Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:19][CH:18]([CH2:20][NH:21][C:22]4[CH:26]=[CH:25][O:24][N:23]=4)[O:17][N:16]=3)=[CH:11][CH:10]=2)=[CH:5][CH2:4]1.C(N(CC)CC)C.CC1(C)[O:39][C@H:38]([C:40](Cl)=[O:41])[CH2:37][O:36]1>C(#N)C>[OH:39][C@@H:38]([CH2:40][OH:41])[C:37]([N:3]1[CH2:8][CH2:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:19][CH:18]([CH2:20][NH:21][C:22]4[CH:26]=[CH:25][O:24][N:23]=4)[O:17][N:16]=3)=[CH:11][CH:10]=2)=[CH:5][CH2:4]1)=[O:36]
Reactant: C1=C(c2ccc(C3=NOC(CNc4ccon4)C3)cc2)CCNC1
Reactant: CC1(C)OC[C@@H](C(=O)Cl)O1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C([C@@H](O)CO)N1CC=C(c2ccc(C3=NOC(CNc4ccon4)C3)cc2)CC1
Reaction time: 0.5 h
Yield: 30.3 %

Procedure:
(5RS)-3-(4-(1,2,5,6-Tetrahydropyrid-4-yl)phenyl)-5-(3-isoxazolylaminomethyl)-4,5-dihydro-isoxazole dihydrochloride (397 mg, 1 mM) was suspended by stirring in acetonitrile (15 ml) under nitrogen, triethylamine (404 mg, 4 mM) added, and the mixture cooled to 0° C. (4S)-2,2-Dimethyl-1,3-dioxolan-4-ylcarbonyl chloride (328 mg, 2 mM) was added dropwise, stirring continued for 30 minutes at 0° C., then for 18 hours allowing the temperature to rise to ambient. Solvent was evaporated, the residue treated with water (25 ml) and extracted into dichloromethane (4×20 ml). The extracts were washed with brine (25 ml), dried (magnesium sulfate), and evaporated. The residue was dissolved in tetrahydrofuran (40 ml), treated with hydrochloric acid (2N, 2 ml), and stirred 48 hours at ambient temperature. Potassium carbonate (2 g) was added, the mixture stirred 30 minutes and filtered. After removal of solvent, the residue was chromatographed on a 10 g silica Mega Bond Elut® column, eluting with a gradient from 5 to 10% methanol in dichloromethane. Relevant fractions were combined to give the desired product (125 mg). MS (ESP): 413 (MH+) for C21H24N4O5 NMR (CDCl3) δ: 2.54 (br, 2H); 3.18 (dd, 1H); 3.26 (m overlapped by H2O, 2H); 3.47 (dd, 2H); 3.55 (m, 1H); 3.74 (m, 2H); 4.13 (br, 1H); 4.26 (m, 1H); 4.38 (m, 1H); 4.67 (d, 1H); 4.89 (overlapping m, 2H); 5.96 (d, 1H); 6.26 (br, 1H); 6.37 (t, 1H); 7.50 (d, 2H); 7.62 (d, 2H); 8.34 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12]C1)[CH:5]=O.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:5][N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:7]=[CH:8][C:9]=1[N:10]1[CH2:12][CH:13]([CH2:16][N:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:14][CH2:15]1
Reactant: Cc1cc(C=O)ccc1N1CCC(CN2CCCC2)CC1
Reactant: C1CCNC1
Product: Cc1cc(CN2CCCC2)ccc1N1CCC(CN2CCCC2)C1

Procedure:
Prepared from the product of Example 66 and pyrrolidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:29])=[C:6]([C:8]2[C:9]3[CH:19]=[CH:18][C:17](=[O:20])[N:16]([C:21]4[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=4[F:28])[C:10]=3[N:11]=[C:12]([S:14][CH3:15])[N:13]=2)[CH:7]=1.CCN(CC)CC.[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[C:42](Cl)=[O:43]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:27][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]([F:28])[C:21]=1[N:16]1[C:10]2[N:11]=[C:12]([S:14][CH3:15])[N:13]=[C:8]([C:6]3[CH:7]=[C:2]([NH:1][C:42]([C:38]4[S:37][CH:41]=[CH:40][CH:39]=4)=[O:43])[CH:3]=[CH:4][C:5]=3[CH3:29])[C:9]=2[CH:19]=[CH:18][C:17]1=[O:20]
Reactant: CSc1nc(-c2cc(N)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: O=C(Cl)c1cccs1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1nc(-c2cc(NC(=O)c3cccs3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 4-(5-amino-2-methylphenyl)-8-(2,6-difluorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (411.0 mg, 1.0 mmol) in CH2Cl2 (10 mL) at 0° C. was added Et3N (200.0 mg, 2.0 mmol, 2.0 eq), DMAP (5.0 mg, 0.2 mmol, 0.2 eq) and 2-thiophenecarbonyl chloride (292.0 mg, 2.0 mmol, 2.0 eq). After addition the reaction mixture was stirred for about 14 h at ambient temperature. The mixture was concentrated and mixed with H2O (5.0 mL) and EtOAc (20.0 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3×15 mL). The combined organic phases were washed with saturated aq. NaCl solution, dried over Na2SO4, filtered, and concentrated. Purification via a CombiFlash system (hexane:EtOAc; 4:1) then afforded the title compound: LC-MS m/z 521 (M+H)+, 2.57 min (ret time).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]=[O:10])=[C:4]([Cl:11])[N:3]=1.[CH:12]([Mg]Br)=[CH2:13].O.Cl>O1CCCC1>[NH2:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]([CH:9]([OH:10])[CH:12]=[CH2:13])=[C:6]([Cl:8])[N:7]=1
Reactant: C=C[Mg]Br
Reactant: Nc1nc(Cl)c(C=O)c(Cl)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C=CC(O)c1c(Cl)nc(N)nc1Cl
Yield: 49 %

Procedure:
2-Amino-4,6-dichloropyrimidine-5-carbaldehyde (100 g) was suspended in tetrahydrofuran (4000 ml), and a 1 N solution of vinylmagnesium bromide in tetrahydrofuran (2200 g) was added dropwise under ice-cooling. After completion of the dropwise addition, the mixture was stirred under ice-cooling for two hours. Water (2000 ml) was added to the reaction solution, and the solution was made acidic with a 1 N hydrochloric acid solution (2500 ml), followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and filtered, followed by concentration. Methanol was added to the resulting residue, followed by stirring for one hour. The insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-chloroform) to obtain the title compound (50 g, 49%) as a solid.
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N1CCOCC1)C.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1.[F:30][C:31]1[CH:32]=[C:33]([CH2:38][O:39][C:40]2[CH:48]=[CH:47][C:46]([CH:49]=[O:50])=[CH:45][C:41]=2[C:42](O)=[O:43])[CH:34]=[CH:35][C:36]=1[F:37]>CN(C)C=O>[F:30][C:31]1[CH:32]=[C:33]([CH2:38][O:39][C:40]2[CH:48]=[CH:47][C:46]([CH:49]=[O:50])=[CH:45][C:41]=2[C:42]([NH:29][C:25]2[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=2)=[O:43])[CH:34]=[CH:35][C:36]=1[F:37]
Reactant: O=Cc1ccc(OCc2ccc(F)c(F)c2)c(C(=O)O)c1
Reactant: Nc1cccnc1
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccc(F)c(F)c2)c(C(=O)Nc2cccnc2)c1
Temperature: 25 °C

Procedure:
EDC (0.79 g, 4.11 mmol), HOBT (0.84 g, 5.48 mmol), N-ethylmorpholine (0.87 ml, 6.84 mmol) and 3-pyridinamine (0.48 g, 5.13 mmol) were added to a solution of 2-{[(3,4-difluorophenyl)methyl]oxy}-5-formylbenzoic acid (may be prepared as described in Description 101; 1 g, 3.42 mmol) in N,N-dimethylformamide (25 ml), and the mixture was stirred at room temperature. The N,N-dimethylformamide was evaporated under reduced pressure and the residue was diluted with ethyl acetate (100 ml). The organic layer was washed with saturated sodium hydrogencarbonate (2×50 ml) and water (2×50 ml). The organic layer was dried (MgSO4), filtered and evaporated under reduced pressure to yield the title compound as a yellow solid. 1.19 g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([CH2:9]Br)[C:3]=1[O:11][CH3:12].[C-:13]#[N:14].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([CH2:9][C:13]#[N:14])[C:3]=1[O:11][CH3:12]
Reactant: COc1c(Br)cc(Br)cc1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1c(Br)cc(Br)cc1CC#N
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of the product of stage (c) (183 g) in ethanol (150 ml) was heated to reflux. A solution of sodium cyanide (25 g) in hot water (50 ml) was added which maintained gentle refluxing. The mixture was then stirred for 5 minutes, poured into ice water, and the product was filtered off, taken up in dichloromethane, washed with water, dried over magnesium sulphate and filtered. The solvent was removed to give a brown oil which slowly crystallised. Recrystallisation from petroleum ether gave the title product as colourless needles, mp 87°-88° C.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:20])[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21][O:22][CH2:23][CH2:24][N:25]1[CH:29]=[CH:28][C:27]([NH2:30])=[N:26]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:20])[C:8]([NH:30][C:27]2[CH:28]=[CH:29][N:25]([CH2:24][CH2:23][O:22][CH3:21])[N:26]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)[C@H](CC1CCCC1)N1Cc2ccccc2C1=O
Reactant: COCCn1ccc(N)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCn1ccc(NC(=O)[C@H](CC2CCCC2)N2Cc3ccccc3C2=O)n1
Temperature: 25 °C
Yield: 64.1 %

Procedure:
To a solution of (S)-3-cyclopentyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (100 mg, 0.37 mmol) and 1-(2-methoxy-ethyl)-1H-pyrazol-3-ylamine (prepared as in US 20080021032, Example 72, 0.054 g, 0.38 mmol) and benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (Chemimpex, 0.19 g, 0.44 mmol) in methylene chloride (5 mL) was added N,N-diisopropylethylamine (0.19 mL, 1.1 mmol) dropwise and the resulting solution stirred at room temperature over night. The solution was diluted with methylene chloride, washed with a 1 N hydrochloric acid solution (15 mL), a saturated sodium chloride solution (20 mL) dried over magnesium sulfate. The mixture was filtered and evaporated and the resulting material purified via automated flash chromatography (Analogix, SF4-40 g column, 50-70% ethyl acetate/hexanes) to give (S)-3-cyclopentyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide (94 mg, 65%) as an off white solid: [α]29D=−62.6°, (C=0.31, chloroform); HR-ES(+) m/e calcd for C22H28N4O3 [M+Na]+ 419.2053, observed 419.2055; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.01-2.09 (m, 7H), 3.18 (s, 4H), 3.61 (t, J=5.28 Hz, 2H), 4.12 (t, J=5.13 Hz, 2H), 4.38-5.23 (m, 4H), 6.37 (d, J=2.11 Hz, 1H), 7.32-7.84 (m, 7H), 10.84 (s, 1H).
Reaction SMILES: [CH:1]([C@H:3]1[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:2].[CH2:17]([Mg]Br)[CH3:18]>O1CCCC1>[OH:2][CH:1]([C@H:3]1[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:17][CH3:18]
Reactant: CC(C)(C)OC(=O)N1[C@@H](C=O)COC1(C)C
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(O)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
(R)-tert-butyl 4-formyl-2,2-dimethyloxazolidine-3-carboxylate (1.53 g, 6.67 mmol) was purged with nitrogen, and then was diluted with tetrahydrofuran (20 mL) and cooled to 0° C. in a ice-water bath. Ethylmagnesium bromide (3.34 mL, 10.01 mmol) was added slowly over 10 minutes. The reaction was stirred for 1 h in the ice water bath. After stirring 1 h, the reaction was slowly quenched with 30 mL sat. ammonium chloride. This was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed 1× brine, then dried over sodium sulfate, filtered and concentrated to afford crude (4R)-tert-butyl 4-(1-hydroxypropyl)-2,2-dimethyloxazolidine-3-carboxylate as a colorless oil (1.65 g) which was carried on directly in the next step.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:14](=[O:16])[CH3:15])[CH:8]=[C:9]([OH:13])[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].Br[CH2:18][CH2:19][CH2:20][O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1.[H-].[Na+].CC(=O)OCC>CN(C=O)C>[C:1]([C:5]1[CH:6]=[C:7]([C:14](=[O:16])[CH3:15])[CH:8]=[C:9]([O:13][CH2:18][CH2:19][CH2:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(O)cc(C(C)=O)cc1C(C)(C)C
Reactant: BrCCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1c(OCCCOC2CCCCO2)cc(C(C)=O)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 112.3 %

Procedure:
1-(3-tert-Butyl-5-hydroxy-4-methoxyphenyl)ethanone (O3.070; 6.9 g) and 2-(3-bromo-propoxy)tetrahydropyran (8.31 g) were dissolved in DMF (80 ml), and sodium hydride (894 mg) was added. After stirring at RT for 5 hours, the solvent was drawn off and the residue was taken up with EA. The EA phase was washed with water, dried and concentrated. 12.7 g of the title compound were obtained as a crude product in sufficient purity.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:7][C:8](=[O:21])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[CH2:19][CH3:20].[C:22]1(=O)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([NH:1][C@H:2]2[CH2:6][CH2:5][CH2:4][C@H:3]2[NH:7][C:8](=[O:21])[C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:11][C:10]=2[CH2:19][CH3:20])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C1CCCC1
Reactant: CCc1cc(C(F)(F)F)ccc1C(=O)N[C@@H]1CCC[C@@H]1N
Product: CCc1cc(C(F)(F)F)ccc1C(=O)N[C@@H]1CCC[C@@H]1NC1CCCC1

Procedure:
The title compound, white solid, MS: m/e=369.2 [(M+H)+], was prepared in accordance with the general method of example 11 from cis-N-(2-Amino-cyclopentyl)-2-ethyl-4-trifluoromethyl-benzamide (intermediate S) and cyclopentanone.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH:5]([O:23][CH2:24][CH3:25])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)[CH3:2].C(N(CC)CC)C.[CH2:34]([S:41](Cl)(=[O:43])=[O:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.O>ClCCl>[CH2:1]([O:3][C:4](=[O:26])[CH:5]([O:23][CH2:24][CH3:25])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][S:41]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[O:43])=[O:42])=[CH:20][CH:21]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(O)cc2)cc1)OCC
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(OS(=O)(=O)Cc3ccccc3)cc2)cc1)OCC
Temperature: 0 °C
Yield: 71.5 %

Procedure:
2-Ethoxy-3-{4-[2-(4-hydroxyphenyl)ethoxy]phenyl}propanoic acid ethyl ester (described in Example 26b) (0.54 g; 1.5 mmole) was dissolved in dichloromethane (15 ml), triethylamine (0.23 g; 0.31 ml; 2.25 mmole) was added. The solution was cooled to 0° C. and benzylsulfonyl chloride (0.43 g; 2.25 mmole) dissolved in dichloromethane (5 ml) was added. The resulting mixture was allowed to reach room temperature and was stirred over night. Water was added, the organic layer separated and the water phase extracted with dichloromethane. The organic phase was washed with hydrochloric acid (1 M), sodium hydrogen carbonate and brine. After drying with sodium sulfate and evaporation a light yellow oil was obtained. The crude product was purified with flash chromatography on silica. The compound was eluated with heptane:ethyl acetate (9:1 followed by 1:1). Pure fractions were pooled and evaporated yielding 0.55 g (71%) of 2-ethoxy-3-{4-[2-(4-phenylmethanesulfonyloxyphenyl)ethoxy]phenyl}propanoic acid ethyl ester.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[N:15]=[CH:14][C:13]([Br:16])=[CH:12][N:11]=1>CC[O-].[Na+]>[CH2:1]([S:8][C:10]1[N:15]=[CH:14][C:13]([Br:16])=[CH:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCc1ccccc1
Reactant: Clc1ncc(Br)cn1
Agent: CC[O-]
Agent: [Na+]
Product: Brc1cnc(SCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 81 %

Procedure:
Benzyl thiol (22 mmol) was added to 0.146 M ethanolic NaOEt (150 ml) at room temperature followed by 2-chloro-5-bromopyrimidine (20 mmol). The mixture was stirred at room temperature for 70 min, heated under reflux for 40 min, the solvent evaporated off at reduced pressure, the residue extracted with chloroform (100 ml), the chloroform solution washed with 2 M NaOH, and the dried (MgSO4) solution evaporated; yield 81%, m.p. 68°-69° C. (dil. MeOH). 1H NMR (CDCl3): δ4.36 (CH2), 7.26 (Ph), 8.50. (H-4, H-6).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:15]2[N:14]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[N:12]([S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[C:11]=2[CH:10]=[CH:9][CH:8]=1)(=O)=O.[Cl-].[Li+].[CH:36]([Sn](CCCC)(CCCC)CCCC)=[CH2:37]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].O1CCCC1>[CH:36]([C:7]1[C:15]2[N:14]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[N:12]([S:25]([C:28]([F:29])([F:31])[F:30])(=[O:27])=[O:26])[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[CH2:37]
Reactant: O=S(=O)(Oc1cccc2c1nc(COc1ccc(Cl)cc1)n2S(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2S(=O)(=O)C(F)(F)F

Procedure:
To a 250 ml round bottom flask were added 4-trifluoromethanesulfonyloxy-2-[(4-chlorophenoxy)methyl]-1-trifluoromethanesulfonylbenzimidazole (5.00 g, 9.28 mmol), palladium tetrakis(triphenylphosphine) (428 mg, 0.371 mmol), lithium chloride (2.95 g, 69.6 mmol) and vinyltributyltin (2.94 g, 9.28 mmol) to anhydrous tetrahydrofuran. The reaction mixture was heated to reflux and maintained at this temperature overnight. The progress of the reaction was monitored by thin layer chromatography. An additional 428 mg of the palladium catalyst was added and the resulting mixture was refluxed an additional three hours. To the reaction mixture was added cuprous iodide (35.3 mg, 0.02 eq) and the reaction mixture was refluxed overnight. The solvents were removed in vacuo. The residue was redissolved in ethyl acetate (500 ml) and was washed with 1:1 water:28% aqueous ammonium hydroxide (3×). The organic fraction was dried over sodium sulfate. The desired title product was further purified by column chromatography.
Reaction SMILES: [CH:1]([C:4]1[CH:43]=[CH:42][C:7]([O:8][CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][NH:25][C:26]([C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=4)=[CH:30][CH:29]=3)=[O:27])=[CH:18][CH:17]=2)[C:10]([O:12]CC)=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+]>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][NH:25][C:26]([C:28]3[CH:29]=[CH:30][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=4)=[CH:32][CH:33]=3)=[O:27])=[CH:20][CH:21]=2)[C:10]([OH:12])=[O:11])=[CH:42][CH:43]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3cccc(OC)c3)cc2)cc1)Oc1ccc(C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1cccc(-c2ccc(C(=O)NCCOc3ccc(CC(Oc4ccc(C(C)C)cc4)C(=O)O)cc3)cc2)c1
Yield: 46.5 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-(4-isopropylphenoxy)-3-[4-[2-(3′-methoxybiphenyl-4-carbonylamino)ethoxy]phenyl]propionate (700 mg), which is the product of Example 92, was reacted with aqueous sodium hydroxide solution (1N, 3.00 ml) and the reaction mixture was treated to give the title compound (310 mg) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]([F:14])([F:13])[F:12])[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][CH3:16].O([CH2:25][C:26]([F:29])([F:28])[F:27])S(C(F)(F)F)(=O)=O>>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]([F:12])([F:13])[F:14])[N:7]([CH2:25][C:26]([F:29])([F:28])[F:27])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COc1ccc2[nH]c(C(F)(F)F)nc2c1Cl
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Product: COc1ccc2c(nc(C(F)(F)F)n2CC(F)(F)F)c1Cl

Procedure:
Synthesized as described in Example 195D from 4-chloro-5-(methyloxy)-2-(trifluoromethyl)-1H-benzimidazole and trifluoroethyl triflate: MS (ESI) m/z 333 (M+1).
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2)C(=O)C>Cl>[CH3:1][NH:2][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2
Reactant: CC(=O)N(C)c1ccc2c(c1)CCC(=O)N2
Agent: Cl
Product: CNc1ccc2c(c1)CCC(=O)N2
Yield: 77.4 %

Procedure:
To 6-(N-methyl-N-acetylamino)-3,4-dihydrocarbostyril (8 g) is added 20% hydrochloric acid (100 ml), and the mixture is refluxed for 6 hours. After the reaction, the reaction mixture is distilled under reduced pressure, and to the residue is added 1N aqueous sodium hydroxide. The resulting precipitate is separated by filtration, washed with water, dried, and then recrystallized from ethyl acetate to give 6-methylamino-3,4-dihydrocarbostyril (5 g), as colorless prisms, m.p. 164°-167° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].C([Li])CCC.CN(C)CCN(C)C.I[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]I.[Cl-].[NH4+]>O1CCCC1.CCOC(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:2]1=[O:10]
Reactant: O=C1Cc2ccccc2N1
Reactant: ICCCCCI
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1Nc2ccccc2C12CCCCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.8 %

Procedure:
A solution of oxindole (25 g, 0.19 mol) in anhydrous tetrahydrofuran (800 cm3) was cooled to −20° C., then n-butyllithium (2.5M in hexanes, 152 cm3,0.38 mol) was added slowly followed by N,N,N′,N′-tetramethylethylenediamine (51 cm3,0.38 mol,). After 15 min. 1,5-diiodopentane (174 g, 0.54 mol) was added slowly and the mixture was allowed to warm to room temperature. After stirring for 16 h. saturated aqueous ammonium chloride solution (1L) and EtOAc (1L) were added. After 15 min. the layers were separated and the aqueous phase was extracted EtOAc (×2). The combined organic layers were extracted with hydrochloric acid (1N), then washed with brine (500 cm3), dried (MgSO4), and concentrated to obtain an oil. The oil was triturated with hexane (200 cm3) and benzene (20 cm3). The precipitate was collected and dried in vacuo to obtain the subtitled compound (26.3g, 69.6%) as colorless crystals: mp 110-114° C.; 1H NMR (DMSO-d6) δ1.67 (m, 1H), 6.84 (d, 1H, J=8 Hz) 6.94 (t, 1H, J=8 Hz), 7.17 (t, 1H, J=8 Hz), 7.44 (d, 1H, J=8 Hz), 10.3 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([N+:20]([O-])=O)=[C:12]2[S:19][CH2:18][CH2:17][N:13]2[C:14](=[O:16])[CH:15]=1.Cl[Sn]Cl.O.Cl>C(O)C>[NH2:20][C:11]1[C:10]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[CH:15][C:14](=[O:16])[N:13]2[CH2:17][CH2:18][S:19][C:12]=12
Reactant: O=c1cc(Nc2ccc(I)cc2F)c([N+](=O)[O-])c2n1CCS2
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1c(Nc2ccc(I)cc2F)cc(=O)n2c1SCC2
Yield: 109.6 %

Procedure:
Using the same reaction conditions and workup as described for the preparation of Intermediate (I-19f), 7-(2-fluoro-4-iodo-phenylamino)-8-nitro-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (0.08 g, 0.181 mmol) in ethanol (2 mL) was reacted with SnCl2.H2O (0.12 g, 0.541 mmol) and concentrated HCl (0.5 mL) to afford 0.08 g of crude product which was used in the next step without further purification. LCMS: 59%, m/z=403.9 (M+1).