Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].Cl.[CH3:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][NH:15][CH2:16]2)=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][N:15]([S:1]([Cl:5])(=[O:3])=[O:2])[CH2:16]2)=[CH:11][CH:10]=1
Reactant: COc1ccc2c(c1)CNCC2
Reactant: O=S(=O)(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CN(S(=O)(=O)Cl)CC2
Reaction time: 1 h

Procedure:
To a stirred, precooled solution (−40° C.) of 0.41 mL of sulfuryl chloride in 10 mL of chloroform was added a mixture of 1.0 g of 7-methoxy-1,2,3,4-tetrahydro-isoquinoline-hydrochloride and 2.1 mL of triethylamine in 25 mL of chloroform at 40° C. Stirring was continued at −30° C. for one hour and additionally at 5° C. for one hour. The mixture was poured on ice, the organic layer extracted with cold water, dried (sodium sulfate) and concentrated. The residue was redissolved in diethyl ether and chromatographed on silica gel (isohexane/ethyl acetate=8/2 v/v) yielding 0.62 g of 7-methoxy-3,4-dihydro-1H-isoquinoline-2-sulfonyl chloride as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([O:10][Si](C)(C)C)[C:8]#N)[CH:2]=1.BrC[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[Na+]>O1CCCC1>[O:10]=[C:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:8][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=1
Reactant: COC(=O)Cc1ccc(CBr)cc1
Reactant: C[Si](C)(C)OC(C#N)c1cccnc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(CC(=O)c2cccnc2)cc1
Reaction time: 0.5 h
Yield: 39.2 %

Procedure:
Diisopropylamine (2.8 g) in 50 ml of tetrahydrofuran in solution was cooled to -35 to -40° C., followed by addition of 1.5M n-butyllithium in 118 ml of hexane in solution, and stirred for 30 minutes to produce lithium diisopropylamide. To the solution was added a solution of 4.7 g of 2-(3-pyridyl)-2-(trimethylsiloxy) acetonitrile in dry tetrahydrofuran at -78° C., and stirred at the same temperature for 30 minutes, followed by addition of a solution of 5.3 g of methyl 4-bromomethylphenylacetate in dry tetrahydrofuran at -78° C., and stirred overnight from -78° C. to room temperature. To the reaction mixture was added 1.0M tetra-n-butylammonium fluoride in dry tetrahydrofuran (23 ml) in solution, and stirred at room temperature for four hours. The reaction solution was poured into saturated aqueous sodium chloride solution, followed by the separation of the organic phase. The aqueous phase was extracted with ethyl acetate subsequently. The organic phase was washed in saturated aqueous sodium chloride solution and dried over magnesium sulfate, to distill off the solvent. The residue was subjected to chromatography on a silica gel column, which was then eluted with chloroform to produce 2.3 g of methyl 4-[2-oxo-2-(3-pyridyl)ethyl]phenylacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:23])=[O:22])=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:36])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[Cl:8].[O:37]1[CH:41]=[CH:40][C:39]([NH2:42])=[N:38]1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH:42][C:39]4[CH:40]=[CH:41][O:37][N:38]=4)(=[O:22])=[O:23])=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:36])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[Cl:8]
Reactant: COc1nc(Cl)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Reactant: Nc1ccon1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1nc(Cl)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 133.5 %

Procedure:
A RBF was charged with perfluorophenyl 1-(5,6-dichloro-2-methoxypyridin-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (1.0 g, 1.763 mmol), isoxazol-3-amine (0.143 ml, 1.939 mmol), and THF (8.81 ml) to give a clear solution. The flask was cooled to 0° C. for 10 min, then lithium bis(trimethylsilyl)amide (1M in THF) (3.88 ml, 3.88 mmol) was added dropwise. The reaction was stirred for 30 minutes. The reaction was diluted with 1N aq. HCl and EtOAc. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with 1N aq. HCl, washed with brine, dried with sodium sulfate, filtered, and concentrated to afford crude 1-(5,6-dichloro-2-methoxypyridin-3-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (1.10 g, 2.354 mmol, 100% yield) as an orange solid. m/z (ESI) 467.0 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:14])[CH2:4][C:5]([O:7][CH2:8][CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:6].[N:15]([O-])=[O:16].[Na+]>C(O)(=O)C.O>[Cl:1][CH2:2][C:3](=[O:14])[C:4](=[N:15][OH:16])[C:5]([O:7][CH2:8][CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:6]
Reactant: CS(=O)(=O)CCOC(=O)CC(=O)CCl
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)(=O)CCOC(=O)C(=NO)C(=O)CCl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
In 315 ml of glacial acetic acid was suspended 156.3 g (0.644 mole) of methylsulfonylethyl 4-chloroacetoacetate as obtained in Example 1. The suspension was cooled to 5° C. or below and a solution of 44.4 g (0.644 mole) of sodium nitrite in 140 ml of water was added at 0°-5° C. over a period of about 2 hours. The mixture was stirred for 30 minutes, poured in ice water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was then distilled off to give 148.7 g of methylsulfonylethyl 4-chloro-2-hydroxyiminoacetoacetate as an oil.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.C([O:35][CH2:36][C:37](Cl)=[O:38])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:31][CH2:30][N:29]([C:36](=[O:35])[CH2:37][OH:38])[CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CCNC1
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CCN(C(=O)CO)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f15) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:11]([C:12]([OH:14])=O)[C:10]=2[C:18]([OH:20])=O)[CH:2]=1.[O:21]=[C:22]1[CH:27]([N:28]2C(=O)C3C(=CC=CC=3NCCOC)C2=O)[CH2:26][CH2:25][C:24](=[O:44])[NH:23]1>CO.C(OCC)(=O)C>[O:21]=[C:22]1[CH:27]([N:28]2[C:18](=[O:20])[C:10]3[C:11](=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[C:12]2=[O:14])[CH2:26][CH2:25][C:24](=[O:44])[NH:23]1
Reactant: COCCNc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(O)c1cccc(NCc2cccnc2)c1C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1CCC(N2C(=O)c3cccc(NCc4cccnc4)c3C2=O)C(=O)N1
Yield: 46 %

Procedure:
3-[(Pyridin-3-ylmethyl)-amino]-phthalic acid (3.03 mmol) was treated in the same manner as described above for the synthesis of 2-(2,6-dioxo-piperidin-3-yl)-4-(2-methoxy-ethylamino)-isoindole-1,3-dione. The solid yellow residue was slurried in 50% methanol/ethyl acetate (20 ml) for 18 h to give 0.50 g (46%) of product as a yellow solid: mp 231-233° C.; 1H NMR (DMSO-d6) δ 11.14 (s, 1H), 8.63 (s, 1H), 8.47 (s, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.53 (t, J=7.8 Hz, 1H), 7.39-7.30 (m, 2H), 7.03 (t, J=6.6 Hz, 2H), 5.09 (dd, J=5.2 and 12.4 Hz, 1H), 4.61 (d, J=6.0 Hz, 2H), 2.97-2.84 (m, 1H), 2.64-2.48 (m, 2H), 2.08-2.04 (m, 1H); 13C NMR (DMSO-d6) δ 172.78, 170.05, 168.65, 167.22, 148.66, 148.27, 145.75, 136.14, 134.79, 134.54, 132.25, 123.58, 117.50, 110.92, 109.82, 48.57, 42.99, 30.96, 22.12; Anal. Calcd. For C19H16N4O4: C, 62.63; H, 4.43; N, 15.38. Found: C, 62.30; H, 4.27; N, 15.30.
Reaction SMILES: [Br-].[CH2:2]([Zn+])[CH2:3][CH2:4][CH3:5].Br[C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([F:16])[CH:15]=1)[CH:11]=[O:12]>O1CCCC1>[CH2:2]([C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([F:16])[CH:15]=1)[CH:11]=[O:12])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC[Zn+]
Reactant: O=Cc1cc(F)cc(Br)c1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCCc1cc(F)cc(C=O)c1
Temperature: 25 °C
Yield: 77.4 %

Procedure:
Add butylzinc bromide (49.3 mL, 24.6 mmol, 0.5 M in THF) followed by Pd(dppf)2Cl2 dichloromethane complex (1.01 g, 1.23 mmol) to a solution of 3-bromo-5-fluorobenzaldehyde (5.00 g, 24.6 mmol) in tetrahydrofuran (123.1 mL). Stir at room temperature in a sealed vessel flushed with nitrogen for 18 hours. Add saturated aqueous ammonium chloride (125 mL). Separate the layers and extract the aqueous layer with ethyl acetate (1×300 mL). Wash combined organic layers with saturated aqueous sodium chloride, dry over magnesium sulfate and concentrate under reduced pressure. Subject residue to silica gel chromatography, eluting with 0-10% ethyl acetate in hexanes to provide the title compound (3.43 g, 77.3%).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([C:8]12[CH2:15][N:12]([CH2:13][CH2:14]1)[CH2:11][CH2:10][CH2:9]2)=[O:7])(=O)[CH3:2].[OH-].[Na+]>>[CH3:2][C:1]1[O:7][C:6]([C:8]23[CH2:15][N:12]([CH2:13][CH2:14]2)[CH2:11][CH2:10][CH2:9]3)=[CH:5][N:4]=1
Reactant: CC(=O)NCC(=O)C12CCCN(CC1)C2
Agent: [Na+]
Agent: [OH-]
Product: Cc1ncc(C23CCCN(CC2)C3)o1
Temperature: 160 °C

Procedure:
A mixture of 5-[α-(acetylamino)acetyl]-1-azabicyclo[3.2.1]octane (D29) (0.12 g, 0.57 mmole) and polyphosphoric acid (6.0 g) under nitrogen was placed in an oil bath at 110° C. and heated to 160° C. over a period of 15 min. The temperature was maintained at this level for a further 15 min and the reaction was then poured onto ice. After basifying with 40% sodium hydroxide the solution was saturated with potassium 5 carbonate and extracted into chloroform (4×20 ml). Concentration of the dried (sodium sulphate) organic layers followed by purification on neutral alumina using a graded eluant of 5-10% methanol in ethyl acetate afforded the title compound (E26) as a colourless oil (40mg; 36%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].Cl.[CH3:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[CH2:24]Cl>CC#N>[CH3:17][N:18]1[CH2:24][CH2:19][CH2:20][CH2:21][CH:22]([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])[CH2:23]1
Reactant: O=Cc1cccc(O)c1
Reactant: CN1CCCCC1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN1CCCCC(Oc2cccc(C=O)c2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-hydroxybenzaldehyde (3.66 g, 0.03 mol), K2CO3 (12.43 g, 0.09 mol), and CH3CN (100 ml) was stirred at room temperature for 1/2 hour, then N-methyl-2-chloromethylpiperidine hydrochloride (5.49 g, 0.03 mol) was added. The reaction mixture was stirred until the reaction was complete, then the solvent was removed in vacuo and the residue was partitioned between CHCl3 and water. The aqueous layer was extracted with CHCl3 (3×100 ml) and the combined organic layers were concentrated in vacuo to afford 3-(1-methyl-3-hexahydroazepinyloxy)benzaldehyde.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][N:9]([CH3:30])[CH2:10][CH2:11][N:12]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]([CH2:27][CH3:28])([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25]C)[CH:20]=2)[C:13]1=[O:29].B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:30][N:9]([CH3:8])[CH2:10][CH2:11][N:12]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]([CH2:27][CH3:28])([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=2)[C:13]1=[O:29]
Reactant: CCC1(c2cccc(OC)c2)CCCCN(CCN(C)C)C1=O
Agent: BrB(Br)Br
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC1(c2cccc(O)c2)CCCCN(CCN(C)C)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(2-dimethylamino-ethyl)-3-ethyl-3-(3-methoxy-phenyl)-azepan-2-one Trifluoroacetate (as described above in Step A) (0.1 g, 0.23 mmol) in CH2Cl2 (10 mL) at −78° C. was added BBr3 (1M, 0.46 mL, 0.46 mmol). After stirring for 2 hr at 25° C. the reaction mixture was quenched with H2O, the solvents removed in vacuo, and the residue purified by prep RP HPLC to obtain the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6](Br)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([CH3:3])[CH3:2].C([Li])CCC.C([O:21][B:22](OC(C)C)[O:23]C(C)C)(C)C>>[CH:1]([C:4]1[CH:5]=[C:6]([B:22]([OH:23])[OH:21])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([CH3:3])[CH3:2]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(Br)cc1C(C)C
Agent: [Li]CCCC
Product: COc1ccc(B(O)O)cc1C(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a cooled (−78° C.), stirred solution of 3-isopropyl-4-methoxybromobenzene (2.5 g) was added n-butyllithium (4.8 mL of a 2.5 M solution in hexanes) dropwise. After 30 min, triisopropylborate (5 mL) was added and the reaction solution was allowed to warm to RT and then stirred for 18 h. The reaction solution was concentrated in vacuo, saturated aqueous sodium bicarbonate was added and the resulting mixture was stirred for 30 min. The reaction was extracted with ethyl acetate. The organic layer was washed with water then brine, dried over sodium sulfate, and concentrated in vacuo to afford a solid, which was triturated with hexanes to afford the title compound as colorless plates (1.1 g).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].N1C=CC=CC=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[CH2:1]([N:3]([CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[S:26]([CH3:25])(=[O:28])=[O:27])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCNCCCCNC(=O)OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN(CCCCNC(=O)OCc1ccccc1)S(C)(=O)=O
Reaction time: 8 h
Yield: 70.3 %

Procedure:
To a mixture of benzyl 4-(ethylamino)butylcarbamate (Step 1, 250 mg, 1.00 mmol) in dichloromethane was added pyridine (145 mg, 1.8 mmol) and then methanesulfonyl chloride (137 mg, 1.20 mmol) at 0° C. The reaction was stirred overnight and diluted with dichloromethane. The phases were separated, and the organic phase was washed with hydrochloride solution (1 N), saturated sodium bicarbonate and saline. The separated organic layer was concentrated and purified by Biotage column chromatography to give benzyl 4-(N-ethylmethylsulfonamido)butylcarbamate (231 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[NH:16][C:15]2=[O:23])[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[S:34](Cl)(=[O:36])=[O:35].C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[S:34]([N:16]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[C:15]1=[O:23])(=[O:35])=[O:36]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=c1n(C2CCNCC2)c2ccccc2n1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A solution of 4-(2-oxo-2,3-dihydrobenzimidazol-1-yl)piperidine-1-carboxylic acid t-butyl ester (64 mg, 0.2 mmol) in CH2Cl2 at room temperature is treated with 2-naphthylsulfonyl chloride (50 mg, 0.2 mmol) followed by diisopropylethylamine (174 uL, 1.0 mmol) and 4-dimethylaminopyridine (24 mg, 0.2 mmol), stirred at 60° C. for 16 h and concentrated in vacuo. The resultant residue is dissolved in THF, treated with HCl in dioxane (4 N) (1 mL), stirred for 4 h and concentrated in vacuo. This residue is dissolved in a mixture of DMSO, methanol and water and purified by Gilson1 preparative HPLC to give the title product, 24 mg, [M+H] 408, retention time (RT) 1.89 minutes. 1Gilson Preparative HPLC conditions: Gilson Preparative HPLC system; YMC Pro C18, 20 mm×50 mm ID, 5 uM column; 2 mL injection; Solvent A: 0.02% TFA/water; Solvent B: 0.02% TFA/acetonitrile; Gradient: Time 0: 95% A; 2 min: 95% A; 14 min: 10% A, 15 min: 10% A, 16 min: 95% A; Flow rate 22.5 mL/min; Detection: 254 nm DAD.
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([NH2:10])=[S:9])[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl-].[Br:16][C:17]1[CH:18]=[CH:19][C:20]([F:29])=[C:21]([CH:28]=1)[CH:22]=[N+:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.BrC1C=CC(F)=C(C=1)C=O.N1CCCC1>>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([F:29])=[C:21]([CH:22]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:5]2[N:1]([C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[C:8]([NH2:10])=[S:9])[CH:2]=[CH:3][CH:4]=2)[CH:28]=1
Reactant: Fc1ccc(Br)cc1C=[N+]1CCCC1
Reactant: NC(=S)c1ccccc1-n1cccc1
Agent: O=Cc1cc(Br)ccc1F
Agent: [Cl-]
Solvent: C1CCNC1
Product: NC(=S)c1ccccc1-n1cccc1C(c1cc(Br)ccc1F)N1CCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-pyrrol-1-yl-thiobenzamide and 1-(5-bromo-2-fluoro-benzylidene)-pyrrolidinium chloride, which had been prepared in accordance with example 4 from 5-bromo-2-fluorobenzaldehyde and pyrrolidine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:38][C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][C:44]=1[O:45][C:46]([F:49])([F:48])[F:47]>>[CH3:1][O:2][C:3](=[O:37])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[C:27]([C:29]([F:31])([F:30])[F:32])[CH:26]=[C:25]([C:33]([F:34])([F:35])[F:36])[CH:24]=2)[CH:12]=[C:13]([C:41]2[CH:42]=[CH:43][C:44]([O:45][C:46]([F:49])([F:48])[F:47])=[C:39]([F:38])[CH:40]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Reactant: OB(O)c1ccc(OC(F)(F)F)c(F)c1
Product: COC(=O)C(CC(C)C)c1cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc(-c2ccc(OC(F)(F)F)c(F)c2)c1
Yield: 73 %

Procedure:
The title compound was prepared in 73% yield from 4-methyl-2-(5-trifluoromethanesulfonyloxy-3′,5′-bis-trifluoromethyl-biphenyl-3-yl)-pentanoic acid methyl ester (prepared in Intermediate A) and 3-fluoro-4-trifluoromethoxyphenylboronic acid under the conditions described in Example 26, step (d).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[CH3:11][C:12]([CH3:16])=[CH:13][CH:14]=O>N1C=CC=CC=1.C(Cl)Cl>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=[C:8]2[C:9]=1[O:10][C:12]([CH3:16])([CH3:11])[CH:13]=[CH:14]2
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: CC(C)=CC=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)C=Cc2cc(C=O)cc(O)c2O1

Procedure:
3,4-Dihydroxybenzaldehyde (2.3 g, 17 mmol) and 3-methylbut-2-enal (1 mL, 10 mmol) were dissolved in 3 mL of pyridine and refluxed overnight. Pyridine was evaporated under vacuum, and the crude reaction mixture was dissolved in methylene chloride. 9 (103 mg, 2.4%) was purified with silica gel chromatography with ethyl acetate/hexane (1/50). 1H NMR (CDCl3): δ 1.50 (s, 6H), 5.70 (d, J=10.1 Hz, 1H), 6.38 (d, J=10.1 Hz, 1H), 7.15 (d, J=2.14 Hz, 1H), 7.32 (d, J=1.83 Hz, 1H), 9.78 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[Cl:30][C:31]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:32]=1[C:33](Cl)=[O:34]>CC#N>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:33](=[O:34])[C:32]3[C:31]([Cl:30])=[CH:39][CH:38]=[CH:37][C:36]=3[Cl:40])=[CH:18][CH:19]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: Nc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C2CN(Cc3ccccc3)CCO2)cc1)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
To a mixture of 4-(4-benzyl-morpholin-2-yl)-phenylamine (0.48 g; 1.8 mmol), and N-ethyldiisopropylamine (0.92 mL; 5.4 mmol) in CH3CN (10 mL) was added 2,6-dichlorobenzoyl chloride (0.31 mL; 2.2 mmol), at 0° C. The resulting mixture was allowed to warm to RT, stirred for 1 h, and partitioned between Et2O and 5% aqueous NaHCO3. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O) to afford N-[4-(4-benzyl-morpholin-2-yl)-phenyl]-2,6-dichloro-benzamide (0.61 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1F)#[N:2].[OH:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>[C:14]([O:13][C:11](=[O:12])[CH2:10][C:5]1[CH:6]=[CH:7][C:8]([O:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][CH:28]=2)=[C:3]([C:1]#[N:2])[CH:4]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)Cc1ccc(F)c(C#N)c1
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Oc2ccc(CC(=O)OC(C)(C)C)cc2C#N)cc1
Temperature: 90 °C
Yield: 69.2 %

Procedure:
To a stirred solution of tert-butyl 2-(3-cyano-4-fluorophenyl)acetate (1.00 mg, 4.25 mmol) and methyl 4-hydroxybenzoate (776 mg, 5.10 mmol) in DMSO (20 ml) was added K2CO3 (704 mg, 5.10 mmol). The reaction was heated to 90° C. overnight via an oil bath. The reaction was diluted with ethyl acetate and 10% aqueous sodium carbonate. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with 10% aqueous sodium carbonate and brine, dried over MgSO4, concentrated and purified by silica gel chromatography to give methyl 4-(4-(2-tert-butoxy-2-oxoethyl)-2-cyanophenoxy)benzoate (1.08 g).