Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[CH2:17]([O:10][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([OH:1])[CH:9]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1ccc(OCc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.7 %

Procedure:
To a 250 mL RB flask fitted with magnetic stirrer was charged with 30 mL of acetonitrile. To the stirred solvent were added 2,4-dihydroxybenzaldehyde (8.0 g, 57.0 mmol), potassium carbonate (15.77 g, 114.0 mmol). The reaction mixture was brought to 0° C., was added benzyl bromide (9.905 g, 57.0 mmol) in acetonitrile (100 mL) drop wise and stirred at room temperature for 3 h. The reaction mixture was concentrated to distill off the solvent. The residue was extracted with ethyl acetate (80 mL). The organic layer was washed with water (50 mL) and saturated brine solution (50 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product obtained as a white solid (4.0 g, yield: 30.77%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:13]#[N:14])=[CH:7][N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].IC.[CH2:23](C(C)=O)[CH3:24]>O>[CH2:23]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:13]#[N:14])=[CH:7][N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1)[CH3:24]
Reactant: CCC(C)=O
Reactant: CCn1cc(C#N)c2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: CCOc1ccc2c(C#N)cn(CC)c2c1
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution 6-hydroxy-1-ethyl-1H-indole-3-carbonitrile (80 mg, 0.43 mmol) in 5 mL of methyl ethyl ketone is added anhydrous K2CO3 (71 mg, 0.52 mmol) and iodomethane (0.05 mL, 0.60 mmol). After stirring overnight at reflux, the reaction mixture is cooled, diluted with H2O and extracted with EtOAc (3×). The combined organic phases are dried and concentrated. Flash chromatography (CH2Cl2) gives 94 mg (100% S) of 6-ethoxy-1-ethyl-1H-indole-3-carbonitrile as a white wax.
Reaction SMILES: [Cl:1][CH2:2][C:3]1([CH3:29])[CH:7]([C:8]([O:10]CC(Cl)(Cl)Cl)=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:5]2[S:4]1.C(O)=O>CN(C)C=O.[Zn]>[Cl:1][CH2:2][C:3]1([CH3:29])[CH:7]([C:8]([OH:10])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:5]2[S:4]1
Reactant: CC1(CCl)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Agent: [Zn]
Solvent: O=CO
Solvent: CN(C)C=O
Product: CC1(CCl)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)O
Yield: 59.7 %

Procedure:
2,2,2-Trichloroethyl 2-chloromethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (1.5 g) was dissolved in dried dimethylformamide (8 ml) and to this solution were added formic acid (1.5 ml) and then zinc powder (1.5 g) under stirring while ice-cooling. After stirring for 2 hours at the same temperature, zinc powder was filtered off and washed with dimethylformamide (5 ml). The filtrate and the washings were added to a mixed cool solution of ethylacetate (30 ml) and 5% hydrochloric acid (15 ml). After extracting with ethyl acetate, the extract was washed with water and dried over magnesium sulfate. The gummy substance (1.16 g) obtained by distilling off the solvent under reduced pressure was crystallized from a mixed solvent of ethyl acetate and isopropyl ether to give 2-chloromethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylic acid (660 mg) mp. 110° to 112° C. (dec.).
Reaction SMILES: C([C:5]([C:22](=[O:66])[C@H:23]([CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[NH:24][C:25](=[O:58])[C@H:26]([CH2:47][C:48](=[O:57])[O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[NH:27][C:28](=[O:46])[CH2:29][CH2:30][NH:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][C:36]([C:39]2[NH:40][O:41][C:42](=[O:44])[N:43]=2)=[CH:35][CH:34]=1)([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][NH2:21])[C:6]([O-:8])=[O:7])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[O:41]1[C:42](=[O:44])[N:43]=[C:39]([C:36]2[CH:35]=[CH:34][C:33]([C:32]([NH:31][CH2:30][CH2:29][C:28]([NH:27][C@H:26]([C:25]([NH:24][C@H:23]([C:22]([CH:5]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][NH2:21])[C:6]([OH:8])=[O:7])=[O:66])[CH2:59][C:60]3[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=3)=[O:58])[CH2:47][C:48](=[O:57])[O:49][CH2:50][C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)=[O:46])=[O:45])=[CH:38][CH:37]=2)[NH:40]1
Reactant: CC(C)(C)C(OCCOCCOCCOCCN)(C(=O)[O-])C(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)CCNC(=O)c1ccc(-c2nc(=O)o[nH]2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCOCCOCCOCCOC(C(=O)O)C(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)CCNC(=O)c1ccc(-c2nc(=O)o[nH]2)cc1

Procedure:
Compound 11 (0.2 g, crude, max. 0.22 mmol) was stirred in a mixture of DCM (5 mL) and TFA (3 mL). After 2 h the solution was concentrated and remains of TFA were removed by repeated concentration in toluene (3×5 mL). The product was purified by preparative HPLC-MS to give compound 12 in pure form (0.11 g, 56% over the three steps from 9).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.N1C2C(=NC=CC=2)N([N:20]2[C:24](/[CH:25]=[C:26]3\[C:27](=[O:36])[NH:28][C:29]4[C:34]\3=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)=[C:23]([CH3:37])[C:22]([C:38]([O-])=[O:39])=[C:21]2[CH3:41])N=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:35][C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:36])/[C:26]/2=[CH:25]\[C:24]1[NH:20][C:21]([CH3:41])=[C:22]([C:38]([NH:1][CH:2]2[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]2)=[O:39])[C:23]=1[CH3:37]
Reactant: NC1CCC(C(=O)O)CC1
Reactant: Cc1c(C(=O)[O-])c(C)n(-n2nnc3cccnc32)c1/C=C1\C(=O)Nc2ccc(F)cc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NC1CCC(C(=O)O)CC1
Temperature: 25 °C
Yield: 88.5 %

Procedure:
4-Amino-cyclohexanecarboxylic acid (84 mg, 0.573 mmol) was added to a solution of A4 (200 mg, 0.478 mmol) and DIEA (0.125 mL, 0.717 mmol) in 15 mL of DMF. The mixture was stirred at r.t. LC-MS was used to determine completion of the reaction. DMF was evaporated under reduced pressure and the residue was triturated with ACN for several times to provide 4-({5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carbonyl}-amino)-cyclohexanecarboxylic acid (180 mg, 88.5%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4](Cl)[N:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>O1CCOCC1.O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[C:4]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[N:3]=[C:2]2[NH2:1]
Reactant: C1COCCN1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Solvent: C1COCCO1
Solvent: O
Product: COc1cc2nc(N3CCOCC3)nc(N)c2cc1OC
Temperature: 85 °C
Yield: 94.7 %

Procedure:
To solution of 4-amino-2-chloro-6,7-dimethoxyquinazoline (0.240 g, 1 mmol) in 10 ml dioxane was added morpholine (0.350 ml, 4 mmol). The mixture was heated at 85° C. for 4 h. After cooling to room temperature, the reaction mixture was diluted with water and solid was precipitated. The resulting precipitate was collected by filtration and washed with water and little amount of methanol and to give A 6,7-dimethoxy-2-morpholin-4-yl-quinazolin-4-ylamine (0.275 g) in 94% yield.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C([O-])([O-])=O.[K+].[K+].Cl[CH2:19][C:20]([O:22][CH3:23])=[O:21]>CC(C)=O>[CH3:11][O:10][C:1](=[O:9])[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[O:4][CH2:19][C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1ccccc1O
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccccc1C(=O)OC
Yield: 17 %

Procedure:
To a mixture of methyl salicylate (100 g, 657 mmol) and anhydrous K2CO3 (360 g, 2.605 mol) in anhydrous acetone (1000 ml) was added methyl chloroacetate (94 g, 866 mmol) and refluxed for 36 hours. The acetone was distilled off and water (1200 ml) was added. Crude 1 was extracted into chloroform, dried over Na2SO4 distilled and purified by column chromatography on silica gel using hexane as eluant to give pure 1 (25 grams, 17%) as a light yellow syrup.
Reaction SMILES: N[C:2]1[C:12](/C=C/C(OC)=O)=[CH:11][C:10](Br)=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6].C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[C:8]1(=[O:9])[NH:7][C:5](=[O:6])[C:4]2=[CH:10][CH:11]=[CH:12][CH:2]=[C:3]12
Reactant: COC(=O)/C=C/c1cc(Br)c2c(c1N)C(=O)NC2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1NC(=O)c2ccccc21
Yield: 225.1 %

Procedure:
In a similar manner to Step 2 of Example 1, (E)-3-amino-4-(2-methoxycarbonylvinyl)-6-bromophthalimide (100 mg, 0.308 mmol) was dissolved in acetonitrile (7 mL), and the solution was treated with Compound BB (292 mg, 0.616 mmol), palladium acetate (5.5 mg, 0.025 mmol), tri(o-tolyl)phosphine (15 mg, 0.049 mmol) and triethylamine (0.429 mL, 3.08 mmol), followed by purification by preparative thin-layer chromatography (chloroform/acetonitrile=6/1) to obtain (E)-3-amino-4-(2-methoxycarbonylvinyl)-6-(tert-butoxycarbonyl)-5-[4-(tert-butoxycarbonyl)piperazin-1-ylcarbonyl]indol-2-yl)phthalimide (102 mg, yield 49%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:18][CH:17]3[O:19][CH:13]([CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16]3)[CH2:12]2)=[CH:3][CH:2]=1.Cl>C(OC(=O)C)C>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:18][CH:17]3[O:19][CH:13]([CH2:14][NH:15][CH2:16]3)[CH2:12]2)=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CC2CN(CCCCc3ccncc3)CC(C1)O2
Agent: Cl
Solvent: CCOC(C)=O
Product: c1cc(CCCCN2CC3CNCC(C2)O3)ccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
tert-Butyl 7-[4-(4-pyridinyl)butyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (0.9 g, 2.5 mmol, from step (i) above) was dissolved in ethylacetate, and then treated with ethylacetate saturated with HCl at 0° C. The mixture was stirred for 1 h at 0° C., and then at rt overnight. The solvent was evaporated. CH3CN (100 mL) and water (2 mL) were added together with K2CO3 (3.22 g). The mixture was stirred overnight. Filtration and evaporation gave the sub-title compound in 94% yield.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:12]=[CH:11][N:10]=[C:9]2[C:5]=1[NH:6][C:7]([CH2:13][CH2:14][CH3:15])=[N:8]2.[C:16]([O:20][C:21]([C:23]1[C:24]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35]Br)=[CH:31][CH:30]=2)=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C>[Cl:3][C:4]1[N:12]=[CH:11][N:10]=[C:9]2[C:5]=1[N:6]=[C:7]([CH2:13][CH2:14][CH3:15])[N:8]2[CH2:35][C:32]1[CH:33]=[CH:34][C:29]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])=[CH:30][CH:31]=1
Reactant: CCCc1nc2ncnc(Cl)c2[nH]1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(Cl)ncnc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 40 °C
Reaction time: 0.33 h

Procedure:
To a suspension of NaH (0.20 g) in dry DMF (3 ml), 6-chloro-8-propyl-purine (0.06 g, 0.3 mmol) was added, and the mixture was stirred at 40° C. for 20 minutes. t-Butyl-4-bromomethylbiphenyl-2'-carboxylate (0.11 g, 0.31 mmol) was then added at room temperature and stirring continued for 3 hours at 40° C. The content of the flask was poured into ice-water (100 ml and extracted with ethylacetate. The organic phase was separated and dried over MgSO4. Removal of the solvent under reduced pressure gave the crude product which was then purified by flash-chromatography on silica-gel using ethylacetate-hexane (1:1). The pure titled compound was obtained as a glass-like solid (0.073 g, 53%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:17][C@@H:18]([CH2:21][CH3:22])[CH2:19]O.S(=O)(=O)(O)O>C1C=CC=CC=1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH:18]([CH3:19])[CH2:21][CH3:22])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CC[C@H](C)CO
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CCC(C)COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Yield: 97.9 %

Procedure:
93 m mol (20 g) of 4'-hydroxybiphenyl-4-carboxylic acid and 467 m mol (41 g) of (S)-(-)-2-methylbutanol were refluxed for 25 hours in 150 ml of benzene in the presence of 2 ml of Conc. sulfuric acid while removing water. The resulting reaction solution was concentrated and was recrystallized from a toluene-hexane solvent mixture to obtain 26.0 g of the objective ester (m.p. 116-117.8° C., [α]D23 =+4.35° (CHCl3)). (Yield: 98 %).
Reaction SMILES: [CH3:1][Sn:2]([CH3:15])([CH3:14])[C:3]1[CH:12]=[N:11][C:10]2[NH:9][C:8](=[O:13])[CH2:7][O:6][C:5]=2[CH:4]=1.[Li]N([Si](C)(C)C)[Si](C)(C)[CH3:19].S(O)(O)(=O)=O.COS(OC)(=O)=O>C1COCC1>[CH3:19][N:9]1[C:8](=[O:13])[CH2:7][O:6][C:5]2[CH:4]=[C:3]([Sn:2]([CH3:15])([CH3:14])[CH3:1])[CH:12]=[N:11][C:10]1=2
Reactant: C[Sn](C)(C)c1cnc2c(c1)OCC(=O)N2
Reactant: [Li]N([Si](C)(C)C)[Si](C)(C)C
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: COS(=O)(=O)OC
Product: CN1C(=O)COc2cc([Sn](C)(C)C)cnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 680 mg of 7-trimethylstannyl-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one (0.0022 mole) in 10 ml of THF is added 2.4 ml of LiN(TMS)2 (0.0024 mole) in THF. The homogenous solution is maintained under nitrogen at room temperature for 20 min , 300 mg (0.0024 mole) of dimethylsulfate sulfate is added and the reaction mixture allowed to stir overnight. The reaction mixture is then quenched with 10 ml of sat. ammonium chloride and extracted with 3×50 ml ethyl acetate. The ethyl acetate is then washed with 3×10 ml sat. ammonium chloride, dried over sodium sulfate and concentrated to obtain off white product whish is used directly in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14](=[O:21])[CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O[CH:29](N(C)C)[N:30]([CH3:32])[CH3:31])(C)(C)C>C(OCC)(=O)C>[CH3:29][N:30]([CH:32]=[C:13]1[C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:10]([C:8](=[O:9])[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:23][CH:22]=2)[CH2:11][CH2:12]1)[CH3:31]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: O=C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc21
Solvent: CCOC(C)=O
Product: CN(C)C=C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc2C1=O
Reaction time: 1.5 h

Procedure:
A mixture of 0.780 g of 1,2,3,4-tetrahydro-1-(4-nitrobenzoyl)-5H-1-benzazepin-5-one and 10 ml of tert-butoxy bis(dimethylamino)methane (Bredereck's Reagent) is heated on a steam bath while stirring for 1.5 hours (solid dissolved). Cooling gives a solid and the mixture is diluted with ethyl acetate and filtered. The solid is dissolved in dichloromethane-ethyl acetate (7:3) and the solution filtered through a thin pad of hydrous magnesium silicate. The filter pad is washed with dichloromethane-ethyl acetate (7:3) and the combined filtrate evaporated to give 0.43 g of yellow crystals, Mass Spec (CI) MH+ =366, m.p. 180°-183° C.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[O:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1.[O-]S([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH2:15]([O:14][C:10]1[C:11]([F:13])=[CH:12][C:2]([NH:1][CH:25]2[CH2:26][CH2:27][O:22][CH2:23][CH2:24]2)=[C:3]([CH:9]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CCOCC1
Reactant: CCOC(=O)c1cc(OCc2ccccc2)c(F)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(OCc2ccccc2)c(F)cc1NC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
A mixture of 10.5 g of the compound obtained in Step 4.2, 29.07 g of tetrahydro-4H-pyran-4-one and 51.56 g of Na2SO4 in 360 ml of acetic acid is stirred overnight at room temperature. 34.62 g of sodium triacetoxyborohydride are then added and the mixture is stirred for 3 hours at room temperature. The resulting mixture is evaporated under reduced pressure and the residue is taken up in EtOAc. This solution is washed with water and then 4 times with saturated aqueous NaHCO3 solution. The resulting solution is dried over MgSO4 and filtered, and the filtrate is evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a PE/EtOAc mixture from (100/0, v/v) to (50/50, v/v) to give 10.55 g of the expected product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3[C:24](=[O:25])[C:23]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[CH:22][NH:21][CH:20]=3)=[O:18])=[C:11]([F:33])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:34][N:35]1[CH:39]=[C:38](B(O)O)[CH:37]=[N:36]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CCOC(C)=O.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:33][C:11]1[CH:10]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:38]3[CH:37]=[N:36][N:35]([CH3:34])[CH:39]=3)[CH:7]=2)[C:14]([F:15])=[CH:13][C:12]=1[NH:16][C:17]([C:19]1[C:24](=[O:25])[C:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:22][NH:21][CH:20]=1)=[O:18]
Reactant: O=C(Nc1cc(F)c(Oc2ccnc(Cl)c2)cc1F)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Reactant: Cn1cc(B(O)O)cn1
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: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cn1cc(-c2cc(Oc3cc(F)c(NC(=O)c4c[nH]cc(-c5ccc(F)cc5)c4=O)cc3F)ccn2)cn1
Temperature: 80 °C
Yield: 82 %

Procedure:
N-(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (0.100 g, 0.212 mmol), 1-methyl-pyrazole-4-boronic acid (0.055 g, 0.265 mmol) and K2CO3 (0.088 g, 0.636 mmol) were combined in dioxane (2 mL) and H2O (0.500 mL), sparged with argon, treated with Pd(PPh3)4 (0.012 g, 10.60 μmol) and heated at 80° C. for 22 h. Additional 1-methyl-pyrazole-4-boronic acid (0.055 g, 0.265 mmol) was added, the mixture sparged with argon, treated with additional Pd(PPh3)4 (0.012 g, 10.60 μmol) and heated at 100° C. overnight. The mixture was cooled to RT, diluted with EtOAc, filtered through diatomaceous earth and the filtrate washed with brine (2×), dried over MgSO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford N-(2,5-difluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (90 mg, 82%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 13.48 (s, 1H), 12.72 (s, 1H), 8.63 (s, 1H), 8.57 (dd, J=12.6, 6.9 Hz, 1H), 8.37 (d, J=5.7 Hz, 1H), 8.27 (s, 1H), 8.09 (s, 1H), 7.97 (s, 1H), 7.69 (m, 2H), 7.58 (dd, J=11.1, 7.6 Hz, 1H), 7.26 (m, 3H), 6.74 (d, J=5.6 Hz, 1H), 3.84 (s, 3H); MS (ESI) m/z: 518.2 (M+H+).
Reaction SMILES: Br.[NH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][C:9]([OH:10])=[C:7]([OH:8])[CH:6]=1.[C:13](O)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1.C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[C:13]([NH:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][C:9]([OH:10])=[C:7]([OH:8])[CH:6]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1
Reactant: O=C(O)c1cccnc1
Reactant: NCCc1ccc(O)c(O)c1
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: O=C(NCCc1ccc(O)c(O)c1)c1cccnc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
To a pyridine solution containing 11.7 g (0.05 mol) dopamine hydrobromide and 6.15 g (0.05 mol) nicotinic acid at 0° C. were added 10.3 g (0.05 mol) dicyclohexylcarbodiimide (DCC). The reaction mixture was stirred at room temperature for 24 hours and the formed dicyclohexylurea was removed by filtration. The pyridine was removed in vacuo and the residue was crystallized from water at 0° C. The product was isolated by filtration and dried over phosphorous pentoxide. Recrystallization from isopropanol gave 9.0 g (0.035 mol), 70% N-nicotinoyldopamine, m.p. 159°-162° C.; aqueous solution of the compound gave a green color with Fe+3 and reduced AgNO3 ; ir (KBr) 3300, 2960, 1725, 1630, 1590, 1520, 1430, 1290, 1190, 1115, 720 and 710 cm-1 ; NMR (d6 -DMSO) δ 9.25-6.25 (m, 7H), 3.3 (m, 2H) and 2.65 (m, 2H) ppm. Anal. (C14H14N2O 3) C, H, N.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C@H:11]([OH:22])[C@@H:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH3:13].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:23]([O:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C@H:11]([OH:22])[C@@H:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17])[CH3:13])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](O)CCc1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](O)CCc1ccc(F)cc1OCc1ccccc1
Yield: 81.4 %

Procedure:
(3S,4S)-1-(2-hydroxy-4-fluorophenyl)-4-tert-butyldimethylsilyloxy-3-pentanol (0.94 g) was treated with benzyl bromide (0.48 ml) and potassium carbonate (0.53 g) in DMF (5 ml) at room temperature for 2 hr. The mixture was diluted with EtOAc and washed with water twice, dried and evaporated. The residual oil (1.43 g) was chromatographed over silica gel (30 g), eluting with a mixture of hexane and EtOAc (40:1) to give a second crop of colorless oil of (3S,4S)-1-(2-benzyloxy-4-fluorophenyl)-4-tert-butyldimethylsilyloxy-3-pentanol (0.79 g, total yield 81.4%).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:5]=1[OH:6].[CH3:12]OS(OC)(=O)=O>O>[CH3:12][O:6][C:5]1[C:4]([CH3:3])=[C:10]([OH:11])[CH:9]=[CH:8][CH:7]=1
Reactant: Cc1c(O)cccc1O
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cccc(O)c1C
Temperature: 95 °C
Reaction time: 2 h

Procedure:
3-Methoxy-2-methyl-phenol was prepared according to published procedure: J. Org. Chem. 55, 5, 1990, 1469. To a solution of 2.0 g (50 mmol) NaOH and 2-methylresorcinol (6.2 g, 50 mmol) in water (50 mL), dimethylsulfate (4.8 mL, 50 mmol) was added at 95° C. over 30 min, then reaction was stirred for 2 h at 95° C. After cooling to RT, the reaction mixture was poured into aqueous NaOH (8.0 g in 200 ml H2O). Extracted with Et2O (2×100 mL). The aqueous phase was acidified with 5 N aq. HCl, extracted with Et2O (2×100 mL), extracts were dried over Na2SO4 and evaporated. The residue was purified on SiO2 (200 g) column, hexane—EtOAc (0 to 20%). Yield 3.37 g (24.0 mmol, 49%), colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([S:19]([NH:22][CH2:23][CH:24]2[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]2)(=[O:21])=[O:20])[C:13]=1[OH:37])=[O:10]>Cl.O1CCOCC1>[ClH:18].[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([S:19]([NH:22][CH2:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)(=[O:20])=[O:21])[C:13]=1[OH:37])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCC(CNS(=O)(=O)c2c(Cl)ccc(NC(=O)Nc3ccccc3Br)c2O)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1ccccc1Br)Nc1ccc(Cl)c(S(=O)(=O)NCC2CCNCC2)c1O
Yield: 131.2 %

Procedure:
A solution of N-(2-bromophenyl)-N′-[3-[N″-[(1-tert-butoxycarbonylpiperidin-4-yl)methyl]aminosulfonyl]-4-chloro-2-hydroxyphenyl] urea (27 mg, 0.044 mmol) in 1.0 mL of 4.1 N HCl in 1,4-dioxane was stirred at room temperature for 10 min. The mixture was concentrated. Recrystallization from acetone and hexane gave desired product (16 mg, 65%). LC-MS (m/z) 519.2 (M+).