]2[CH:43]=[CH:44][C:45]([CH2:48][N:49]([NH:73][C:11](=[O:13])[C@H:6]([C:7]([CH3:8])([CH3:9])[CH3:10])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:50][C@H:51]([OH:72])[C@@H:52]([NH:60][C:61](=[O:71])[C@H:62]([CH:68]([CH3:70])[CH3:69])[NH:63][C:64]([O:66][CH3:67])=[O:65])[CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[CH:46][CH:47]=2)[CH2:38][CH2:37]1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(N2CCN(C)CC2)cc1)C(C)C
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCO
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(N2CCN(C)CC2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(C)C
Reaction time: 0.33 h

Procedure:
129 mg (0.68 mmol) of N-methoxycarbonyl-(L)-tert-leucine, 244 mg (1.28 mmol) of EDC and 115 mg (0.85 mmol) of HOBT are initially introduced, under a N2 atmosphere, in 5.4 ml of DMF. After 20 min at RT, 0.355 ml (2.55 mmol) of triethylamine is added. 232 mg (0.425 mmol) of 1-[p-(4-methylpiperazin-1-yl)phenyl]-4(S)-hydroxy-2-amino-5(S)-[N-(N-methoxycarbonyl-(L)-valyl)amino]-6-phenyl-2-azahexane (Example 16g) are then added and the mixture is thoroughly stirred overnight; working-up then takes place in analogy with Example 16. Column chromatography (SiO2; ethyl acetate/ethanol 1:1) results in the title compound:
Reaction SMILES: [CH:1]1([C:6]2[CH2:10][CH2:9][C:8](=[O:11])[C:7]=2I)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:13]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)=[O:14].C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([C:6]2[CH2:10][CH2:9][C:8](=[O:11])[C:7]=2[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:13]=[O:14])[CH:20]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: O=C1CCC(C2CCCC2)=C1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=Cc1cccc(C2=C(C3CCCC3)CCC2=O)c1
Yield: 63.3 %

Procedure:
A mixture of 120 mg 3-cyclopentyl-2-iodo-2-cyclopenten-1-one, 80 mg 3-formylphenylboronic acid and 20 mg tetrakis(triphenylphosphine)palladium was stirred at 80° C. overnight in 8 ml toluene, 4 ml ethanol and 4 ml 2 N aqueous sodium carbonate. Then the reaction mixture was diluted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, hexane/ethyl acetate=2:1) to yield 70 mg of 3-cyclopentyl-2-(3-formylphenyl)-2-cyclopenten-1-one. 3-cyclopentyl-2-(3-formylphenyl)-2-cyclopenten-1-one in benzene was stirred with one drop of acetic acid and 100 mg sodium triacetoxyborohydride at 70-80° C. for 2 hours. Then the reaction mixture was poured into saturated aqueous ammonium chloride, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, hexane/ethyl acetate=2:1) to yield 40 mg of 3-cyclopentyl-2-(3-hydroxymethylphenyl)-2-cyclopenten-1-one, which was then condensed with hydroxylamine hydrochloride according to a procedure similar to that described in STEP 4 for Example 1 to afford 20 mg of 3-cyclopentyl-2-(3-hydroxymethylphenyl)-2-cyclopenten-1-one oxime as a solid. 1H NMR (CDCl3, 300 MHz): δ 8.75 (bs, 1H), 7.40-7.29 (m, 3H), 7.12 (d, J=7.2 Hz, 1H), 4.66 (s, 2H), 2.98 (m, 1H), 2.75 (m, 2H), 2.61 (m, 2H), 1.71 (m, 4H), 1.55 (m, 4H).
Reaction SMILES: [CH2:1]([S:8][C:9]([CH3:15])([CH3:14])[CH2:10][N+:11]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH2:1]([S:8][C:9]([CH3:15])([CH3:14])[CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C[N+](=O)[O-])SCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(CN)SCc1ccccc1
Yield: 45.5 %

Procedure:
A solution of 2-benzylthio-1-nitro-2-methylpropane (19 g) in dry ether (75 cm3) was added dropwise over a period of about 1 h to a stirred suspension of lithium aluminium hydride (9.6 g) in dry ether (500 cm3), cooled in an ice bath. When the addition was complete the mixture was heated under reflux for an additional hour. Excess lithium aluminium hydride was destroyed by the careful addition of water, and then an aqueous solution of sodium potassium tartrate (500 cm3, 20% w/w) was added. The mixture was stirred until the solids had dissolved and the ether layer was then separated. The aqueous solution was then extracted with ether (3×50 cm3) and the combined extracts then dried (MgSO4). Removal of the ether under reduced pressure gave the crude product which was purified via recrystallisation of its hydrochloride salt from isopropanol. The purified amine (7.5 g, 46%) was obtained as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.C([Li])CCC.[Br:17]C(Cl)(Cl)C(Br)(Cl)Cl.O>O1CCCC1>[Br:17][C:10]1[N:5]2[N:4]=[C:3]([O:2][CH3:1])[CH:11]=[C:6]2[CH:7]=[CH:8][CH:9]=1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Reactant: COc1cc2ccccn2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2cccc(Br)n2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
A solution of 2-methoxypyrazolo[1,5-a]pyridine (Reference; Bull. Chem. Soc. Japan, vol. 49(7), 1980–1984(1976)) (7.15 g) in tetrahydrofuran (140 mL) was cooled to −78° C. under a nitrogen stream, and after adding n-butyllithium (1.6M hexane solution: 46 mL) dropwise thereto, the reaction mixture was stirred for 30 minutes. A solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (18.9 g) in tetrahydrofuran (30 mL) was added dropwise to the reaction mixture at −78° C., and stirring was continued for 1 hour. The reaction mixture was raised to room temperature, water was added, and then extraction was performed with ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate and filtered, the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography and the title compound (7.1 g) was obtained as a yellow oil from the n-hexane:ethyl acetate (50:1) fraction.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[CH2:12]([NH:14][CH2:15][C:16]([CH2:22][NH:23][C:24]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]2[C:25]=1[CH:26]=[N:27][N:28]2[C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)([OH:21])[C:17]([F:20])([F:19])[F:18])[CH3:13]>>[CH2:12]([N:14]([CH2:15][C:16]([CH2:22][NH:23][C:24]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]2[C:25]=1[CH:26]=[N:27][N:28]2[C:34]1[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=1)([OH:21])[C:17]([F:19])([F:20])[F:18])[C:4](=[O:5])[C:3]1[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=1[F:11])[CH3:13]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: CCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Product: CCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1c(F)cccc1F

Procedure:
Prepared similarly to Example 48 from 2,6-difluorobenzoyl chloride and 3-(ethylamino)-1,1,1-trifluoro-2-({[1-(4-fluorophenyl)-6-methyl-1H-indazol-4-yl]amino}methyl)-2-propanol.
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.[NH:39]1[CH:43]=[C:42](B(O)O)[CH:41]=[N:40]1.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>[NH:39]1[CH:43]=[C:42]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:41]=[N:40]1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: OB(O)c1cn[nH]c1
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(-c3cn[nH]c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 39.5 %

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 (57 mg, 0.10 mmol) was treated with (1H-pyrazol-4-yl)boronic acid (64 mg, 0.58 mmol), sodium carbonate (65 mg, 0.61 mmols) and bis(triphenylphosphine)palladium(II) dichloride (33 mg, 0.03 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 100%, hexane-ethyl acetate) to give 23 mg (41% yield) of the title compound. Purity 99%.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[N+]([O-])([O-])=O.[Ag+:14]>C(OCCCC)(=O)C.O>[Ag:14].[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: c1ccc2[nH]nnc2c1
Solvent: O
Solvent: CCCCOC(C)=O
Product: [Ag]

Procedure:
Benzotriazole (17.9 g) was dissolved in n-butyl acetate (300 ml), followed by the addition of water (300 ml). Silver nitrate (25.5 g) was dissolved in water (150 ml). The resulting solution was added to the previously prepared butyl acetate solution of benzotriazole under vigorous agitation. After 30-minute agitation, the aqueous phase was removed from the mixture, and the n-butyl acetate phase was washed with water. It was then washed with methanol and finally centrifuged to give benzotriazole silver (33.2 g). A portion (22.6 g) of the benzotriazole was added to a mixture of a 6% aqueous polyvinyl alcohol solution (600 ml) and a 6% aqueous gelatin solution (200 ml), and the reactants were mixed under agitatioh for 48 hrs. in a ball mill until a silver salt dispersion formed. An 8% aqueous polyvinyl alcohol solution was prepared in an amount of 150 ml, and in this solution, a 1% methanol solution of 3-amino-4-allyl-5-mercapto-1,2,4-triazole (14 ml), phthalazine (0.80 g), phthalic acid (1.0 g) and t-butylhydroquinone (2.1 g or 0.0125 mol) were dissolved. To the resultion solution, an 8% aqueous gelatin solution (50 ml) and 200 ml of the separately prepared silver salt dispersion were added. To the mixture, 25 ml of a silver iodobromide emulsion (particle size: 0.06 μm, silver iodide content: 4 mol %, gelatin content: 60 g per kg of the emulsion) was added, and the resulting coating solution was applied to photographic baryta paper to give a wet thickness of 55 μm, and the web was dried. Subsequently, a 3% acetone solution of diacetyl cellulose was applied to the emulsion layer to give a wet thickness of 55 μm, and the applied layer was dried to form a protective film.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][S:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:20](=O)[CH3:21].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:20][CH3:21])[CH:14]2[CH2:19][CH2:18][S:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CC=O
Reactant: COC(=O)c1cc(Br)cc(NC2CCSCC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCN(c1cc(Br)cc(C(=O)OC)c1C)C1CCSCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.1 %

Procedure:
To a stirred solution of methyl 5-bromo-2-methyl-3-((tetrahydro-2H-thiopyran-4-yl)amino)benzoate (2.5 g, 5.83 mmol) and acetaldehyde (513 mg, 11.66 mmol) in dichloroethane (50 mL), acetic acid (2.0 ml, 34.9 mmol) was added and reaction was stirred at room temperature for 20 minutes. The reaction mixture was cooled to 0° C. and sodium triacetoxyborohydride (3.7 g, 17.49 mmol) was added and stirred at room temperature for overnight. The mixture was neutralized with sat. NaHCO3 and compound was extracted in DCM, dried over Na2SO4, concentrated under reduced pressure. The crude material was purified by column chromatography to afford methyl 5-bromo-3-(ethyl(tetrahydro-2H-thiopyran-4-yl)amino)-2-methylbenzoate (2.0 g, 74.0%).
Reaction SMILES: [CH3:1][CH:2]([O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]([C:13]1[C:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:15][CH:16]=[C:17]([O:19]C(=O)C)[CH:18]=1)=[O:12])[CH2:3][CH2:4][CH3:5].[NH4+].[OH-]>CO>[CH3:1][CH:2]([O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]([C:13]1[C:14]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:15][CH:16]=[C:17]([OH:19])[CH:18]=1)=[O:12])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(C)OCCCOC(=O)c1cc(OC(C)=O)ccc1-c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C)OCCCOC(=O)c1cc(O)ccc1-c1ccccc1

Procedure:
After the p-acetyloxybiphenylcarboxylic acid (2-pentyloxy)propyl ester was diluted with 50 ml of methanol, a mixture of methanol: NH4OH (28%)=1:1 was added under stirring to carry out hydrolysis. Then, the reaction mixture was extracted with anhydrous sodium sulfate (×3), the ether layer was washed with 50 ml of water (×3) and dried over anhydrous sodium sulfate, followed by evaporation of the solvent to obtain an oily product. The product was purified by silica gel chromatography to obtain 2.6 g of p-hydroxybiphenylcarboxylic acid (2-pentyloxy)propyl ester.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](Cl)(=[O:24])[CH:21]([CH3:23])[CH3:22].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[C:20]([C:5]1[CH:4]=[CH:3][C:2]([CH2:1][CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:19])[C:15]([F:18])([F:16])[F:17])[CH2:10][CH2:9]2)=[CH:7][CH:6]=1)(=[O:24])[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)C(=O)Cl
Reactant: O=C(N1CCC(Cc2ccccc2)CC1)C(F)(F)F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)C(=O)c1ccc(CC2CCN(C(=O)C(F)(F)F)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.6 %

Procedure:
To a stirred solution of 4-benzyl-1-(trifluoroacetyl)piperidine (4.34 g, 16.0 mmol) and isobutyryl chloride (2.18 mL, 20.8 mmol) in dichloromethane (50 mL) was added aluminum chloride (5.33 g, 40.0 mmol) at 0° C., and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice water (50 g), the organic layer was separated and the aqueous layer was extracted with dichloromethane (30 mL) The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (3×15 mL), brine (15 mL), dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using ethyl acetate/hexane (1/19 to 1/9) as eluent to afford the title compound (3.60 g, 10.5 mmol, 66%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4](O)=O.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[C:13]=1[NH2:19].[OH-].[Na+]>O>[Br:11][C:8]1[CH:7]=[C:3]([C:4]2[NH:18][C:14]3[C:13]([N:19]=2)=[N:12][CH:17]=[CH:16][CH:15]=3)[C:2]([NH2:1])=[N:10][CH:9]=1
Reactant: Nc1ncc(Br)cc1C(=O)O
Reactant: Nc1cccnc1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ncc(Br)cc1-c1nc2ncccc2[nH]1
Temperature: 160 °C
Reaction time: 96 h

Procedure:
50 mg (0.230 mmol) I) of 2-amino-5-bromonicotinic acid and 27.6 mg (0.253 mmol) of pyridine-2,3-diamine are added to 451.5 mg (5 mmol) of polyphosphoric acid, and the mixture is stirred at 160° C. for 4 days. The reaction mixture is cooled to room temperature, water is added, and the mixture is adjusted to pH 12 by means of 1N NaOH. The precipitate formed is filtered off with suction and dried, giving 5-bromo-3-(1H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-ylamine.