Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[SH:19]CCC(OC)=O.C[O-].[Na+].CO.CCCC(OC)=O>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([C@H:11]([SH:19])[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: C[C@@H]1O[C@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: COC(=O)CCS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCCC(=O)OC
Product: C[C@@H](S)[C@@](O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 3 h

Procedure:
In methanol (25 ml) were dissolved (2S,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane (1.0 g), methyl 3-mercaptopropionate (3.5 ml) and 28% sodium methoxide-methanol (3.07 g) and the solution was refluxed in an oil bath. After 2 and after 3 hours, methyl 3-methylpropionate (1.75 ml) and 28% sodium methoxide-methanol (1.5 g) were added at each time. The oil bath was removed after heating for 4 hours and the reaction mixture was neutralized with cold 1N hydrochloric acid (32 ml) and extracted with dichloromethane (200 ml). The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane-ethyl acetate=1:3). The desired fraction was concentrated and the resulting crystals were recrystallized from ethyl acetate-hexane to give (2S,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1 H-1,2,4-triazol-1-yl)-2-butanol (compound 117, 472 mg) as colorless needles.
Reaction SMILES: [CH3:1][S:2][C:3]1[O:7][C:6]([CH:8]=O)=[CH:5][CH:4]=1.Cl.[NH2:11][OH:12].C([O-])(=O)C.[Na+]>C(O)C>[CH3:1][S:2][C:3]1[O:7][C:6]([CH:8]=[N:11][OH:12])=[CH:5][CH:4]=1
Reactant: NO
Reactant: CSc1ccc(C=O)o1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CSc1ccc(C=NO)o1
Temperature: 23 °C
Reaction time: 18 h
Yield: 25 %

Procedure:
To a solution of 5-(methylthio)furan-2-carbaldehyde (1.0 g, 7.04 mmol) in ethanol (10 mL) was added an aqueous solution of hydroxylamine hydrochloride (3.75M) (2.26 mL, 8.45 mmol) and an aqueous solution of sodium acetate (1.5 M) (3.78 mL, 5.63 mmol). The reaction mixture was stirred a 23° C. for 18 hours. The ethanol was concentrated in vacuo, H2O was added (50 mL) and the precipitate was filtered and dried in oven (60° C.) for 10 minutes to afford 277 mg (25%) of the title compound. LCMS (+ESI, M+H+) m/z 158.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]2[CH3:33])=[CH:4][CH:3]=1.I[CH2:35][CH2:36][CH3:37].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.O>[CH3:33][C:9]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:35][CH2:36][CH3:37])=[CH:7][CH:6]=2)[C:13](=[O:14])[C:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=1
Reactant: CCCI
Reactant: CCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1ccc(-n2c(C)nc(CCC)c(Cc3ccc(-c4ccccc4C#N)cc3)c2=O)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of 4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g) and 1-iodopropane (1.1 mL) in N,N-dimethylformamide (10 mL) was added cesium carbonate (1.5 g), and the mixture was stirred at 80° C. for 5 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.91 g, 83%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:10][CH3:11])=[N:6][C:7]=1[O:8][CH3:9].C(O[CH:15]=[C:16]([C:22]([O:24]CC)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>>[I:1][C:2]1[CH:3]=[C:4]2[C:5](=[N:6][C:7]=1[O:8][CH3:9])[N:10]([CH3:11])[CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:22]2=[O:24]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CNc1ccc(I)c(OC)n1
Product: CCOC(=O)c1cn(C)c2nc(OC)c(I)cc2c1=O
Temperature: 140 °C
Yield: 16 %

Procedure:
6-Methoxy-N-methyl-2-pyridinamine (17.24 g, 124 mmol) is dissolved in DMF (160 mL) and cooled to 0° C. followed by the addition of NIS (28 g, 124 mmol, 1 equiv), at a rate which keeps the reaction temperature below 10° C. The reaction is then allowed to warm to room temperature and stirred for 1 h. The reaction is distilled to dryness in vacuo and the residue is dissolved in CH2Cl2 and passed through a silica plug eluting with heptane/EtOAc (9/1) affording 32 g of crude 5-iodo-6-methoxy-N-methyl-2-pyridinamine. The crude 5-iodo-6-methoxy-N-methyl-2-pyridinamine is dissolved in diethyl ethoxymethylenemalonate (32 mL) and the mixture is heated at 140° C. for 2 h, then cooled to room temperature and passed through a silica plug eluting with heptane/EtOAc (19/1, 0/1). The product is then dissolved in Eaton's reagent (132 mL) and heated at 100° C. for 40 min, cooled to rt and poured into Na2CO3. The basic aqueous layer is then extracted with CH2Cl2 (3×), washed with water, and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography (heptane/EtOAc, 4/1, 1/1, CH2Cl2/MeOH 19/1) the desired product is then triturated with MeOH to afford 7.9 g (16%) of ethyl 6-iodo-7-methoxy-1-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylate. Physical characteristics are as follows: 1H NMR (CDCl3) δ 9.04, 8.52, 4.41, 4.13, 3.91, 1.43; IR (diffuse reflectance) 2491, 2427, 2350, 2282, 2242, 1678, 1632, 1613, 1579, 1384, 1309, 1275, 1227, 1106, 804, cm−1; MS (EI) m/z 388, 344, 343, 317, 316, 185, 159, 86, 84, 51; Anal calcd for C13H13IN2O4: C, 40.23; H, 3.38; N, 7.22. Found: C, 40.20; H, 3.40; N, 7.16.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[CH2:6][NH:7][C:8](=[O:38])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28](=[O:37])[C:29]2(CCl)[CH:34]=[CH:33][CH:32]=[CH:31][NH:30]2)[CH:10]=1.[NH:44]1[CH2:48][CH2:47][C@@H:46]([NH:49][C:50](=[O:52])[CH3:51])[CH2:45]1.[C:53](=[O:56])([O-])[O-:54].[K+].[K+].[I-].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]([F:43])([F:42])[C:53]([OH:54])=[O:56].[C:50]([NH:49][C@@H:46]1[CH2:47][CH2:48][N:44]([CH2:53][C:31]2[N:30]=[C:29]([C:28]([NH:27][C:16]3[CH:17]=[CH:18][C:19]([N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:20][C:15]=3[C:11]3[CH:10]=[C:9]([C:8](=[O:38])[NH:7][CH2:6][C:5]4[CH:39]=[CH:40][CH:41]=[C:3]([C:2]([F:43])([F:1])[F:42])[CH:4]=4)[CH:14]=[CH:13][N:12]=3)=[O:37])[CH:34]=[CH:33][CH:32]=2)[CH2:45]1)(=[O:52])[CH3:51]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)N[C@@H]1CCNC1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)C2(CCl)C=CC=CN2)c1
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H]1CCN(Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)n2)C1
Product: O=C(O)C(F)(F)F
Temperature: 60 °C
Reaction time: 3 h
Yield: 54.7 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-(2-(chloromethyl)picolinamido)-5-(piperidin-1-yl)phenyl)isonicotinamide (100 mg, 0.15 mmol, 1.00 equiv, 90%) in N,N-dimethylformamide (3 mL), (R)—N-(pyrrolidin-3-yl)acetamide (42 mg, 0.33 mmol, 2.00 equiv), potassium carbonate (45 mg, 0.33 mmol, 2.00 equiv), and potassium iodide (14 mg, 0.08 mmol, 0.50 equiv). The resulting solution was stirred for 3 h at 60° C. in an oil bath. The resulting solution was diluted with 100 mL of ethyl acetate. The resulting mixture was washed with 3×20 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product (100 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 33.4 mg (27%) of a yellow solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.90 (d, J=6 Hz, 1H), 8.40 (s, 1H), 8.26 (m, 1H), 8.21-8.09 (m, 2H), 7.98 (d, J=3 Hz, 1H), 7.82 (d, J=6 Hz, 1H), 7.71-7.50 (m, 6H), 4.65 (m, 4H), 4.20 (m, 1H), 3.85 (m, 1H), 3.66-3.63 (m, 4H), 2.50 (m, 1H), 2.00 (m, 4H), 1.80 (m, 3H), 1.68 (m, 3H). MS (ES, m/z): 700 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)CC)C.[C:24](Cl)(=[O:26])[CH3:25]>C(Cl)Cl>[C:24]([N:14]1[CH2:15][CH2:16][N:11]([C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[F:1])[CH2:12][CH2:13]1)(=[O:26])[CH3:25]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)c(F)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A stirred solution of 1-(2-fluoro-4-nitrophenyl)piperazine (15 g, 66.6 mmol) in DCM (160 ml) was cooled to 0° C. Triethylamine was then added (11.23 ml, 79.92 mmol) followed by dropwise addition of acetyl chloride (5.68 ml, 79.92 mmol). The solution was allowed to warm to ambient temperature and stir for 1.5 hour. The reaction mixture was diluted with DCM, washed with water, sat. sodium hydrogen carbonate and brine. It was dried and the solvent was evaporated to give the title compound as a solid which was dried in vac oven overnight at 50° C. (17.46 g, 98%). NMR (400 MHz) 2.05 (s, 3H), 3.30 (dt, 4H, under H2O signal), 3.61 (m, 4H), 7.18 (t, 1H), 8.02 (d, 1H), 8.02 (dd, 1H); m/z 268.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:7]=2[S:8][C:9]=1[OH:10])=[O:4].C(Cl)Cl.[O:19](S(C(F)(F)F)(=O)=O)[S:20]([C:23]([F:26])([F:25])[F:24])(=O)=[O:21]>CCN(CC)CC>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:7]=2[S:8][C:9]=1[O:10][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:21])=[O:19])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1c(O)sc2cc(Cl)ccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)sc2cc(Cl)ccc12
Reaction time: 1 h
Yield: 69 %

Procedure:
6-chloro-2-hydroxy-benzo[b]thiophene-3-carboxylic acid methyl ester (2.46 g, 10.1 mmol) was cooled to 0° C. in a solution of DCM (25 ml) and Et3N (25 ml). Tf2O (2.56 ml, 15.2 mmol, 1.5 equiv) was added dropwise, then stirred for 1 hr. The resulting solution was washed twice with water, saturated NaHCO3, then water, followed by drying over MgSO4. This was filtered and the solvent removed in vacuo. The crude material was purified by column chromatography leaving 2.61 g (68%) of 6-chloro-2-trifluoromethanesulfonyloxy-benzo[b]thiophene-3-carboxylic acid methyl ester as a white solid.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13](=[O:23])[N:14]([CH3:22])[CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:7][CH:6]=1)(=O)C.O.[OH-].[K+]>CO>[OH:4][C:5]1[CH:6]=[CH:7][C:8](/[CH:11]=[CH:12]/[C:13]([N:14]([CH3:22])[CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[O:23])=[CH:9][CH:10]=1
Reactant: CC(=O)Oc1ccc(/C=C/C(=O)N(C)Cc2cccnc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(Cc1cccnc1)C(=O)/C=C/c1ccc(O)cc1
Yield: 77.1 %

Procedure:
1.50 g of 4-[(E)-2-[N-methyl-N-(3-pyridylmethyl)carbamoyl]ethenyl]phenyl acetate was dissolved in 10 ml methanol, and then stirred with 1 ml of water and 0.36 g of potassium hydroxide at room temperature for 1.5 hours. After the reaction mixture was concentrated under reduced pressure, the residue was neutralized with diluted hydrochloric acid, extracted with ethyl acetate, washed with water, and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give a residue, which was then purified via column chromatography on silica gel (dichloromethane:methanol=30:1) to provide (E)-3-(4-hydroxyphenyl)-N-methyl-N-(3-pyridylmethyl)-2-propenoic acid amide (1.00 g).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:10]3[C:15]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[CH:22]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)O1.Cl[C:25]1[CH:26]=[C:27]([CH2:31][N:32]2[CH:36]=[CH:35][N:34]=[C:33]2[CH3:37])[N:28]=[N:29][CH:30]=1>>[CH3:37][C:33]1[N:32]([CH2:31][C:27]2[N:28]=[N:29][CH:30]=[C:25]([C:9]3[C:10]4[C:15]([C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=5[CH:22]=3)=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:26]=2)[CH:36]=[CH:35][N:34]=1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Reactant: CC1(C)OB(c2cc3ccccc3c3ccccc23)OC1(C)C
Product: Cc1nccn1Cc1cc(-c2cc3ccccc3c3ccccc23)cnn1

Procedure:
The title compound, MS: m/e=351.4 (M+H+), was prepared from 4,4,5,5-tetramethyl-2-phenanthren-9-yl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[C:10]([F:17])[CH:9]=2)=[CH:6][C:5]([Br:18])=[CH:4][N:3]=1.[NH2:19][C@@H:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1)[CH2:21][OH:22].O.CCOC(C)=O>C1COCC1>[NH2:1][C:2]1[C:7]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH:19][C@@H:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[CH2:21][OH:22])=[O:14])=[C:10]([F:17])[CH:9]=2)=[CH:6][C:5]([Br:18])=[CH:4][N:3]=1
Reactant: N[C@H](CO)c1cccc(Cl)c1
Reactant: Nc1ncc(Br)cc1-c1ccc(C(=O)O)c(F)c1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ncc(Br)cc1-c1ccc(C(=O)N[C@H](CO)c2cccc(Cl)c2)c(F)c1
Reaction time: 15 h

Procedure:
To a solution of 4-(2-amino-5-bromopyridin-3-yl)-2-fluorobenzoic acid (300 mg, 0.964 mmol) in THF (8.036 mL) was added (S)-2-amino-2-(3-chlorophenyl)ethanol (331 mg, 1.157 mmol). The reaction mixture was stirred for 15 h. After water was added, the reaction mixture was worked up with EtOAc, the organic layer was dried over anhydrous Na2SO4, filtered off and concentrated in vacuo. The crude (S)-4-(2-amino-5-bromopyridin-3-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide was used for the next step without further purification. LCMS (m/z): 464.1/466.1 (MH+), 0.69 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:19]([O:21]C)=[O:20])[C:11](=[O:18])[N:12](CC(C)C)[N:13]=2)=[CH:4][C:3]=1C.[F:24]C1C=C(C(=O)CC(C(OCC)=O)(O)C(OCC)=O)C=CC=1F>>[C:19]([C:10]1[C:11](=[O:18])[NH:12][N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([F:24])[CH:4]=2)[CH:9]=1)([OH:21])=[O:20]
Reactant: COC(=O)c1cc(-c2ccc(F)c(C)c2)nn(CC(C)C)c1=O
Reactant: CCOC(=O)C(O)(CC(=O)c1ccc(F)c(F)c1)C(=O)OCC
Product: O=C(O)c1cc(-c2ccc(F)c(F)c2)n[nH]c1=O
Yield: 88.9 %

Procedure:
Following the procedure of Example 1 (4), ethyl 4-(3,4-difluorophenyl)-2-ethoxycarbonyl-2-hydroxy-4-oxo-butanoate was reacted to yield the title compound as a pale yellow crystalline powder (yield: 88.9%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]([C:23]2[S:24][CH:25]=[CH:26][N:27]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH:18]([CH3:21])[O:17][C:16]=3[CH:22]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.F[C:31]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:32]=1[C:33]#[N:34].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:33]([C:32]1[CH:35]=[C:36]([C:39]([F:40])([F:41])[F:42])[CH:37]=[CH:38][C:31]=1[N:20]1[CH2:19][CH:18]([CH3:21])[O:17][C:16]2[CH:22]=[C:12]([S:9]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:29][CH:28]=3)[C:23]3[S:24][CH:25]=[CH:26][N:27]=3)(=[O:11])=[O:10])[CH:13]=[CH:14][C:15]1=2)#[N:34]
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OC(C)CN3)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OC(C)CN3c2ccc(C(F)(F)F)cc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of N-(4-methoxybenzyl)-2-methyl-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (INTERMEDIATE AE) (1.3 g, 3.02 mmol) and 2-fluoro-5-(trifluoromethyl)benzonitrile in DMF (20 ml) was added Cs2CO3 (1.8 g, 5.56 mmol) at 25° C. and the reaction mixture was stirred at 90° C. for 2 h. The reaction mixture was poured into ice water and the resulting mixture was extracted with EtOAc. The layers were separated and the organic layer was washed with water, dried over sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography using a gradient of 0-50% EtOAc in hexanes to afford 1.2 g of 4-(2-cyano-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-2-methyl-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide as off white solid in 75% yield. 1H-NMR (400 MHz, DMSO): 6.44 (s, 1H), 8.12 (d, J=8.8 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.75-7.77 (m, 1H), 7.43-7.44 (m, 1H), 7.19-7.25 (m, 4H), 6.78-6.86 (m, 3H), 5.02 (s, 2H), 4.37-4.42 (m, 1H), 3.89-3.92 (m, 1H), 3.70 (s, 3H), 3.55-3.61 (m, 1H), 1.35 (s, 3H); m/z (ESI, positive ion) 601.0 (M+H)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2-:16][C:17]([CH3:19])=[O:18].Cl[CH2:21][C@@H:22]([OH:25])[CH2:23]O.O>CN(C=O)C>[CH3:16][C:17]1([CH3:19])[O:25][C@H:22]([CH2:23][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:21][O:18]1
Reactant: OC[C@H](O)CCl
Reactant: O=Cc1ccc(O)cc1
Reactant: [CH2-]C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OC[C@@H](COc2ccc(C=O)cc2)O1
Temperature: 160 °C
Reaction time: 16 h

Procedure:
31.2 g (255.4 mmol) of 4-hydroxybenzaldehyde are initially charged in 400 ml of dry DMF, and 105.7 g (766.1 mmol) of potassium carbonate and 50.0 g (332.0 mmol) of (S)-(−)-3-chloro-1,2-propanediol acetonide are added at RT. The mixture is stirred at 160° C. for 16 h. 4000 ml of water are then added, and the mixture is extracted three times with in each case 500 ml of ethyl acetate. The combined organic phases are washed in each case once with 500 ml water and 500 ml of sat. aqueous sodium chloride solution. After drying over magnesium sulfate, the solvent is removed on a rotary evaporator and the residue is purified by column chromatography on silica gel 60 (mobile phase gradient: ethyl acetate/petroleum ether 1:9→2:8).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH2:22]([CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O.C(O)C>[CH2:22]([CH:29]1[CH2:34][CH2:33][N:32]([CH2:19][C@H:17]([OH:18])[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([C:6]3[C:5]4[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=4[O:8][N:7]=3)=[CH:10][CH:11]=2)[CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: Fc1ccc2c(-c3ccc(OC[C@@H]4CO4)cc3)noc2c1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCC(Cc2ccccc2)CC1
Temperature: 85 °C
Yield: 70 %

Procedure:
Combine (S)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole (150 mg, 0.526 mmol) dissolved in dimethylformamide (˜2 mL) and add 0.13 M solution of 4-benzylpiperidine in ethanol (˜4 mL) and heat for 10 hours at 85° C. Concentrate and purify the reaction mixture by flash (silica) chromatography on a Water's Sep-Pak 5 g silica cartridge using a graded solvent mixture of dichloromethane to 10% methanol in dichloromethane to give the title compound (169.9 mg, 70% Yield). Purity by LC/MS=99%, [M+H]+=461.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]([O:28][CH2:29][CH2:30][N:31]([CH3:56])[C:32]([C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][S:42]([N:45]2[CH2:50][CH2:49][C:48]([NH2:54])([C:51]([NH2:53])=[O:52])[CH2:47][CH2:46]2)(=[O:44])=[O:43])=[C:36]([CH3:55])[CH:35]=1)=[O:33])[CH:26]=[CH2:27].[CH2:57]([O:61][C:62]1[CH:63]=[C:64]([CH:68]=[CH:69][C:70]=1[C:71]([F:74])([F:73])[F:72])[C:65](O)=[O:66])[CH2:58][CH:59]=[CH2:60].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH2:25]([O:28][CH2:29][CH2:30][N:31]([CH3:56])[C:32]([C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][S:42]([N:45]2[CH2:46][CH2:47][C:48]([NH:54][C:65](=[O:66])[C:64]3[CH:68]=[CH:69][C:70]([C:71]([F:73])([F:74])[F:72])=[C:62]([O:61][CH2:57][CH2:58][CH:59]=[CH2:60])[CH:63]=3)([C:51]([NH2:53])=[O:52])[CH2:49][CH2:50]2)(=[O:44])=[O:43])=[C:36]([CH3:55])[CH:35]=1)=[O:33])[CH:26]=[CH2:27]
Reactant: C=CCCOc1cc(C(=O)O)ccc1C(F)(F)F
Reactant: C=CCOCCN(C)C(=O)c1ccc(CCS(=O)(=O)N2CCC(N)(C(N)=O)CC2)c(C)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: C=CCCOc1cc(C(=O)NC2(C(N)=O)CCN(S(=O)(=O)CCc3ccc(C(=O)N(C)CCOCC=C)cc3C)CC2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
HATU (245 mg, 0.644 mmol) was added to a solution of 1-(2-{4-[(2-allyloxy-ethyl)-methyl-carbamoyl]-2-methyl-phenyl}-ethanesulfonyl)-4-amino-piperidine-4-carboxylic amide (250 mg), 3-but-3-enyloxy-4-trifluoromethyl-benzoic acid (155 mg, 0.596 mmol) and diisopropylethylamine (0.140 ml, 0.812 mmol) in DMF (5 ml), and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1-(2-{4-[(2-allyloxy-ethyl)-methyl-carbamoyl]-2-methyl-phenyl}-ethanesulfonyl)-4-(3-but-3-enyloxy-4-trifluoromethyl-benzoylamino)-piperidine-4-carboxylic amide as a crude compound (381 mg).
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li][CH2:17][CH2:18][CH2:19][CH3:20].C(OCC)(=[O:23])C.C([O-])(O)=O.[Na+]>C1COCC1.CCCCCC>[OH:23][CH2:17][CH2:18][CH2:19][CH2:20][CH2:12][C:11]1[CH:14]=[CH:15][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: [Li]CCCC
Reactant: CCOC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OCCCCCc1ccc(Oc2ccccc2)cc1
Reaction time: 24 h

Procedure:
To a solution of 4-phenoxybenzaldehyde (704 mg, 3.56 mmol) in 15 mL of THF at -78° C. was added n-BuLi dropwise (3.73 mmol, 2.5M in hexane). After 24 hours, the reaction was poured into ethyl acetate and sat. aq. NaHCO3 solution, then washed with brine, dried (Na2SO4) and concentrated in vacuo to provide the crude product.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:13][O:14][C:15](=[O:38])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:23]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2I)[C:24](=[O:30])[C:25]#[C:26][CH:27]([CH3:29])[CH3:28])[CH:17]=1>>[CH3:13][O:14][C:15](=[O:38])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:23]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)/[C:25](=[C:26](\[C:7]3[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=3)/[CH:27]([CH3:29])[CH3:28])/[C:24]2=[O:30])[CH:17]=1
Reactant: COC(=O)c1cccc(CN(C(=O)C#CC(C)C)c2ccccc2I)c1
Reactant: CC(=O)c1ccc(B(O)O)cc1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(/c3ccc(C(C)=O)cc3)C(C)C)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 84 starting from 4-acetyl-phenylboronic acid (commercially available) and 3-{[(2-iodo phenyl)-(4-methyl-pent-2-ynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (CDCl3, 300 MHz) δppm 8.03-8.11 (m, 4H), 7.94 (d, 1H), 7.71 (d, 1H), 7.52 (d, 1H), 7.40 (t, 1H), 7.29 (d, 2H), 7.00 (t, 1H), 6.61 (d, 1H), 6.54 (t, 1H), 5.61 (d, H), 5.02-5.07 (m, 3H), 3.90 (s, 3H), 2.70 (s, 3H), 1.19 (d, 3H), 1.17 (d, 3H).