Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:15](=[O:16])[N:14]3[CH:17]=[C:18](I)[CH:19]=[CH:20][C:13]3=[N:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.[CH2:31]([OH:34])[C:32]#[CH:33]>CN(C=O)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>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:15](=[O:16])[N:14]3[CH:17]=[C:18]([C:33]#[C:32][CH2:31][OH:34])[CH:19]=[CH:20][C:13]3=[N:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(I)cn2c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(C#CCO)cn2c1=O
Temperature: 90 °C
Yield: 58 %

Procedure:
To a solution of N-(4-chlorobenzyl)-7-iodo-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide (Procedure 3, 500 mg), PdCl2(PPh3)2 (21 mg), and Et3N (0.73 mL) in anhydrous DMF (3 mL) is added propargyl alcohol (0.094 mL). The mixture is heated at 90° C. for 1 h, then allowed to cool to room temperature. The reaction mixture is placed under high vacuum to remove the DMF. The resulting solid is dissolved in CH2Cl2 and washed with water. The aqueous layer is extracted with CH2Cl2 (2×). The combined organic layers are dried (Na2SO4), filtered, and condensed to afford a solid. The crude solid is adsorbed onto silica and chromatographed (1% MeOH/CH2Cl2 (1 L), 1.5% MeOH/CH2Cl2 (1 L), and 2% MeOHICH2Cl2 (1.5 L)). Product-containing fractions are combined and concentrated to afford 243 mg (58%) of the title compound as a creme solid. Physical characteristics: m.p. 179-181° C.; 1H NMR (300 MHz, DMSO-d6) δ9.34, 9.07, 9.00, 8.10, 7.85, 7.36, 5.50, 4.54, 4.36; IR (drift) 3294, 1676, 1632, 1618, 1561, 1541, 1521, 1490, 1353, 1335, 1131, 1061, 1040, 842, 797 cm−1; MS (ESI+) m/z 368 (M+H)+; Anal. found: C, 61.96; H, 3.69; N, 11.44.
Reaction SMILES: C(S[C:4]1[C:5]([C:14]2[N:26]([CH3:27])[C:17]3=[N:18][CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=[C:16]3[N:15]=2)=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)C.Cl[C:29]1C=CC=C(C(OO)=O)[CH:30]=1.[S:39]([O-:43])([O-])(=[O:41])=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH2:29]([S:39]([C:4]1[C:5]([C:14]2[N:26]([CH3:27])[C:17]3=[N:18][CH:19]=[C:20]([C:22]([F:25])([F:23])[F:24])[CH:21]=[C:16]3[N:15]=2)=[N:6][CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1)(=[O:43])=[O:41])[CH3:30]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1cc(C(F)(F)F)cnc1-c1nc2cc(C(F)(F)F)cnc2n1C
Reactant: O=S([O-])([O-])=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1cc(C(F)(F)F)cnc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a mixture of 2-(3-ethylsulfanyl-5-trifluoromethylpyridin-2-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (0.61 g) and chloroform (10 ml) was added m-chloroperbenzoic acid (purity: not less than 65%) (0.66 g) while ice-cooling, and the mixture was stirred at room temperature for 10 hours. To the reaction mixture were added aqueous 10% sodium thiosulfate solution and saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 2-(3-ethylsulfonyl-5-trifluoromethylpyridin-2-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (0.62 g), which is hereinafter referred to as “the present compound 5”.
Reaction SMILES: [O:1]=[C:2]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:3][CH2:4][NH:5][CH:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:7]([O:9]CC)=O.[CH3:28][N:29]=[C:30]=[O:31]>>[CH2:21]([O:20][C:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:6]1[N:5]([CH2:4][CH2:3][C:2](=[O:1])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:30](=[O:31])[N:29]([CH3:28])[C:7]1=[O:9])=[O:19])[CH3:22]
Reactant: CCCCCC(=O)CCNC(CCCCCCC(=O)OCC)C(=O)OCC
Reactant: CN=C=O
Product: CCCCCC(=O)CCN1C(=O)N(C)C(=O)C1CCCCCCC(=O)OCC

Procedure:
Diethyl 2-((3-oxooctyl)amino)nonanedioate was allowed to react with methyl isocyanate as described in Example 89 to give 5-(6-ethoxycarbonylhexyl)-3-methyl-1-(3-oxooctyl)hydantoin, which was hydrolysed to 5-(6-carboxyhexyl)-3-methyl-1-(3-oxooctyl)hydantoin, a colourless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:9][CH:8]=1.[CH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O)=[O:26].C(=O)([O-])[O-].[K+].[K+].C(O)C>C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[CH:24]=[CH:23][CH:22]=[C:4]([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:9][CH:8]=2)[CH:3]=1)=[O:26]
Reactant: O=Cc1ccccc1B(O)O
Reactant: CC(C)(C)OC(=O)CCc1ccc(OCc2cccc(Br)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCc1ccc(OCc2cccc(-c3ccccc3C=O)c2)cc1
Temperature: 80 °C
Reaction time: 14 h
Yield: 97.2 %

Procedure:
A mixture of tert-butyl 3-[4-[(3-bromobenzyl)oxy]phenyl]propanoate (3.5 g, 8.94 mmol), 2-formylphenylboronic acid (1.47 g, 9.83 mmol), tetrakistriphenylphosphine palladium (413 mg, 0.36 mmol), 2N potassium carbonate aqueous solution (7 mL), ethanol (7 mL) and toluene (70 mL) was stirred under an argon atmosphere at 80° C. for 14 hrs. The reaction mixture was cooled, diluted with ethyl acetate, washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-4/1) to give the title compound (3.62 g, 97%) as a colorless oil.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].COC(=O)CC.[H][H]>CO>[CH:3]([OH:2])=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCC=CC(=O)OC
Reactant: [H][H]
Solvent: CCC(=O)OC
Solvent: CO
Product: CCCCCCCCCC=CO
Reaction time: 5 h

Procedure:
In about the same way as described under Example 2, an experiment was carried out with difference being that 10 ml methyl-undecenoate was included in the autoclave instead of 10 ml methylpropionate, while after 5 min hydrogen was added until a pressure increase of 30 bar was reached. The autoclave was kept at 80° C. for 5 hours giving a yield of 2.4 g methanol and about 1 g 1-undecenol.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9]([C:11]([NH2:14])([CH3:13])[CH3:12])=[CH:8][C:6]=2[N:7]=1.CCN(CC)CC.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CC1(C)C(C)(C)OB([C:45]2[CH:53]=[CH:52][CH:51]=[C:50]3[C:46]=2[CH:47]=[N:48][NH:49]3)O1>C(Cl)Cl.Cl>[NH:49]1[C:50]2[C:46](=[C:45]([C:2]3[N:3]=[C:4]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:5]4[S:10][C:9]([C:11]([NH:14][C:28](=[O:35])[C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)([CH3:13])[CH3:12])=[CH:8][C:6]=4[N:7]=3)[CH:53]=[CH:52][CH:51]=2)[CH:47]=[N:48]1
Reactant: CC(C)(N)c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)c1ccccc1)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-amine (1.1 g, 3.5 mmol) in CH2Cl2 (50 mL) was added Et3N (0.6 mL, 4.9 mmol) and benzoyl chloride (0.6 mL, 4.2 mmol). The resulting mixture stirred at room temperature overnight. The reaction was diluted with 1 M HCl and extracted with DCM, dried over MgSO4, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-50% EtOAc in hexane). A portion (0.65 mmol) of the crude material was utilized in a Suzuki coupling using General Procedure A with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to provide 388 after reverse phase HPLC purification (133 mg). MS (Q1) 499 (M)+
Reaction SMILES: C([O:8][CH2:9][C:10]1[NH:11][C:12]([C:19]2[C:20]([CH3:30])=[CH:21][C:22]([CH3:29])=[C:23]([CH:28]=2)[C:24]([O:26][CH3:27])=[O:25])=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=1)C1C=CC=CC=1.Cl.[H][H]>CO.[Pd]>[OH:8][CH2:9][C:10]1[NH:11][C:12]([C:19]2[C:20]([CH3:30])=[CH:21][C:22]([CH3:29])=[C:23]([CH:28]=2)[C:24]([O:26][CH3:27])=[O:25])=[C:13]([C:15]([F:16])([F:18])[F:17])[N:14]=1
Reactant: [H][H]
Reactant: COC(=O)c1cc(-c2[nH]c(COCc3ccccc3)nc2C(F)(F)F)c(C)cc1C
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(-c2[nH]c(CO)nc2C(F)(F)F)c(C)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
Into a 50-mL round-bottom flask, under a nitrogen atmosphere, was placed a solution of methyl 5-(2-((benzyloxy)methyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoate (compound 219.3, 150 mg, 0.36 mmol) in methanol (8 mL). Palladium on carbon (150 mg, 1.00 equiv) and HCl (4 M, 2 mL) were added to the reaction under a nitrogen atmosphere. To the above hydrogen (1 atm) was introduced. The reaction mixture was stirred for 2 h at room temperature. The system was purged with nitrogen, then the solids were removed by filtration and the filtrate was concentrated under reduced pressure to give 100 mg (85%) of the title compound as a light yellow oil.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].S(Cl)([Cl:14])=O>N1C=CC=CC=1.ClCCl>[Cl:14][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: O=S(Cl)Cl
Reactant: C=CCCCCCCCCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCCCCCCCCCl
Yield: 95.3 %

Procedure:
To 26.0 g of 9-decene-1-ol was added 10-drops of pyridine and the mixture was placed into an eggplant flask. To the eggplant flask was added dropwise 24.0 g of thionyl chloride during cooling with ice. After dropping, the mixture was reacted for 8.5 hours at 70° C. After the conclusion of the reaction, the reaction product was diluted with dichloromethane and then washed with an aqueous potassium carbonate solution. The reaction solution was then dried over magnesium sulfate and subsequently concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain 27.7 g of 10-chloro-1-decene. (Yield: 95%)
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:9]=1)=[O:4].[NH2:27][CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[O:31]1[CH2:32][CH2:33][CH:28]([NH:27][C:3]([C:5]2[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([C:19]4[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=4)=[N:14][O:15][C:16]=3[CH2:17][OH:18])[CH:9]=2)=[O:4])[CH2:29][CH2:30]1
Reactant: NC1CCOCC1
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nn1C
Product: Cn1nc(OCc2c(-c3ccc(Cl)cc3)noc2CO)cc1C(=O)NC1CCOCC1
Yield: 42 %

Procedure:
As described for example 100f, 5-[3-(4-chloro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.27 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (50 mg, 42%) which was obtained as a white solid. MS: m/e=447.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.[CH3:13][C:14]([CH3:19])=[CH:15][C:16]([NH2:18])=[O:17].CO[Si](OC)(OC)OC.[F-].[Cs+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]3[C:14]([CH3:19])([CH3:13])[CH2:15][C:16](=[O:17])[NH:18][C:7]=3[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: CC(C)=CC(N)=O
Reactant: O=C1CCc2cc(Cl)ccc2C1
Agent: CO[Si](OC)(OC)OC
Agent: [Cs+]
Agent: [F-]
Solvent: Cc1ccccc1
Product: CC1(C)CC(=O)NC2=C1c1ccc(Cl)cc1CC2

Procedure:
A suspension of 127 g (0.7 mol) of 6-chloro-2-tetralone, 70.0 g (0.7 mol) of 3,3-dimethylacrylamide, 63.6 ml (0.42 mol) of tetramethoxysilane and 85.3 g (0.56 mol) of cesium fluoride in 400 ml of toluene is boiled under reflux for 18 hours. Distillation of the solvent in a vacuum, extraction with methylene chloride/water, chromatography on silica gel with ethyl acetate/hexane (1:1) and recrystallization from methylene chloride/hexane yields 8-chloro-1,1-dimethyl-1,2,5,6-tetrahydrobenzo[f]-quinolin-3-one as white crystals with melting point 213°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.CC(C)([O-])C.[Na+].O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:7][C:2]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: C1CCNC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccc(N3CCCC3)cc2)cc1

Procedure:
10.0 g (0.043 mol) of 4-bromobiphenyl were suspended in 600 ml of toluene together with 3.7 g (0.052 mol) of pyrrolidine and 6.2 g (0.0642 mol) of sodium tertiary-butoxide and 900 mg of the catalyst dichlorobis(tritolylphosphine)palladium(II) were added. The mixture was heated to reflux for 8 h, cooled, treated with water/ethyl acetate, and the organic phase was washed with water, dried over sodium sulfate and concentrated. The residue was dissolved in approximately 300 ml of tertiary-butyl methyl ether and the hydrochloride of the product was precipitated by addition of 50 ml of 1N ethereal HCl.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C@H:8]([OH:17])[CH2:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1.[CH2:20]([O:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[CH2:20]([O:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:19]=[CH:18][C:5]([O:6][CH2:7][C@H:8]([OH:17])[CH2:9][CH2:10][C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:4][CH:3]=2)[CH:31]=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
Reactant: O[C@H](CCc1cccnc1)COc1ccc(Br)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: Cc1ccccc1
Solvent: CCO
Product: O[C@H](CCc1cccnc1)COc1ccc(-c2cccc(OCc3ccccc3)c2)cc1
Temperature: 120 °C
Yield: 83.5 %

Procedure:
Prepared according to the method described in Example 33a) from (2R)-1-(4-bromophenoxy)-4-(3-pyridyl)-2-butanol (0.97 g, Example 40a), 3-(benzyloxy)benzeneboronic acid (1.0 g, Example 93b), tetrakis(triphenylphosphine)palladium(0) (0.09 g), toluene (7.5 ml), ethanol (2 ml) and aqueous sodium carbonate (2 M, 3.5 ml) with heating at 120° C. for 2 hours 30 minutes. After work up the residue was purified by column chromatography over silica eluting with methanol:dichloromethane (5:95) to give the title compound as a white solid (1.07 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16]CC2C=CC(OC)=CC=2)=[CH:12][C:11]=1[C:26](=O)[C:27]([CH3:32])([CH3:31])[CH2:28][CH2:29][CH3:30]>C1COCC1.C(O)(=O)C.[OH-].[OH-].[Pd+2]>[CH3:31][C:27]([CH3:32])([CH2:28][CH2:29][CH3:30])[CH2:26][C:11]1[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:10]=1[C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: CCCC(C)(C)C(=O)c1cc(OCc2ccc(OC)cc2)ccc1-c1cc(OC)ccc1F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCC(C)(C)Cc1cc(O)ccc1-c1cc(OC)ccc1F
Reaction time: 17 h

Procedure:
1-(2′-Fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)-[1,1′-biphenyl]-2-yl)-2,2-dimethylpentan-1-one (43.3 mg) was dissolved in a mixed solution of THF (10 mL) and acetic acid (2 mL), and the reaction was performed in H-Cube having a 20% palladium hydroxide/carbon cartridge (70 mm) at 60° C., 40 atm, flow rate 1 ml/min for 17 hr. The solvent was evaporated under reduced pressure to give the title, compound. This compound was used for the next step without purification.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([OH:19])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[C:20]1([CH2:26]Br)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CO[Na]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([OH:19])[C:11]2[C:16]([C:17]=1[O:18][CH2:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: BrCc1ccccc1
Reactant: CCCCOC(=O)c1nc(O)c2ccccc2c1O
Agent: CO[Na]
Product: CCCCOC(=O)c1nc(O)c2ccccc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 30.7 %

Procedure:
A mixture of 1,4-dihydroxy-isoquinoline-3-carboxylic acid butyl ester (26.13 g, 100 mmol; Example D-20 b), PhCH2Br (18.2 ml, 150 mmol), MeONa (0.5 M in MeOH, 200 ml, 100 mmol) was stirred at ambient temperature for 48 h. Then the solvent was evaporated and EtOAc (100 ml) was added to the residue. The mixture was stirred vigorously for 10 min before it was filtered. The filtrate was washed with aqueous 2.5N NaOH (2×100 ml) and aqueous 2N HCl (1×100 ml). The organic phase was dried over MgSO4 and evaporated in vacuo. The residue was recrystallized from MeOH (500 ml)/water (300 ml). The resulting yellow solid was further purified by flash column chromatography on silica gel using hexanes:EtOAc: NEt3=65:30:5 as the eluent to give 10.8 g of a yellow solid. 2 g of this material were further purified by flash column chromatography on silica gel using hexanes:EtOAc:NEt3=75:20:5 as the eluent to give 1.57 g of the title compound as a slightly yellowish solid; 1H NMR (CDCl3): δ=8.88 (bs, 1H), 8.46 (d, 1H), 8.42 (d, 1H), 7.26 to 7.96 (m, 7H), 5.06 (s, 2H), 4.38 (t, 2H), 1.69 (m, 2H), 1.37 (m, 2H), 0.91 (t, 3H).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]([C:18]2[CH:23]=[C:22]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])[CH:21]=[C:20]([F:31])[CH:19]=2)=O)[CH:12]=[CH:13][C:14]=1[F:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:32][C:33]([S@:36]([NH2:38])=[O:37])([CH3:35])[CH3:34]>C1COCC1>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]([C:18]2[CH:23]=[C:22]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])[CH:21]=[C:20]([F:31])[CH:19]=2)=[N:38][S@@:36]([C:33]([CH3:35])([CH3:34])[CH3:32])=[O:37])[CH:12]=[CH:13][C:14]=1[F:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(C(=O)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)N=C(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 75 °C
Yield: 80 %

Procedure:
A round bottom flask was charged with (3-(tert-butyldimethylsilyloxy)-4-fluorophenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanone (2.09 g, 4.50 mmol), (R)-2-methylpropane-2-sulfinamide (653 mg, 5.4 mmol), Ti(OEt)4 (1.54 g, 6.76 mmol) and anhydrous THF (40 mL). The resulting solution was heated at 75° C. under argon for 14 h. The solvents were removed and the residue was diluted with ether (50 mL) and sat. NaCl (20 mL). The resulting mixture was filtered through a glass frit and the filtrate transferred to a separatory funnel. The organic portion was separated and the aqueous phase extracted with diethyl ether (2×20 mL). The combined organic portions were dried over Na2SO4, filtered and concentrated. The residue was dissolved in hexane:EtOAc and purified by ISCO chromatography (2×120 g column) using hexanes/EtOAc (0-100% over 30 min) to yield (R)—N-((3-(tert-butyldimethylsilyloxy)-4-fluorophenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methylene)-2-methylpropane-2-sulfinamide at a retention time of 14 min (2.05 g, 80% yield) LCMS: RT=2.37 min [M+H] 568.24 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm). NMR: 400 MHz 1H (CDCl3) 7.36 ppm, 1H, m; 7.11 ppm, 5H, m; 5.90 ppm, 1H, t, J=52.73 Hz; 0.97 ppm, 9H, s; 0.18 ppm, 6H, s.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1)[CH:23]=O.O>CO>[CH3:29][O:28][C:26]1[CH:25]=[C:22]([CH:21]=[C:20]([O:19][CH3:18])[CH:27]=1)[CH2:23][NH:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4]
Reactant: C[C@H](N)[C@H](O)c1ccc(O)c(NS(C)(=O)=O)c1
Reactant: COc1cc(C=O)cc(OC)c1
Solvent: CO
Solvent: O
Product: COc1cc(CN[C@@H](C)[C@H](O)c2ccc(O)c(NS(C)(=O)=O)c2)cc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.7 %

Procedure:
To a solution of the amine (4) (363 mg, 1.39 mmol) and 3,5-dimethoxybenzaldehyde (301 mg, 1.81 mmol) in methanol (10 mL) was added borane-pyridine complex (445 μL, 4.18 mmol) at 40° C. and the resulting mixture was stirred for 2 hours. The reaction mixture was cooled to room temperature and water was added thereto, followed by extraction with a mixed solvent (ethyl acetate:methanol=10:1) and subsequent washing of the organic layer with saturated brine. The organic layer was dried and concentrated and the obtained crude product was purified by amine silica gel column chromatography (eluent; chloroform:methanol=7:1) to obtain the desired amine (5) as a pale yellow solid (329 mg, Yield: 57%).
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([C:13]2[C:14]([C:19]([F:22])([F:21])[F:20])=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:12])=[CH:4][C:3]=1[O:23]C.[Cl-].[Al+3].[Cl-].[Cl-].N1C=CC=CC=1.Cl>ClCCCl>[OH:23][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[C:14]([C:19]([F:22])([F:20])[F:21])=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[OH:1]
Reactant: COc1cc(C(=O)c2cccnc2C(F)(F)F)cc([N+](=O)[O-])c1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: c1ccncc1
Product: O=C(c1cc(O)c(O)c([N+](=O)[O-])c1)c1cccnc1C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (4-hydroxy-3-methoxy-5-nitrophenyl)(2-(trifluoromethyl)pyridin-3-yl)methanone (0.287 g, 0.84 mmol) in 1,2-dichloroethane (10 mL) cooled in an ice-water bath was added aluminium chloride (0.14 g, 1.05 mmol) in one portion followed by pyridine (0.26 g, 3.35 mmol) dropwise. The resulting red suspension was stirred at 80° C. for two hours, then cooled to room temperature and poured onto cold 2 N aqueous hydrochloric acid (100 mL). The precipitate was filtered off, washed with water and dried to give (3,4-dihydroxy-5-nitrophenyl)(2-(trifluoromethyl)pyridin-3-yl)methanone, 0.182 g, (66%).