Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:38]([OH:40])=O)=[C:10]([CH2:25][N:26]3[CH2:31][CH2:30][CH:29]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[CH2:28][CH2:27]3)[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)=[N:12]2)=[CH:7][C:6]=1[S:41]([CH3:44])(=[O:43])=[O:42])[CH3:3].[F:45][C:46]([F:56])([F:55])[C@@H:47]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[NH2:48].C(N(CC)C(C)C)(C)C.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>C(OCC)(=O)C.ClCCl.C([O-])(O)=O.[Na+]>[CH3:3][CH:2]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:38]([NH:48][C@H:47]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:46]([F:45])([F:55])[F:56])=[O:40])=[C:10]([CH2:25][N:26]3[CH2:27][CH2:28][CH:29]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[CH2:30][CH2:31]3)[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)=[N:12]2)=[CH:7][C:6]=1[S:41]([CH3:44])(=[O:42])=[O:43])[CH3:1]
Reactant: CC(C)Oc1cc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCOCC4)CC3)c(C(=O)O)c2cc1S(C)(=O)=O
Reactant: N[C@H](c1ccccc1)C(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCOCC4)CC3)c(C(=O)N[C@H](c3ccccc3)C(F)(F)F)c2cc1S(C)(=O)=O
Temperature: 25 °C
Yield: 54.9 %

Procedure:
A solution of 7-[(1-methylethyl)oxy]-6-(methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.200 mg, 0.315 mmol), (1R)-2,2,2-trifluoro-1-phenylethanamine (0.072 g, 0.409 mmol), N,N-diisopropylethylamine (10.99 μL, 0.063 mmol), and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide (0.262 mL of a 50% solution in ethyl acetate, 0.440 mmol) in dichloromethane (2 mL) was stirred at 0° C. for 2 h. The solution was warmed to room temperature overnight, diluted with saturated aqueous NaHCO3, and extracted with methylene chloride (three times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via HPLC (Waters, Sunfire 30×100 mm, 25-60% CH3CN/H2O with 0.1% TFA) to afford 7-[(1-methylethyl)oxy]-6-(methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.137 g, 52% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ9.85 (br. s., 1H), 8.79 (s, 1H), 7.81 (s, 1H), 7.75-7.80 (m, 1H), 7.64-7.69 (m, 2H), 7.52-7.59 (m, 3H), 7.42-7.48 (m, 3H), 6.25 (t, J=6.90 Hz, 1H), 4.91 (dt, J=6.02, 12.05 Hz, 1H), 3.65-3.72 (m, 5H), 3.52-3.65 (m, 2H), 3.31 (s, 3H), 2.64 (br. s., 1H), 2.38-2.45 (m, 4H), 2.20 (br. s., 1H), 2.03 (t, J=10.67 Hz, 1H), 1.66 (br. s., 4H), 1.59 (d, J=11.54 Hz, 2H), 1.54 (s, 3H), 1.53 (s, 3H); MS (m/z) 793.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]2[N:6]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([CH3:21])([CH3:20])[C:18]#[N:19])=[CH:13][CH:12]=3)[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[CH:3]=1.C(Cl)(Cl)Cl.[C:29]1([CH3:41])[CH:34]=[CH:33][C:32]([S:35]([N:38]=[C:39]=[O:40])(=[O:37])=[O:36])=[CH:31][CH:30]=1.C(N(CC)CC)C>C(O)C.O=[Pt]=O>[Cl:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]2[N:6]([C:11]3[CH:12]=[CH:13][C:14]([C:17]([CH3:21])([CH3:20])[CH2:18][NH:19][C:39]([NH:38][S:35]([C:32]4[CH:33]=[CH:34][C:29]([CH3:41])=[CH:30][CH:31]=4)(=[O:37])=[O:36])=[O:40])=[CH:15][CH:16]=3)[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: CCc1nc2cc(Cl)c(Cl)cc2n1-c1ccc(C(C)(C)C#N)cc1
Agent: O=[Pt]=O
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCc1nc2cc(Cl)c(Cl)cc2n1-c1ccc(C(C)(C)CNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
A mixture of 2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]-2-methylpropanenitrile (step 3, 102 mg, 0.28 mmol), PtO2 (one portion), chloroform (0.5 mL) in ethanol (15 mL) was stirred under hydrogen atmosphere (4.5 Kg/cm2) at room temperature. After 8 h, the mixture was filtered through a pad of Celite, and the filtrate was concentrated. The residue was suspended in dichloromethane (10 mL). To the suspension was added p-toluenesulfonyl isocyanate (0.3 mL, 1.96 mmol), and triethylamine (0.3 mL, 2.1 mmol) at room temperature. After 0.5 h, the mixture was concentrated. The residue was dissolved in dichloromethane (100 mL) and washed with 10% aqueous citric acid (50 mL), water (50 mL), and brine (50 mL). The organic layer was dried (MgSO4) and concentrated. The residue was purified by preparative TLC (ethyl acetate/hexane=2:1) to give 62 mg (37%) of the title compound as white solids: 1H-NMR (CDCl3) δ 7.83 (1H, s), 7.67 (2H, d, J=9.3 Hz), 7.55 (2H, d, J=9.3 Hz), 7.38–7.22 (4H, m), 7.18 (1H, s), 3.45 (1H, br), 2.76 (2H, q, J=8.4 Hz), 2.34 (3H, s), 1.37 (6H, s), 1.31 (3H, t, J=8.2 Hz).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]([OH:45])([C:21]3[N:22]=[CH:23][N:24](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:25]=3)[CH:18]([CH3:20])[CH3:19])[CH:13]=2)[CH:8]=1)(=O)=O.C([Sn](CCCC)(CCCC)[C:53]1[S:54][CH:55]=[CH:56][CH:57]=1)CCC>>[NH:24]1[CH:25]=[C:21]([C:17]([C:12]2[CH:11]=[CH:10][C:9]3[C:14](=[CH:15][CH:16]=[C:7]([C:53]4[S:54][CH:55]=[CH:56][CH:57]=4)[CH:8]=3)[CH:13]=2)([OH:45])[CH:18]([CH3:20])[CH3:19])[N:22]=[CH:23]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CC(C)C(O)(c1ccc2cc(OS(=O)(=O)C(F)(F)F)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: CC(C)C(O)(c1ccc2cc(-c3cccs3)ccc2c1)c1c[nH]cn1

Procedure:
In a similar manner to that described in Example 2-(i), the reaction was carried out by using 6-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-2-naphthyl trifluoromethanesulfonate (2.0 g) and 2-(tributylstannyl)thiophene (1.27 mL) to give the titled compound (1.43 g) as a colorless powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH:5]([C:13]1[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[C:15]([O:22][CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:25][CH2:24]2)[N:14]=1)C(OC(C)(C)C)=O)[CH3:2]>C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][C:13]1[C:18]([NH2:19])=[CH:17][CH:16]=[C:15]([O:22][CH:23]2[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28]2)[N:14]=1)[CH3:2]
Reactant: CCOC(=O)C(C(=O)OC(C)(C)C)c1nc(OC2CCN(CCOC)CC2)ccc1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Cc1nc(OC2CCN(CCOC)CC2)ccc1N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.6 %

Procedure:
A mixture of 3 (0.856 mmol) in TFA (15 mL) was agitated at room temperature for 20 min. LCMS indicated a mixture of ˜1:1 of the tButyl cleavage/decarboxylation to tButyl and Ethyl cleavage/decarboxylation. The TFA was removed in vacuo. The resulting oil was put up in ethyl acetate and washed with sodium bicarbonate (aq., satd.), brine then dried over MgSO4 and concentrated in vacuo. The free based material (4) was dissolved in ethanol (20 mL) and hydrogenated in the presence of 10% Pd/C (30 mg) at 20 psi on the Parr shaker for 1 hour. The suspension was filtered over celite and concentrated in vacuo yielding an orange-yellow oil (253 mg, 87.4%).
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:39])[CH2:23][NH:24][C:25](=[O:38])[C@@H:26]4[CH2:30][CH2:29][CH2:28][N:27]4C(OC(C)(C)C)=O)[CH3:21])[C:14]=3[Cl:40])[C:5]2=[N:4][C:3]=1[CH3:41]>Cl.C(OCC)(=O)C>[ClH:19].[ClH:19].[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:39])[CH2:23][NH:24][C:25](=[O:38])[C@@H:26]4[CH2:30][CH2:29][CH2:28][NH:27]4)[CH3:21])[C:14]=3[Cl:40])[C:5]2=[N:4][C:3]=1[CH3:41]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)[C@@H]4CCCN4C(=O)OC(C)(C)C)c3Cl)cccn2c1Br
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)[C@@H]4CCCN4)c3Cl)cccn2c1Br
Yield: 298.7 %

Procedure:
3-Bromo-8-[3-[N-(tert-butoxycarbonyl-L-prolylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylimidazo[1,2-a]pyridine (67 mg) was dissolved in 4N solution of hydrogen chloride in ethyl acetate (3 ml). The solution was evaporated in vacuo to give 3-bromo-8-[2,6-dichloro-3-[N-(L-prolylglycyl)-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine dihydrochloride (64 mg) as colorless glass.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:6][N:7]([CH2:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=1[C:24]1[CH:29]=[C:28]([CH:30]([CH3:32])[CH3:31])[CH:27]=[CH:26][C:25]=1[O:33][CH3:34])[C:8]1[N:9]=[N:10][NH:11][N:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:63][S:64][CH2:65][CH2:66]O.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1.O>[F:41][C:38]([F:39])([F:40])[C:36]1[CH:35]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:42])[F:43])[CH:37]=1)[CH2:6][N:7]([CH2:13][C:14]1[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[CH:16][C:15]=1[C:24]1[CH:29]=[C:28]([CH:30]([CH3:31])[CH3:32])[CH:27]=[CH:26][C:25]=1[O:33][CH3:34])[C:8]1[N:9]=[N:10][N:11]([CH2:66][CH2:65][S:64][CH3:63])[N:12]=1
Reactant: CSCCO
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nn[nH]n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(CCSC)n1

Procedure:
(3,5-Bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-(2H-tetrazol-5-yl)-amine (300 mg) is dissolved in tetrahydrofuran (5 ml) and thereto are added triphenylphosphine (191 mg), 2-(methylthio)ethanol (63 μl), a 40% diethyl azodicarboxylate/toluene solution (332 μl) and the mixture is stirred at room temperature for 2 hours and a half. To reaction mixture is added water and the mixture is extracted with diethylether. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=12:1) to give (3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-[2-(2-methylsulfanyl-ethyl)-2H-tetrazol-5-yl]-amine (270 mg). MS (m/z): 692 [M+H]+
Reaction SMILES: [CH2:1]([C:3]1([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([O:15][CH3:16])[C:10]=2[CH:17]=[O:18])[O:8][CH2:7][CH2:6][CH2:5][O:4]1)[CH3:2].[BH4-].[Na+]>C(O)(C)C.O>[CH2:1]([C:3]1([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([O:15][CH3:16])[C:10]=2[CH2:17][OH:18])[O:8][CH2:7][CH2:6][CH2:5][O:4]1)[CH3:2]
Reactant: CCC1(c2ccnc(OC)c2C=O)OCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CCC1(c2ccnc(OC)c2CO)OCCCO1
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
To stirred solution of 3.178 g of 4-(2-ethyl-[1,3]dioxan-2-yl)-2-methoxy-pyridine-3-carbaldehyde as obtained from Example 4 (12.65 mmol) in 95 mL isopropanol and 15.8 mL water were added at 0° C. 134.6 mg sodium borohydride (3.416 mmol, 0.27 eq). The reaction was monitored by HPLC, and after 30 min (<0.2% area starting material as obtained from Example 4), the reduction was quenched by addition of 11 mL acetone and stirring was continued for 30 min at room temperature. 190 mL saturated aqueous NH4Cl were added and the mixture was extracted three times with 180 mL, in total with 540 mL dichloromethane. The combined organic phases were dried over 20 g Na2SO4 (30 min) and filtered. The solid was washed with 40 mL dichloromethane. After evaporation of solvent in a rotary evaporator (40° C./10 mbar), the crude product (3.184 g, 99% by weight) was obtained as a yellow oil. Purification was achieved by trituration with 16 mL heptane for 24 h at room temperature and subsequent standing for 4 days at −20° C. After cold filtration and removement of residual solvent in a rotary evaporator (40° C./10 mbar), the title compound (2.827 g, 11.2 mmol, 88% by weight) was obtained as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH:13]=[N:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[OH-].[K+].S(OC)(O[CH3:32])(=O)=O.O>CN(C)C=O>[CH2:24]([O:23][C:21]([C:18]1[CH:19]=[CH:20][C:15]([N:14]([CH3:32])[CH:13]=[N:12][C:9]2[CH:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][CH:10]=2)=[CH:16][CH:17]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)c1ccc(N=CNc2ccc(C(=O)OCC)cc2)cc1
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(N=CN(C)c2ccc(C(=O)OCC)cc2)cc1
Reaction time: 8 h

Procedure:
To a stirred solution of N,N'-bis(4-ethoxycarbonylphenyl)formamidine (6.8 g, 0.02 mol) in 50 ml of dimethylformamide was added 2.0 g of potassium hydroxide and 2 ml (0.02 mole) of dimethyl sulfate. The solution was stirred overnight and heated at 100° for 3 hrs. The reaction mixture was poured into 100 ml of water and the solid which precipated was collected by filtration and dried. The solid was triturated with 150 ml of benzene. The undissolved material was removed by filtration and the filtrate was concentrated to a solid residue. This solid residue was then triturated with 50 ml of chloroform. The remaining solids were removed by filtration. Concentration of the filtrate produced the desired product, mp 89°-91° C. ##STR10##
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:9])=[N:6][C:7]=1[CH3:8].C(N(C(C)C)C(C)C)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][S:20]([CH3:19])(=[O:22])=[O:21])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(N)ccc1Br
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(NS(C)(=O)=O)ccc1Br
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 5-bromo-6-methylpyridin-2-amine (0.3 g, 1.604 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.559 mL, 3.21 mmol) in DCM (10 mL) was added methanesulfonyl chloride (0.137 mL, 1.764 mmol) at 0° C. The reaction mixture was stirred at room temperature for 48 hours and was subsequently concentrated in vacuo to give the title compound.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH:11]=[CH2:12])[C:5]=1[OH:13])[CH:2]=[CH2:3].Cl[C:15]([O:17][CH3:18])=[O:16]>C(N(CC)CC)C>[C:15](=[O:16])([O:17][CH3:18])[O:13][C:5]1[C:4]([CH2:1][CH:2]=[CH2:3])=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:10][CH:11]=[CH2:12]
Reactant: COC(=O)Cl
Reactant: C=CCc1cccc(CC=C)c1O
Solvent: CCN(CC)CC
Product: C=CCc1cccc(CC=C)c1OC(=O)OC

Procedure:
2,6-Diallylphenol (3.48, 0.02 mol) and triethylamine (4 ml) was diluted with 1,2-dichloromethane (50 ml). Methyl chloroformate (2.00 gm, 0.027 mol) was diluted with 1,2-dichloromethane (10 ml) and added drop wise to the phenol-amine solution. After the addition was complete, the reaction was refluxed for 1 hr, cooled and poured onto water. The organic layer was washed with water (2×) dried over MgSO4 and evaporated to give 2,6-diallylphenyl methyl carbonate. MS m/z 232 (M+ calcd for C15H16O3=232). H NMR (300 MHz, CDCl3) d 3.30–3.40 (d, 4. CH2), 3.90 (s, 3, CH3), 5.05–5.20 (m, 4, CH2 vinyl), 5.85–6.00 (m, 2, CH vinyl), 7.10–7.27 (m, 3, aromatic). Oxidation of the product as described in Example 1 gave 2,6-di(2,3-epoxypropyl)phenyl methyl carbonate as an oil. MS m/z 264 (M+ calcd for C14H16O5=264). H NMR (300 MHz, CDCl3) d 2.60–2.70 (m, 2, CH2 epoxypropyl), 2.40–2.90 (m, 6, CH2 epoxypropyl), 3.25–3.40 (m, 2, CH2 epoxypropyl), 3.85 (s, 3, OCH3), 7.30–7.65 (m, 3, aromatic).
Reaction SMILES: [Mg].[F:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[CH:11]1[C:16]([C:17]([CH2:19][CH2:20][CH2:21][Cl:22])=[O:18])=[CH:15][CH:14]=[C:13]([F:23])[CH:12]=1.[NH4+].[Cl-]>CCOCC>[F:23][C:13]1[CH:12]=[CH:11][C:16]([C:17]([OH:18])([CH2:7][C:6]2[CH:9]=[CH:10][C:3]([F:2])=[CH:4][CH:5]=2)[CH2:19][CH2:20][CH2:21][Cl:22])=[CH:15][CH:14]=1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: Fc1ccc(CCl)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: OC(CCCCl)(Cc1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C

Procedure:
A Grignard solution was prepared from 13.8 g (0.575 mol) of magnesium filings and 83.1 g (0.575 mol) of 4-fluorobenzyl chloride in 560 ml of absolute ether. This solution was added dropwise to a solution of 92 g (0.46 mol) of ω-chloro-4-fluorobutyrophenone in 300 ml of absolute ether and the mixture was heated under reflux for 2 hours. It was then poured onto 500 ml of ice, 1 liter of NH4Cl solution was added, the mixture was extracted several times with ether and the organic phases were dried and concentrated.
Reaction SMILES: CCN(CC)CC.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.[CH3:18][C:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:22])[CH2:20][NH2:21]>C(Cl)Cl>[CH3:22][C:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:18])[CH2:20][NH:21][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(CN)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CNC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
4.0 ml (30 mmol) of NEt3 and 4.22 g (30 mmol) of benzoylchloride were added in succession at 0° C. to a solution of 1.86 g (10.0 mmol) of 2-methyl-2-phenylpropylamine hydrochloride in DCM (30 ml) and the mixture was stirred for 1 h at RT. It was then diluted with DCM and washed with a 10% aqueous hydrochloric acid, a saturated aqueous Na2CO3 solution and brine. The organic phase was dried over Na2SO4, filtered and concentrated to small volume under vacuum. 2.48 g (9.8 mmol, 98%) of N-(2-methyl-2-phenylpropyl)benzamide were obtained as the residue, which was reacted further with no additional purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:34]=[CH:33][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([O:31]C)=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].C1COCC1.CO.[OH-].[Na+].Cl>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([OH:31])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:33][CH:34]=1)=[O:11]
Reactant: COC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2)c1
Temperature: 72 °C

Procedure:
To a stirred solution of methyl 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate (1.38 g, 3.00 mmol) in a mixture of solvents THF/MeOH (20 ml/20 ml) was added 2 ml of 5M NaOH (10 mmol) solution. The mixture was heated in a 72° C. bath for 5 hours, cooled to room temperature and poured into 200 ml of water. 2M HCl was added until pH=3. The resulting precipitates were filtered, washed with water, and dried in vacuo to give 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid as light brown solid. Yield: 1.28 g, 96%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:13](=[O:18])(=[O:17])[N:14]([CH3:16])[CH3:15])=[C:6]([CH:12]=1)[CH2:7][NH:8]C(=O)C.Cl>C(O)C>[ClH:1].[NH2:8][CH2:7][C:6]1[CH:12]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[S:13]([N:14]([CH3:16])[CH3:15])(=[O:17])=[O:18]
Reactant: CC(=O)NCc1cc(Cl)ccc1S(=O)(=O)N(C)C
Agent: Cl
Solvent: CCO
Product: CN(C)S(=O)(=O)c1ccc(Cl)cc1CN
Yield: 185.5 %

Procedure:
(Step 2) To a solution of N-[5-chloro-2-(dimethylsulfamoyl)benzyl]acetamide obtained in Step 1 (1.77 g) in ethanol (20 ml) was added 6N hydrochloric acid (20 ml) at room temperature. The mixture was stirred with heating under reflux for 3 hr, and then stirred overnight at 80° C. The solvent was evaporated under reduced pressure. The residue was collected by filtration, and washed with diethyl ether to give 2-(aminomethyl)-4-chloro-N,N-dimethylbenzenesulfonamide hydrochloride (1.61 g) as a white solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([NH:18][CH3:19])[C@H:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:13]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:28]1([C:34]2[O:38][N:37]=[C:36]([C:39]([OH:41])=O)[CH:35]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([N:18]([CH3:19])[C:39]([C:36]3[CH:35]=[C:34]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[O:38][N:37]=3)=[O:41])[C@H:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:13]2)=[O:11])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: O=C(O)c1cc(-c2ccccc2)on1
Reactant: CN[C@@H]1CCN(C(=O)C2CCN(C(C)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Product: CC(=O)N1CCC(C(=O)N2CC[C@@H](N(C)C(=O)c3cc(-c4ccccc4)on3)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1

Procedure:
Using the compound obtained in Example 78 and 5-phenylisoxazole-3-carboxylic acid, and by the reaction and purification in the same manner as in Example 3, the title compound was obtained.
Reaction SMILES: [I-:1].[Na+].CS(O[CH2:8][CH2:9][CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)=O>CC(C)=O>[C:11]1([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][CH2:8][I:1])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)OCCC(c1ccccc1)c1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: ICCC(c1ccccc1)c1ccccc1
Yield: 84.8 %

Procedure:
To a solution of sodium iodide (2.80 g, 18.9 mmol) in acetone (20 mL) was added a solution of 3,3-diphenylpropyl methanesulfonate (5.00 g, 17.2 mmol) in acetone (10 mL) at 0° C. and the mixture was refluxed for 3 hours. After cooling, the solvent was distilled off under reduced pressure and the residue was diluted with water (30 mL) and extracted with 2 portions of ethyl acetate. The pooled extract was washed with saturated aqueous sodium chloride solution, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was crystallized from methanol to provide 4.70 g of the title compound. Yield 85%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:14]([CH3:16])[CH3:15])[C:6]([O:8][CH3:9])=[O:7])#[N:2].[OH-].[Na+].FC(F)(F)C(OC1[C:29]([F:30])=[C:28]([F:31])[C:27]([F:32])=[C:26]([F:33])[C:25]=1[F:34])=O.C(N(CC)CC)C>CO.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:14]([CH3:16])[CH3:15])[C:6]([O:8][C:9]1[C:29]([F:30])=[C:28]([F:31])[C:27]([F:32])=[C:26]([F:33])[C:25]=1[F:34])=[O:7])#[N:2]
Reactant: COC(=O)c1ccc(OC(C)C)c(C#N)c1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: CC(C)Oc1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
20.5 g (0.093 mol) of methyl 3-cyano-4-isopropoxybenzoate 4 was dissolved in 200 mL of a 6:4 mixture of methanol and water. To this was added 5.61 g (0.14 mol) of NaOH and the mixture stirred for 2 hours at room temperature. The solution was then filtered through a silica gel plug and the solvents removed under vacuum. The resulting solid was re-dissolved in 200 mL of CH2Cl2 and treated with 19.3 mL (0.11 mol) of perfluorophenyl 2,2,2-trifluoroacetate 5 and 19.5 mL (0.14 mol) of triethylamine. After stirring overnight, the solution was filtered and any solids rinsed with CH2Cl2. The combined organic fractions were run through a short silica gel column and then evaporated to dryness to give 29 g (83.5% yield) of 6 which was characterized by LCMS and HNMR.