Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][CH:11]([C:17](=[O:23])[NH:18][CH2:19][CH2:20][CH:21]=O)[CH:12]([OH:16])[CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][C@@H:26]([C@H:34]([C@@H:36]1[C@@H:40]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[C@@H:39]([O:49][Si:50]([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51])[C@H:38]([N:57]2[CH:62]=[CH:61][C:60](=[O:63])[N:59]([CH2:64][C:65]3[CH:70]=[CH:69][C:68]([O:71][CH3:72])=[CH:67][CH:66]=3)[C:58]2=[O:73])[O:37]1)[OH:35])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C(O)(=O)C>[Si:42]([O:41][C@H:40]1[C@@H:39]([O:49][Si:50]([C:53]([CH3:55])([CH3:56])[CH3:54])([CH3:51])[CH3:52])[C@H:38]([N:57]2[CH:62]=[CH:61][C:60](=[O:63])[N:59]([CH2:64][C:65]3[CH:70]=[CH:69][C:68]([O:71][CH3:72])=[CH:67][CH:66]=3)[C:58]2=[O:73])[O:37][CH:36]1[C@H:34]([OH:35])[C@@H:26]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[NH:25][CH2:21][CH2:20][CH2:19][NH:18][C:17](=[O:23])[C@H:11]([C@@H:12]([OH:16])[CH:13]([CH3:15])[CH3:14])[NH:10][C:9](=[O:24])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:45]([CH3:46])([CH3:47])[CH3:48])([CH3:44])[CH3:43]
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3O[C@H]([C@H](O)[C@H](N)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Reactant: CC(C)C(O)C(NC(=O)OCc1ccccc1)C(=O)NCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@@H](NC(=O)OCc4ccccc4)[C@@H](O)C(C)C)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Reaction time: 2.5 h
Yield: 59.5 %

Procedure:
A solution of [2-hydroxy-3-methyl-1-(3-oxo-propylcarbamoyl)-butyl]-carbamic acid benzyl ester (175 mg, 0.519 mmol, obtained from Reference Example 14) and tert-butyl (2S,3R)-2-amino-3-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl-(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-tetrahydro-2-furanyl]-3-hydroxypropanoate (300 mg, 0.416 mmol, obtained from Reference Example 6) in anhydrous tetrahydrofuran was stirred at room temperature under a nitrogen atmosphere for 15 minutes. Acetic acid (3 drops) and sodium triacetoxyborohydride (176 mg, 0.831 mmol) were added and the resulting solution was stirred under nitrogen for an additional 2.5 hours. The reaction mixture was basified to pH 9 with aqueous sodium carbonate solution, and the aqueous layer was extracted with ethyl acetate (3×75 mL). The combined extracts were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed (flash column, silica gel, 2.5% methanol in methylene chloride) to provide tert-butyl (5S,12S)-12-[(R)-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-5-[(1S)-1-hydroxy-2-methylpropyl]-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (258 mg, 60%) as a white amorphous solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[C:6]([F:13])=[CH:5][C:4]=1[NH:14][C@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:16]1=[O:27].CCN(C(C)C)C(C)C.Cl[C:38]1[N:43]=[CH:42][C:41]([CH2:44][CH3:45])=[CH:40][N:39]=1>CN(C=O)C>[F:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[C:6]([F:13])=[CH:5][C:4]=1[NH:14][C@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH:21]2[CH2:22][CH2:23][N:24]([C:38]3[N:43]=[CH:42][C:41]([CH2:44][CH3:45])=[CH:40][N:39]=3)[CH2:25][CH2:26]2)[C:16]1=[O:27]
Reactant: CS(=O)(=O)c1cc(F)c(N[C@H]2CCCN(C3CCNCC3)C2=O)cc1F
Reactant: CCc1cnc(Cl)nc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cnc(N2CCC(N3CCC[C@H](Nc4cc(F)c(S(C)(=O)=O)cc4F)C3=O)CC2)nc1
Temperature: 100 °C
Yield: 50.8 %

Procedure:
(S)-3-(2,5-difluoro-4-(methylsulfonyl)phenylamino)-1,4′-bipiperidin-2-one hydrochloride (2.6 g, 6.1 mmol) was dissolved in DMF (30 mL) and DIEA (3.2 mL, 18 mmol) and 2-chloro-5-ethylpyrimidine (1.1 g, 8.0 mmol) were added and heated at 100° C. overnight. The reaction was concentrated and purified over silica gel (25-100% EtOAc in hexanes) to afford (S)-3-(2,5-difluoro-4-(methylsulfonyl)phenylamino)-1′-(5-ethylpyrimidin-2-yl)-1,4′-bipiperidin-2-one (1.5 g, 3.1 mmol, 51% yield) as a white solid. Mass spectrum (apci) m/z=494.3 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]([S:15][CH:16]([CH3:18])[CH3:17])=[C:4]([C:8]2[O:9]CC(C)(C)N=2)[O:5][C:6]=1[Br:7].Cl.C[OH:21].[Li+].[OH-]>O1CCCC1>[Br:1][C:2]1[C:3]([S:15][CH:16]([CH3:18])[CH3:17])=[C:4]([C:8]([OH:9])=[O:21])[O:5][C:6]=1[Br:7]
Reactant: CO
Reactant: CC(C)Sc1c(C2=NC(C)(C)CO2)oc(Br)c1Br
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)Sc1c(C(=O)O)oc(Br)c1Br
Temperature: 0 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
A mixture of 3.01 g (7.58 mmol) of 2-(4,5-dibromo-3-isopropylthio-2-furanyl)-4,4-dimethyloxazoline and aqueous 4N HCl is warmed at reflux under N2 atmosphere for 0.5 hr. The reaction is cooled to 0° C. and treated with methanol (60 mL), tetrahydrofuran (30 mL), and 4.25 g (177.0 mmol) of anhydrous LiOH. The reaction is stirred at 0° C. for 2 hr and 25° C. for 16 hr, then concentrated in vacuo. The resulting residue is dissolved in H2O and extracted with diethyl ether (2X). The aqueous solution is acidified with aqueous 10% HCl and extracted with ethyl acetate (4X). The combined extracts are washed with aqueous saturated NaCl, dried (Na2SO4), and concentrated in vacuo to afford 1.63 g (2.61 g theo.; 62%) of the carboxylic acid as a beige solid. Recrystallization from diethyl ether/hexane affords an analytical sample; mp 130°-131° C.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[O:9])[CH2:4][CH2:3]1.O=[CH:16][CH2:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:27])[CH3:26])[CH2:20][CH2:19]1>>[S:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[C:8]([CH:5]1[CH2:6][CH2:7][N:2]([CH2:16][CH2:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:27])[CH3:26])[CH2:20][CH2:19]2)[CH2:3][CH2:4]1)=[O:9]
Reactant: CC(=O)N[C@H]1CC[C@H](CC=O)CC1
Reactant: O=C(c1cccs1)C1CCNCC1
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCC(C(=O)c3cccs3)CC2)CC1

Procedure:
From piperidin-4-yl-thiophen-2-yl-methanone hydrochloride (74 mg) and N-[trans-4-(2-oxo-ethyl)-cyclohexyl]-acetamide (64 mg, intermediate AG). Yield: 75 mg (65%). Light yellow solid. MS (m/z): 363.4 ([M+H]+).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH:3]([C:5]1[S:9][C:8]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)=[N:7][CH:6]=1)[OH:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[F:21][C:2]([F:1])([F:20])[C:3]([C:5]1[S:9][C:8]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)=[N:7][CH:6]=1)=[O:4]
Reactant: OC(c1cnc(-c2ccc3ccccc3c2)s1)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1cnc(-c2ccc3ccccc3c2)s1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of the crude product I2 in DCM was treated with Dess-Martin Periodinane (3.0 eq.) and stirred for 3 h at RT. Aq. sodium thiosulfate was added and the aqueous phase was extracted with DCM. The combined organic phase was dried (Na2SO4) and solvents were removed under reduced pressure. The crude was purified by RP-HPLC (Waters SYMMETRY C18, 7 micron, 19×300 mm; flow: 20 mL/min; Gradient: A: H2O (+0.1% TFA); B: MeCN (+0.1% TFA); 60% A linear to 10% A in 14 min) to afford the title compound as a solid after freeze drying the desired fractions. 1H NMR (300 MHz, DMSO-d6, 300K) δ 7.69-7.50 (3H, m), 8.27-7.92 (4H, m), 8.55 (1H, s). MS (ES+) C15H8F3NOS requires: 307, found: 308 (M+H)+ and 326 (M+H+H20)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[CH2:9]([O:16][C:17]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([O:16][C:17]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([O:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1)=[O:23])=[O:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=c1cc(O)cc[nH]1
Reactant: O=C(Cl)c1cccc(C(=O)OCc2ccccc2)c1
Product: O=C(OCc1ccccc1)c1cccc(C(=O)Oc2cc[nH]c(=O)c2)c1
Yield: 48.7 %

Procedure:
The general procedure of Example 1 was repeated using 2.80 g of 4-hydroxy-2-pyridone and 14.70 g of 3-benzyloxycarbonylbenzoyl chloride, thereby producing 4.29 g of the title compound in a yield of 49%.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:18].[S:19](Cl)(Cl)=O.C(N(CC)CC)C>C1COCC1>[CH:10]1[CH:11]=[CH:12][C:13]2[C:14](=[O:16])[C:15]3[C:2]4=[N:1][S:19][N:18]=[C:3]4[CH:4]=[CH:5][C:6]=3[C:7](=[O:17])[C:8]=2[CH:9]=1
Reactant: O=S(Cl)Cl
Reactant: Nc1ccc2c(c1N)C(=O)c1ccccc1C2=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)c2c1ccc1nsnc21

Procedure:
The compound 1,2-Diaminoanthraquinone (1.19 g, 5 mmol) is dissolved in THF (30 mL), and thionyl chloride (0.15 g, 20 mmol) is then dripped thereinto; triethylamine (TEA, 3 mL) is lastly added thereinto for catalyzation. After being mixed at room temperature for one hour, the mixture is transferred into a container with 200 mL of icy water for crystallization. After filtration, a precipitate is collected and re-crystallized with hot alcohol, so as to obtain the yellow compound NSC745885 with a melting point of 227-228° C., and the production rate is about 74%.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:8](=[O:23])[NH:9][N:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=1.N>>[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:9]2[C:8](=[O:23])[C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:25][CH:24]=3)=[C:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=3)[CH:11]=[N:10]2)=[CH:29][CH:28]=1
Reactant: Fc1ccc(I)cc1
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2Oc2ccc(F)cc2)cc1
Agent: N
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)cc3)c(=O)c2Oc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to Example 93, starting with 4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 1-fluoro-4-iodobenzene in place of 4-bromothioanisole (yield: 60 mg, 53%). mp 83–85° C. 1H NMR (300 MHz, CDCl3) δ 3.10 (s, 3H), 6.89–7.03 (m, 4H), 7.15 (t, J=9 Hz, 2H), 7.65 (dd, J=9 Hz, 6 Hz, 2H), 7.83 (d, J=6 Hz, 2H), 8.07 (d, J=9 Hz, 2H), 8.08 (s, 1H). MS (DCI/NH3) m/z 455 (M+H)+, 472 (M+NH4)+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:26][O:25][C:16]3[CH:17]=[CH:18][C:19]4[N:20]=[C:21]([CH3:24])[O:22][C:23]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.[F:27][C:28]1[CH:36]=[C:35]2[C:31]([C:32]([C:37]3[CH2:38][CH2:39][NH:40][CH2:41][CH:42]=3)=[CH:33][NH:34]2)=[CH:30][CH:29]=1>CS(C)=O.C(OCC)(=O)C>[F:27][C:28]1[CH:36]=[C:35]2[C:31]([C:32]([C:37]3[CH2:38][CH2:39][N:40]([CH2:12][CH:13]4[O:14][C:15]5[C:16](=[CH:17][CH:18]=[C:19]6[N:20]=[C:21]([CH3:24])[O:22][C:23]6=5)[O:25][CH2:26]4)[CH2:41][CH:42]=3)=[CH:33][NH:34]2)=[CH:30][CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)oc4c3O2)cc1
Reactant: Fc1ccc2c(C3=CCNCC3)c[nH]c2c1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1nc2ccc3c(c2o1)OC(CN1CC=C(c2c[nH]c4cc(F)ccc24)CC1)CO3
Temperature: 80 °C

Procedure:
[(8R)-2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-yl]methyl 4-methylbenzenesulfonate (0.50 g, 1.31 mmole) and 6-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (1.0 g, 4.6 mmole) were combined in 10 mL of DMSO under nitrogen. This solution was heated at 80° C. under nitrogen. After completion, the reaction was cooled to room temperature and diluted with 400 mL of ethyl acetate. The organic phase was washed with 400 mL portions of saturated aqueous sodium bicarbonate, water and saturated brine and concentrated in vacuum. The crude residue was column chromatographed on silica gel using 1% methanol/methylene chloride to give 0.52 g of the (S)-enantiomer of the title compound, which was a yellow solid (m.p. 188-190° C.) after evaporation of the solvent.
Reaction SMILES: [F:1][S:2]([F:13])([F:12])([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.Br[C:15]1[C:24]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([CH3:29])[CH:16]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:28][S:25]([C:24]1[C:15]([S:9][C:6]2[CH:7]=[CH:8][C:3]([S:2]([F:10])([F:11])([F:12])([F:13])[F:1])=[CH:4][CH:5]=2)=[CH:16][C:17]([CH3:29])=[C:18]([CH:23]=1)[C:19]([O:21][CH3:22])=[O:20])(=[O:26])=[O:27]
Reactant: FS(F)(F)(F)(F)c1ccc(S)cc1
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(Br)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(S(C)(=O)=O)c(Sc2ccc(S(F)(F)(F)(F)F)cc2)cc1C
Temperature: 110 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
0.28 g of 4-pentafluorosulfanylthiophenol, 0.36 g of methyl 4-bromo-5-methanesulfonyl-2-methylbenzoate and 0.33 g of K2CO3 were dissolved in 8 ml of anhydrous DMF and stirred at 110° C. for 2 h. The reaction mixture was then poured into 100 ml of water and extracted twice with 100 ml of EA each time. The EA phase was then washed twice with 30 ml of water each time. The residue after drying over MgSO4 and removal of the solvent in vacuo was chromatographed on silica gel with CH2Cl2/DIP 1:2. 320 mg of a colorless foam were obtained.
Reaction SMILES: C(OC([N:8]1[C@H:13]([C:14](=[O:28])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[C:17]=2[F:27])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=O)(C)(C)C.[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30]>C(Cl)Cl>[F:32][C:31]([F:34])([F:33])[C:29]([OH:35])=[O:30].[F:27][C:17]1[C:18]([O:22][C:23]([F:26])([F:24])[F:25])=[CH:19][CH:20]=[CH:21][C:16]=1[NH:15][C:14]([C@@H:13]1[CH2:12][C@@H:11]2[C@@H:9]([CH2:10]2)[NH:8]1)=[O:28]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)Nc1cccc(OC(F)(F)F)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(OC(F)(F)F)c1F)[C@@H]1C[C@H]2C[C@H]2N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of ((1R,3S,5R)-3-(2-fluoro-3-trifluoromethoxy-phenylcarbamoyl)-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (2.56 g, 6.33 mmol) in CH2Cl2 (20 mL) was added TFA (10 mL, 130 mmol) and the solution was stirred at RT for 16 h. CH2Cl2 was concentrated, the residue was suspended in MeOH, concentrated again and dried under high vacuum to give the desired material which was used without further purification in the next step. MS: 305 [M+H]+; tR (HPLC conditions c): 3.55 min.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8](=[O:22])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3][CH2:2]1.[O:23]1[CH2:27][CH2:26][O:25][CH:24]1[C:28]1[C:33]([CH3:34])=[CH:32][C:31]([NH:35][C:36](=[O:39])[CH:37]=[CH2:38])=[C:30]([CH3:40])[CH:29]=1.ClCCl>C(O)C>[O:23]1[CH2:27][CH2:26][O:25][CH:24]1[C:28]1[C:33]([CH3:34])=[CH:32][C:31]([NH:35][C:36]([CH2:37][CH2:38][N:1]2[CH2:2][CH2:3][CH:4]([O:7][C:8](=[O:22])[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:5][CH2:6]2)=[O:39])=[C:30]([CH3:40])[CH:29]=1
Reactant: O=C(Nc1ccccc1-c1ccccc1)OC1CCNCC1
Reactant: C=CC(=O)Nc1cc(C)c(C2OCCO2)cc1C
Solvent: CCO
Solvent: ClCCl
Product: Cc1cc(C2OCCO2)c(C)cc1NC(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Temperature: 25 °C
Yield: 82.8 %

Procedure:
To a 500 mL round-bottom flask was added biphenyl-2-ylcarbamic acid piperidin-4-yl ester (17.0 g, 58 mmol) and N-(4-[1,3]dioxolan-2-yl-2,5-dimethylphenyl)acrylamide (13.1 g, 52.9 mmol). Ethanol (150 mL) and dichloromethane (150 mL) were added to form a slurry. The reaction mixture was heated at 50° C. to 55° C. for about 24 hours and then cooled to room temperature. Most of the solvent was removed on a rotary evaporator, resulting in a thick slurry. Ethanol (reagent grade) was added to form a total volume of about 200 mL and the resulting mixture was heated to 80° C. and then cooled slowly to room temperature. The resulting thick white slurry was filtered, washed with ethanol (20 mL) and dried in vacuum to provide biphenyl-2-ylcarbamic acid 1-[2-(4-[1,3]dioxolan-2-yl-2,5-dimethylphenylcarbamoyl)ethyl]piperidin-4-yl ester (23.8 g, about 98% purity) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][C:18](=[O:20])[CH3:19]>CC(C)=O>[OH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:17][C:18](=[O:20])[CH3:19])=[CH:3][CH:4]=1
Reactant: OCc1ccc(O)cc1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1ccc(CO)cc1
Temperature: 25 °C
Yield: 67.6 %

Procedure:
To a stirred solution of 4-hydroxybenzyl alcohol (1.0 g, 8.06 mmol) in acetone (80 mL) was added potassium carbonate (1.34 g, 9.68 mmol) and chloroacetone (0.771 mL, 9.68 mmol). After completion of addition the reaction mixture was heated to reflux. After 20 hours the reaction mixture was cooled down to room temperature and the solvent was removed. Water and ethyl acetate were added to the crude material. The aqueous layer was separated and extracted with ethyl acetate (3×, 100 mL). All combined organic layers were dried over Na2SO4, filtered, and concentrated to provide an oil. The crude material was purified using silica gel chromatography (gradient from 4:1 to 1:1 pentane:ethyl acetate) to provide the desired product (0.981 g, 5.45 mmol) in 98% yield. 1H (CDCl3, 600 MHz): δ 7.30 (2H, d, J=8.7 Hz), 6.87 (2H, d, J=8.7 Hz), 4.63 (2H, d, J=5.7 Hz), 4.54 (2H, s), 2.27 (3H, s), 1.66 (1H, t, J=5.8 Hz); 13C (CDCl3, 150 MHz): δ 205.7, 157.3, 134.3, 128.8, 114.6, 73.1, 64.8, 26.6.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[N:33]=[C:34]1[S:38]S[N:36]=[C:35]1Cl)[C:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:15]([F:27])([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[CH2:28][CH3:29])=[O:6].C(OCC)(=O)C>N1C=CC=CC=1.[Cu]I>[C:35]([C:34]1[S:38][C:2]2[CH:3]=[C:4]([C:5]([NH:7][C:8]3[C:13]([CH3:14])=[CH:12][C:11]([C:15]([F:27])([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=3[CH2:28][CH3:29])=[O:6])[CH:30]=[CH:31][C:32]=2[N:33]=1)#[N:36]
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(N=c2ssnc2Cl)c(Br)c1
Agent: [Cu]I
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(C)c1NC(=O)c1ccc2nc(C#N)sc2c1
Yield: 49.6 %

Procedure:
3-bromo-4-{[4-chloro-5H-1,2,3-dithiazol-5-ylidene]amino}-N-[2-ethyl-6-methyl-4-(1,1,1,2,3,3,4,4,4-nonafluorobutan-2-yl)phenyl]benzamide (0.195 g) and copper(I) iodide (0.057 g) were suspended in pyridine (5 ml), and irradiated(150° C., 20 minutes). After cooling, to the reaction mixture was added ethyl acetate. The mixture was washed with 1N hydrochloric acid and water, and dried over anhydrous magnesium sulfate. The drying agent (anhydrous magnesium sulfate) was removed by filtration and the solvent was distilled off under the reduced pressure. The residue was purified by column chromatography to obtain 2-cyano-N-[2-ethyl-6-methyl-4-(1,1,1,2,3,3,4,4,4-nonafluorobutan-2-yl)phenyl]-1,3-benzothiazole-6-carboxamide (0.076 g, 49%).
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[OH:7][C:6]1[CH:5]=[C:4]([CH2:3][CH2:2][C:1]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])[CH:11]=[CH:10][C:8]=1[OH:9]
Reactant: C1COCCN1
Reactant: O=C(O)CCc1ccc(O)c(O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Product: O=C(CCc1ccc(O)c(O)c1)N1CCOCC1
Reaction time: 8 h
Yield: 92.1 %

Procedure:
3 g of dihydrocaffeic acid and 1.43 g of morpholine were dissolved in 20 ml of DMF (dimethylformamide), and 202 mg of DMAP (dimethylaminopyridine) and 3.4 g of DCC (dicyclohexylcarbodiimide) were further added thereto under cooling, followed by allowing the mixture to stand overnight. The deposited dicyclohexyl urea was removed therefrom by filtration, and the resultant filtrate was then distilled off under reduced pressure. Afterward, the residue was washed with ether in order to obtain 3.8 g of N-[3-(3,4-dihydroxyphenyl)propionyl]morpholine in the state of light yellow crystals having a melting point of from 211° to 213° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[CH:19][CH:18]=[N:17]4)[N:11]([CH:24]([C:26]3[CH:38]=[CH:37][C:29]([C:30]([O:32]C(C)(C)C)=[O:31])=[CH:28][CH:27]=3)[CH3:25])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[CH:19][CH:18]=[N:17]4)[N:11]([CH:24]([C:26]3[CH:38]=[CH:37][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=3)[CH3:25])[N:10]=2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(c1ccc(C(=O)OC(C)(C)C)cc1)n1nc(-c2cc(Cl)cc(Cl)c2)cc1-c1ccc2nccnc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(c1ccc(C(=O)O)cc1)n1nc(-c2cc(Cl)cc(Cl)c2)cc1-c1ccc2nccnc2c1

Procedure:
The intermediate from step F (40 mg, 0.07 mmol) was dissolved in 1:1 CH2Cl2:TFA (4 mL) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated in vacuo and azeotroped with toluene (3×). The resulting light yellow solid was used without further purification. LC-MS: 4.18 min. (M+H)=490.35.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:39][C:40]1[CH:41]=[CH:42][C:43](F)=[N:44][CH:45]=1>CN(C)C=O.O>[Br:39][C:40]1[CH:41]=[CH:42][C:43]([N:24]([C:5]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:23][C:8]3[C:9]([C:19]([NH:21][CH3:22])=[O:20])=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)[O:11][C:7]=3[CH:6]=2)[S:25]([CH3:28])(=[O:27])=[O:26])=[N:44][CH:45]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Reactant: Fc1ccc(Br)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(Br)cn3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 80 °C
Yield: 77.5 %

Procedure:
To a solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-1-benzofuran-3-carboxamide (400 mg, 1.00 mmol) in dimethylformamide (5 mL) at 0° C. was added lithium bis(trimethylsilyl)amide (1.5 mL, 1.50 mmol). After 1 hour 5-bromo-2-fluoropyridine (350 mg, 2.00 mmol) was added and stirring was maintained at 80° C. for 16 hours. The solution was cooled to room temperature, diluted with water, and extracted with ethyl acetate (3×50 mL). The combined extracts were washed with brine, dried over sodium sulfate and concentrated to dryness at reduced pressure. The crude material was purified by column chromatography to afford 6-(N-(5-bromopyridin-2-yl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (430 mg, 0.775 mmol, 77.5% yield) as a yellow solid. LCMS (m/z, ES+)=559 (M+H+).