Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5](Br)[N:4]([CH2:11][CH3:12])[N:3]=1.O.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([NH:21][C:5]1[N:4]([CH2:11][CH3:12])[N:3]=[C:2]([Br:1])[C:6]=1[N+:7]([O-:9])=[O:8])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCn1nc(Br)c([N+](=O)[O-])c1Br
Reactant: NCc1ccccc1
Solvent: O
Product: CCn1nc(Br)c([N+](=O)[O-])c1NCc1ccccc1
Yield: 76 %

Procedure:
6.3 g (21 mmoles) of 3,5-dibromo-1-ethyl-4-nitropyrazole are heated in 10 ml benzylamine for 1 hour at 80° C. The reaction mixture is then poured on 50 ml water and the separated oil is collected. The product is crystallized from the oil by adding 20 to 30 ml acetic acid ethyl ester. After recrystallizing from methanol once, 5.2 g (76 percent of theory) of 5-benzylamino-3-bromo-1-ethyl-4-nitropyrazole are obtained n the form of bright yellow needles with a melting point of 92° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([O:13]C)[C:8]([O:11]C)=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3].C(O)(=O)C.Br>O>[CH2:1]([C:5]1[CH:6]=[C:7]([OH:13])[C:8](=[CH:9][CH:10]=1)[OH:11])[CH:2]([CH3:4])[CH3:3]
Reactant: COc1ccc(CC(C)C)cc1OC
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CC(C)Cc1ccc(O)c(O)c1
Temperature: 25 °C
Yield: 82 %

Procedure:
A mixture of 50.83 g (262 mM) of 4-iso-butylveratrole, 167.82 g (2.795 mM) of acetic acid and 502.18 g (2.917 mM) of 47% hydrobromic acid was heated under reflux for 19 hours with stirring. The reaction mixture was cooled to the room temperature added with 400 ml of water. The separated oil was extracted with ether. The ether solution was successively washed with 400 ml of water, 660 g of 5% aqueous sodium thiosulfate solution, and further twice with each 400 ml of water. The resulting solution was dried with anhydrous sodium sulfate, distilled off ether, and vacuum distilled to obtain 35.68 g (215 mM) of 4-iso-butylcatechol as yellow viscous liquid having a boiling point of 117°-120° C./ 2 mmHg.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:9]=1[C:10](OC)=[O:11].O>C(OCC)C>[NH2:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:9]=1[CH2:10][OH:11]
Reactant: COC(=O)c1c(N)cccc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: Nc1cccc(F)c1CO
Temperature: 0 °C
Reaction time: 2 h

Procedure:
676.3 mg (17.8 mmol) lithium aluminium hydride are placed in 65 ml diethyl ether under an N2 atmosphere and cooled to 0° C. 2.01 g (11.9 mmol) methyl 2-amino-6-fluoro-benzoate, dissolved in 65 ml diethyl ether, are slowly added dropwise thereto and the mixture is stirred for 2 h at 0° C. Then the reaction mixture is combined dropwise at 0° C. with 100 ml dist. H2O. The aqueous phase is extracted twice with 100 ml diethyl ether. The combined organic phases are washed once with 100 ml of a saturated, aqueous NaCl solution, dried with MgSO4 and the solvent is eliminated in vacuo.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH2:21][C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C:18]([OH:20])=[O:19]>CN(C=O)C>[CH2:25]([NH:24][C:22]([CH2:21][CH:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[C:18]([OH:20])=[O:19])=[O:23])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: NC(CC(=O)NCc1ccccc1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Solvent: CN(C)C=O
Product: O=C(CC(Nc1nc2ccc(Cl)cc2cc1C(=O)O)C(=O)O)NCc1ccccc1

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-N-benzyl-succinamic acid [J. Pharm. Sci. 1980, 69 (5), 553-555.] in DMF to provide the title compound in good yield.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=1[F:22].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[F:22][C:16]1[CH:17]=[C:18]([OH:21])[CH:19]=[CH:20][C:15]=1[C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=1
Reactant: Oc1ccc(Br)c(F)c1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
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: COCCOC
Product: CS(=O)(=O)c1ccc(-c2ccc(O)cc2F)cc1
Yield: 71.4 %

Procedure:
2-Fluoro-4′-(methylsulfonyl)-4-biphenylol (0.58 g, 71%) was prepared as a white solid from [4-(methylsulfonyl)phenyl]boronic acid (0.69 g, 3.38 mmol), 4-bromo-3-fluorophenol (0.6 g, 3.05 mmol), 2M Na2CO3 (18 mL) and Pd(PPh3)4 (30 mg, 0.03 mmol) in DME (18 mL) in a manner similar to Example 1, Step 1. 1H NMR (400 MHz, CDCl3): δ 7.98 (d, 2H, J=8.3 Hz), 7.69 (d, 2H, J=7.4 Hz), 7.40-7.30 (m, 1H), 6.80-6.65 (m, 2H), 5.10 (s, 1H), 3.09 (s, 3H); LRMS (ESI), m/z 267 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[CH:4][N:3]=1.C([N-]C(C)C)(C)C.[Li+].[Cl:20][C:21]1[N:26]=[C:25]([O:27][CH3:28])[C:24]([CH:29]=[O:30])=[CH:23][N:22]=1>C1COCC1>[F:10][C:8]([F:9])([F:11])[C:6]1[C:7]([CH:29]([C:24]2[C:25]([O:27][CH3:28])=[N:26][C:21]([Cl:20])=[N:22][CH:23]=2)[OH:30])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: COc1nc(Cl)ncc1C=O
Reactant: FC(F)(F)c1cc(Cl)ncn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1nc(Cl)ncc1C(O)c1c(Cl)ncnc1C(F)(F)F
Reaction time: 0.17 h
Yield: 9.6 %

Procedure:
4-Chloro-6-trifluoromethylpyrimidine (1.10 g, 6.02 mmol) in THF (15 ml) was added to a solution of lithium diisopropyl amide (LDA) (prepared from n-BuLi (3.7 ml, 5.9 mmol, 1.6M in hexanes) added to diisopropylamine (820 ul, 591 mg, 5.84 mmol) in THF (30 ml) at -78° C., allowing to warm to room temperature for 30 minutes, and re-cooling to -78° C.) at -78° C. The solution turned brown and was stirred for 10 minutes. Then 2-chloro-4-methoxypyrimidine-5-carboxaldehyde (0.96 g, 5.56 mmol) in THF (25 ml) was added dropwise and allowed to stir at -78° C. for 1 hour. The solution was quenched at -78° C. with 30% aqueous HOAc, diluted with water and extracted with EtOAc (3 times). The combined extracts were washed with brine (sat.), dried (MgSO4), filtered and concentrated in vacuo to give 1.61 g of crude product. Preparative radial chromatography (SiO2 ; hexane/EtOAc gradient elution) gave 190 mg (21% based on 530 mg of recovered starting material) of 1-(4-trifluoromethyl-6-chloropyrimidin-5-yl)-1-(2-chloro-4-methoxypyrimidin-5-yl)methanol.
Reaction SMILES: [C:1]1([C@H:7]2[C@H:16]3[CH2:17][CH2:18][N:19](C(OC(C)(C)C)=O)[C@H:15]3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:27]>C(OCC)(=O)C>[ClH:27].[ClH:27].[C:1]1([C@H:7]2[C@H:16]3[CH2:17][CH2:18][NH:19][C@H:15]3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21
Agent: Cl
Solvent: CCOC(C)=O
Product: c1ccc([C@@H]2Nc3ccccc3[C@@H]3NCC[C@H]23)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 77 %

Procedure:
tert-Butyl (3aR*,4R*,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-carboxylate (2.65 g, 7.56 mmol) was dissolved in ethyl acetate (10 ml), and a 4N hydrogen chloride in ethyl acetate solution (20 ml) was added, and the mixture was stirred at room temperature for 12 hrs. The precipitated crystals were collected by filtration, washed with ethyl acetate, and dried under reduced pressure to give the title compound (2.60 g, 77%).
Reaction SMILES: [H-].[Na+].[C:3]([O:6][C:7]1[C:16]2[O:15][CH2:14][C:13](=[O:17])[NH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)(=[O:5])[CH3:4].[C:18]1([CH:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:25][CH2:26][CH2:27]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.C1COCC1>[C:3]([O:6][C:7]1[C:16]2[O:15][CH2:14][C:13](=[O:17])[N:12]([CH2:27][CH2:26][O:25][CH:24]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1)(=[O:5])[CH3:4]
Reactant: BrCCOC(c1ccccc1)c1ccccc1
Reactant: CC(=O)Oc1cccc2c1OCC(=O)N2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)Oc1cccc2c1OCC(=O)N2CCOC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
Anhydrous THF (15 ml) was added to sodium hydride (106 mg) to form a suspension, and a solution of 8-acetoxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (498 mg) in anhydrous DMF (5 ml) was added to the resulting suspension, and the mixture was stirred at room temperature for 1 hour. 2-diphenylmethoxyethyl bromide (980 mg) was added to the mixture, and the mixture was stirred at room temperature overnight. The reaction solution was poured into a 3% citric acid aqueous solution, and then extracted with ethyl acetate. The resultant organic layer was washed with water and saturated brine, dried over sodium sulfate, and then concentrated. The residue was purified by medium-pressure column chromatography (solvent:ethyl acetate/cyclohexane=1/3) to obtain the colorless oily object compound (640 mg, yield 66%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[H-].[Na+].FS([C:18](C(O)=O)([F:20])[F:19])(=O)=O.O>CC#N>[F:19][CH:18]([F:20])[O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc(O)nc1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1ccc(OC(F)F)nc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of commercially available methyl 6-hydroxynicotinate (3.000 g; 19.59 mmol) in anh. MeCN (320 ml) was treated portionwise with NaH (60% dispersion in mineral oil; 2.115 g; 52.89 mmol), and stirring at rt, under nitrogen, was continued for 20 min. FSO2CF2CO2H (5.931 g; 33.30 mmol) was then added dropwise, and the resulting heterogeneous mixture was further stirred at rt, under nitrogen, for 30 min. Water (10 ml) was slowly added, and acetonitrile was removed under reduced pressure. Water (150 ml) and AcOEt (150 ml) were added, and the separated aq. layer was further extracted with AcOEt (2×100 ml). The mixed organic layers were washed with brine (100 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM) afforded methyl 6-(difluoromethoxy)nicotinate as a beige solid. LC-MS (conditions D): tR=0.93 min.; no ionisation.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[CH3:19][S:20]([CH:23]=[CH2:24])(=[O:22])=[O:21]>O1CCOCC1>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][N:16]([CH2:24][CH2:23][S:20]([CH3:19])(=[O:22])=[O:21])[CH2:15][CH2:14]1
Reactant: COc1cc(N2CCNCC2)c(C)cc1[N+](=O)[O-]
Reactant: C=CS(C)(=O)=O
Solvent: C1COCCO1
Product: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 60 %

Procedure:
To 1-[2-methyl-5-(methyloxy)-4-nitrophenyl]piperazine (0.300 g, 1.2 mmol) in 10 mL of dioxane was added, ethenyl methyl sulfone (0.32 g, 3 mmol). The mixture was heated to 120° C. 1 hour. The solvent was rotovaped down and the crude product was purified by flash chromatography, followed by a wash of the solids with 30% ether in hexanes to give 1-[2-methyl-5-(methyloxy)-4-nitrophenyl]-4-[2-(methylsulfonyl)ethyl]piperazine (0.257 g, 0.72 mmol, 60%). 1H NMR (400 MHz, CDCl3) δ ppm 7.80 (s, 1 H), 6.54 (s, 1 H), 3.93 (s, 3 H), 3.18-3.30 (m, 2 H), 2.99-3.10 (m, 9 H), 2.71-2.82 (m, 4 H), 2.23 (s, 3 H).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]([C:12]2[N:13]=[N:14][C:15]([CH2:32][CH2:33][CH2:34][CH3:35])=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:20][CH:19]=3)[CH:17]=2)=[O:11])[CH2:5][CH2:4]1.C=O.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:38][N:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]([C:12]2[N:13]=[N:14][C:15]([CH2:32][CH2:33][CH2:34][CH3:35])=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:20][CH:19]=3)[CH:17]=2)=[O:11])[CH2:5][CH2:4]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCCCc1nnc(C(=O)NC2CCNCC2)cc1-c1ccc(OCc2ccccc2)cc1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CCCCc1nnc(C(=O)NC2CCN(C)CC2)cc1-c1ccc(OCc2ccccc2)cc1

Procedure:
A solution of 5-(4-benzyloxy-phenyl)-6-butyl-pyridazine-3-carboxylic acid piperidin-4-ylamide dihydrochloride salt (0.096 mmol, 50 mg) and paraformaldehyde (0.96 mmol, 87 mg) in DCM was stirred for 20 min, and then sodium triacetoxyborohydride (0.96 mmol, 204 mg) was added, and stirring continued over night. The solvent was evaporated and to the residue was added saturated NaHCO3 solution, and extracted with ethyl acetate. The organic layer was washed with water, brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The resultant product was purified by column chromatography using 5% methanolic solution of ammonia (2.0 M ammonia in methanol) in DCM to provide 5-(4-benzyloxy-phenyl)-6-butyl-pyridazine-3-carboxylic acid (1-methyl-piperidin-4-yl)-amide LCMS: m/z 460.3 [M+2].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12](=O)[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1([C@H]([NH2:23])C)C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C@H:12]([NH2:23])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC(C)=O)cc1OC
Reactant: C[C@@H](N)c1ccccc1
Product: COc1ccc(C[C@@H](C)N)cc1OC
Yield: 71.6 %

Procedure:
Using 10 ml of the above cell-free extract, the mixture was reacted in a 100 ml reaction mixture comprising 0.1 M Tris-hydrochloric acid buffer (pH 8.5) containing 0.5 g 1-(3,4-dimethoxyphenyl)-2-propanone and 0.34 g (R)-1-phenylethylamine at 30° C. for 24 hours. As a result, 0.36 g (R)-(3,4-dimethoxyphenyl)-2-aminopropane was formed.
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].Cl.[S:8]1[CH:12]=[CH:11][C:10]2[CH:13]([NH2:18])[CH2:14][CH2:15][CH2:16][CH2:17][C:9]1=2.C(N(CC)CC)C>O1CCCC1>[CH:1]([NH:4][C:5]([NH:18][CH:13]1[C:10]2[CH:11]=[CH:12][S:8][C:9]=2[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:6])([CH3:3])[CH3:2]
Reactant: NC1CCCCc2sccc21
Reactant: CC(C)N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)NC(=O)NC1CCCCc2sccc21

Procedure:
In dry tetrahydrofuran, stoichiometric quantities of isopropyl isocyanate, 5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophen-4-amine hydrochloride, and triethylamine are stirred at room temperature for 2 hours and then heated at reflux for half an hour. The title product is then collected and washed with water.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:5][C:4](=[O:16])[CH:3]=1.[S-:17][C:18]#[N:19].[K+].N1C=CC=CC=1.BrBr>CN(C)C=O>[NH2:1][C:2]1[NH:7][C:6]([S:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:5][C:4](=[O:16])[C:3]=1[S:17][C:18]#[N:19]
Reactant: N#C[S-]
Reactant: Nc1cc(=O)nc(SCc2ccccc2)[nH]1
Agent: BrBr
Agent: [K+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: N#CSc1c(N)[nH]c(SCc2ccccc2)nc1=O
Temperature: 5 °C
Reaction time: 2 h

Procedure:
6-Amino-2-[(phenylmethyl)thio]-4(1H)-pyrimidinone (10.5 g) [preparation as described in WO 9635678] and potassium thiocyanate (25 g) in N,N-dimethylformamide (200 ml) were heated together at 65° C. Pyridine (6.3 ml) was added and the solution cooled to 5° C. Bromine (2.2 ml) was added slowly and the reaction mixture stirred for 2 hours at 5-10° C. The reaction mixture was poured onto ice water, stirred for 1 hour and the solid was isolated by filtration. After washing with water and ether, a pure sample was obtained after trituration with hot methanol.
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[C:7]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH:6]=1)#[N:4]>CO>[C:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)[CH:6]=1)#[N:4]
Reactant: COC(=O)c1ccc(C#N)cc1COc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc(C(=O)O)c(COc2ccc(O)cc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.6 %

Procedure:
20 ml of a 3N-sodium hydroxide aqueous solution was added to 9.5 g of methyl 4-cyano-2-(4-hydroxyphenoxy)methylbenzoate obtained in Reference example 22 dissolved in 80 ml of methanol and the mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, the solvent was removed under reduced pressure, water was added to the residue and the mixture was washed with diethyl ether and then adjusted to about pH 2 with conc. sulfuric acid. Crystals precipitated were collected by filtration and dissolved in ethyl acetate and the organic layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was removed from the solution to obtain 5.2 g of the title compound.
Reaction SMILES: [Si]([O:8][C@H:9]([C:48]1[CH:57]=[CH:56][C:55]([OH:58])=[C:54]2[C:49]=1[CH:50]=[CH:51][C:52](=[O:59])[NH:53]2)[CH2:10][NH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([C@@H:32]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:33][CH2:34][N:35]([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])[CH:26]=2)=[CH:16][CH:15]=1)(C(C)(C)C)(C)C.CCN(CC)CC.F.F.F.N>O1CCCC1>[NH3:11].[CH:39]([N:35]([CH:36]([CH3:38])[CH3:37])[CH2:34][CH2:33][C@@H:32]([C:27]1[CH:26]=[C:25]([CH2:24][CH2:23][CH2:22][CH2:21][O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]([C:48]3[CH:57]=[CH:56][C:55]([OH:58])=[C:54]4[C:49]=3[CH:50]=[CH:51][C:52](=[O:59])[NH:53]4)[OH:8])=[CH:15][CH:16]=2)[CH:30]=[CH:29][C:28]=1[OH:31])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:41])[CH3:40]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCOc2ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c4[nH]c(=O)ccc34)cc2)ccc1O)C(C)C
Agent: F
Agent: N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCOc2ccc(CCNC[C@H](O)c3ccc(O)c4[nH]c(=O)ccc34)cc2)ccc1O)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-[(1R)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-({2-[4-(4-{3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-hydroxyphenyl}butoxy)phenyl]ethyl}amino)ethyl]-8-hydroxyquinolin-2(1H)-one (Preparation 32, 305 mg, 0.37 mmol) was dissolved in tetrahydrofuran (5 ml) and triethylaminetrihydrofluoride (0.30 ml, 1.9 mmol) was added, and the mixture stirred overnight at room temperature. Tetrahydrofuran (6 ml) and 880 ammonia (6 ml) were then added, the mixture stirred for 20 minutes, organics were then separated and washed with saturated aqueous sodium hydrogen carbonate (10 ml), then brine (10 ml), then dried (magnesium sulphate) and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (98/2/0.2 to 88/12/1.2 by volume) to furnish the title compound as a yellow solid, 99 mg.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[CH3:15][C:16]([CH3:21])([CH3:20])[CH2:17][CH:18]=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH2:18][CH2:17][C:16]([CH3:21])([CH3:20])[CH3:15])=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Reactant: CC(C)(C)CC=O
Product: Cc1noc(-c2ccc(Br)cc2)c1NCCC(C)(C)C

Procedure:
Prepared according to the procedure described in Example 20, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 3,3-dimethyl-butyraldehyde.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[F:21][C:22]1[CH:23]=[C:24]([C@H:28]([NH2:30])[CH3:29])[CH:25]=[CH:26][CH:27]=1>>[F:21][C:22]1[CH:23]=[C:24]([C@H:28]([NH:30][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH3:29])[CH:25]=[CH:26][CH:27]=1
Reactant: C[C@@H](N)c1cccc(F)c1
Reactant: COc1ccc(C(=O)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl
Product: COc1ccc(C(N[C@H](C)c2cccc(F)c2)c2cccc([N+](=O)[O-])c2)cc1

Procedure:
Following a similar procedure to that described in Example (1a), 11.16 g of 4-methoxyphenyl 3-nitrophenyl ketone and 7.62 g of (R)-1-(3-fluorophenyl)ethylamine hydrochloride were reacted, to obtain 15.11 of the title compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[C:4]([CH:10]=[C:11](I)[CH:12]=1)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[C:38]2[C:33](=[N:34][CH:35]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:37]=2)[N:32]([S:48]([C:51]2[CH:56]=[CH:55][C:54]([CH3:57])=[CH:53][CH:52]=2)(=[O:50])=[O:49])[CH:31]=1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[F:1][C:2]1[C:3]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[C:4]([CH:10]=[C:11]([C:36]2[CH:37]=[C:38]3[C:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[O:23][CH3:22])=[CH:31][N:32]([S:48]([C:51]4[CH:52]=[CH:53][C:54]([CH3:57])=[CH:55][CH:56]=4)(=[O:50])=[O:49])[C:33]3=[N:34][CH:35]=2)[CH:12]=1)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6]
Reactant: CN(C)C(=O)c1cc(I)cc(F)c1NCc1ccncc1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(F)c(NCc4ccncc4)c(C(=O)N(C)C)c3)cc12
Yield: 22.3 %

Procedure:
Crude 3-fluoro-5-iodo-N,N-dimethyl-2-[(pyridin-4-ylmethyl)-amino]-benzamide (˜1.63 mmol) from the previous step and 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (822 mg, 1.63), [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with dichloromethane (1:1, 133 mg, 0.16 mmol), acetonitrile (8 ml) and 2 M aqueous sodium carbonate solution (4 ml) were placed in a microwave reactor and irradiated to 100° C. for 10 minutes. The reaction mixture was concentrated in vacuo and the residue partitioned between dichloromethane and water. The organic layer was dried over sodium sulfate, and concentrated. The crude product was purified by flash chromatography on silica gel (0 to 100% [10% methanol in ethyl acetate] in hexanes) to afford 236 mg (22% for 2 steps) of 3-fluoro-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-2-[(pyridin-4-ylmethyl)-amino]-benzamide. MS: m/z 650.3 (M+H+).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[CH2:14][C:13](=[O:15])[C:12]1(Cl)Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)C>C(O)(=O)C.[Zn]>[CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[CH2:12][C:13](=[O:15])[CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(CCOCc2ccccc2)C1(Cl)Cl
Agent: [Zn]
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C1CC(CCOCc2ccccc2)C1
Temperature: 60 °C

Procedure:
Zinc dust was added to a solution of 3-(benzyloxyethyl)-2,2-dichlorocyclobutanone in glacial acetic acid at room temperature. The reactants were heated at 60° C. for 1 hr, after which time dry diethyl ether was added to the cooled products, which were then filtered. The residue was washed with diethyl ether and the combined filtrate and washings were concentrated under reduced pressure. The residue was dissolved in CH2Cl2, which was washed with saturated NaHCO3 twice and water once. The organic phase was dried over MgSO4 and the solvent was evaporated to give an oily product, which was purified by silica gel flash chromatography (Hexane: EtOAc=6:1). 1H NMR (CDCl3, 400 MHz): δ 1.85-1.90 (q, J=6.0, 2H), 2.45-2.56 (m, 1H), 2.66-2.74 (m, 2H), 3.07-3.15 (m, 2H), 3.48-3.51 (t, J=6.0, 2H), 4.48 (s, 2H), 7.24-7.35 (m, 5H). 13C NMR (CDCl3, 100 MHz): δ 21.29, 36.02, 52.56, 68.85, 72.99, 127.56, 127.62, 128.40, 138.33, 208.25. Rf=0.45 (Hexane: EtOAc=3:1). IR (neat) νmax 3054, 2927, 2856, 1779, 1266, 737, 704.