Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:3][C:4]([O:6]C(C)(C)C)=[O:5].[SH:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35].FC(F)(F)C(O)=O>C(Cl)Cl>[C:34]([CH2:33][CH2:32][S:31][CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:3][C:4]([OH:6])=[O:5])([O:36][CH3:37])=[O:35]
Reactant: COC(=O)CCS
Reactant: CC(C)(C)OC(=O)CC(O)c1ccccc1CCCCCCCCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CCSC(CC(=O)O)c1ccccc1CCCCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of t-butyl 3-hydroxy-3-[2-(8-phenyloctyl)phenyl]propanoate (4.0 gm, 9.7 mmole) in methylene chloride (40 ml) was stirred under an inert atmosphere at -10° C. To this cold solution was added methyl 3-mercaptopropionate (6.2 ml, 56 mmole) in one portion followed by dropwise addition of trifluoroacetic acid (80 ml). The reaction mixture was then stirred for 5 hours at 0° C. Solvent and excess trifluoroacetic acid were removed on a rotary evaporator. The residue was redissolved in methylene chloride and washed twice with water and once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated. Chromatography on silica gel elutinq with hexane-ethyl acetate-formic acid (85/15/0.5) gave the title compound. Anal.: Calcd. for C27H36O4S: C, 71.17; H, 7.74. Found: C, 70.46; H, 7.72. 250 MHz NMR (CDCl3)δ1.28-1.68 (12H,m) 2.48 (2H,t) 2.56-2.72 (6 H,m) 2.93 (2H,d) 3.66 (3H,s) 4.60 (1H,t) 7.18-7.39 (9H,m).
Reaction SMILES: Br[CH:2](Br)[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]3=[CH:8][CH:9]=2)[N:4]=1.CC[OH:20]>C1COCC1.O.[N+]([O-])([O-])=O.[Ag+]>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]3[CH:13]=[CH:14][CH:15]=[CH:16][C:6]3=2)[CH:11]=[CH:12][C:3]=1[CH:2]=[O:20]
Reactant: CCO
Reactant: BrC(Br)c1ccc2ccc3ccccc3c2n1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc2ccc3ccccc3c2n1

Procedure:
To a mixture of 2-(dibromomethyl)benzo[h]quinoline (52 mg, 0.148 mmol) in EtOH (2 mL) and THF (1 mL) was added a solution of AgNO3 (75 mg, 0.444 mmol) in H2O (1 mL). The mixture was stirred at reflux for 2 h. The solid was filtered off and the organic solvent was removed under reduced pressure. DCM (5 mL) was added and the layers were separated. The aqueous layer was extracted with DCM (5 mL×2). The combined organic layers were washed with brine (2 mL) and dried by anhydrous Na2SO4. The organic layer was concentrated to give benzo[h]quinoline-2-carbaldehyde (30 mg) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:25])=O>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=1)[C:10]([Cl:25])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)C(=O)Cl

Procedure:
(2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,5-difluorophenyl)propanoic acid (I) is dissolved in THF and stirred at 20-250. Oxalyl chloride (1 equivalent) is added and the mixture stirred for about 15 min to give t-butyl-(1S)-2-chloro-1-[3,5-difluorobenzyl]-2-oxoethylcarbamate (XI). The mixture is cooled to <0° and LiCHICl (greater than 2 equivalents) is added. The mixture is stirred until the reaction is complete. The reaction is quenched with water and the product is extracted into ethyl acetate. The combined organic phases are washed with saline, dried over sodium sulfate and concentrated under reduced pressure to give the title compound.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]1(=[O:15])[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH2:9]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[C:8]1(=[O:15])[C:9]2[CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][CH:1]3[O:14][C:10]=2[CH2:11][CH2:12][CH2:13]1
Reactant: O=C1CCCC(=O)C1
Reactant: O=C1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: O=C1CCCC2=C1C1CCCCC1O2

Procedure:
A solution of cyclohexanone (5.28 mL, 50.9 mmol), cyclohexane-1,3-dione (5.89 g, 50.9 mmol), and p-toluenesulfonic acid monohydrate (0.485 g, 2.55 mmol) in xylene (600 mL) was heated at reflux under a Dean Stark trap for 16 hours. The mixture was filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 0-30% ethyl acetate in hexanes to provide the title compound: 1H NMR (CDCl3) δ 1.21-1.31 (m, 2H), 1.43-1.57 (m, 3H), 1.72-1.83 (m, 1H), 1.96-2.08 (m, 4H), 2.33 (t, 2H), 2.41 (t, 2H), 2.96-3.06 (m, 1H), 4.61-4.69 (m, 1H); MS (DCl/NH3) m/z 193 (M+H)30.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[Br:9]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][Br:9])=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Br)cn1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(Br)cn1

Procedure:
A 4.69 g (27 mmol) sample of 5-bromo-2-picoline from step 1 was dissolved in 250 mL of carbon tetrachloride, treated with 4.85 g (27 mmol) of N-bromosuccinimide (NBS) and 400 mg (2.4 mmol) of azobisisobutyronitrile (AIBN), and stirred at reflux for 3 h. Filtration and concentration in vacuo provided crude 5-bromo-2-bromomethylpyridine which was 64% monobrominated by NMR; no purification was attempted: NMR (CDCl3) δ4.50 (s, 2H), 7.34 (d, J=8 Hz, 1H), 7.82 (dd, J=8 and 2 Hz, 1H), 8.63 (d, J=2 Hz, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]([CH3:6])([CH3:5])[CH3:4].C(N(CC)CC)C.ClC(Cl)(O[C:18](=[O:24])OC(Cl)(Cl)Cl)Cl.[Cl-].[F:27][C:28]1[CH:29]=[C:30]([CH:53]=[C:54]([F:56])[CH:55]=1)[CH2:31][NH2+:32][CH2:33][C:34]([NH:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[CH2:42][C@@:41]1([C:49](=[O:50])[NH:48][C:47](=[O:51])[N:46]1[CH3:52])[CH2:40]2)=[O:35]>C(Cl)Cl.CCOC(C)=O>[C:3]([N:2]([CH3:1])[C:18]([N:32]([CH2:31][C:30]1[CH:53]=[C:54]([F:56])[CH:55]=[C:28]([F:27])[CH:29]=1)[CH2:33][C:34]([NH:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[CH2:42][C@@:41]1([C:49](=[O:50])[NH:48][C:47](=[O:51])[N:46]1[CH3:52])[CH2:40]2)=[O:35])=[O:24])([CH3:6])([CH3:5])[CH3:4]
Reactant: CNC(C)(C)C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN1C(=O)NC(=O)[C@@]12Cc1ccc(NC(=O)C[NH2+]Cc3cc(F)cc(F)c3)cc1C2
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(C(=O)N(CC(=O)Nc1ccc2c(c1)C[C@@]1(C2)C(=O)NC(=O)N1C)Cc1cc(F)cc(F)c1)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 88.9 %

Procedure:
To a solution of N,2-dimethylpropan-2-amine (16.0 mg, 0.189 mmol) and triethylamine (19.1 mg, 0.189 mmol) in DCM (1.5 mL), cooled to 0° C., was added triphosgene (19.0 mg, 0.0640 mmol), followed by additional triethylamine (28.7 mg, 0.284 mmol). After 10 minutes of stirring at 0° C., the ice bath was removed and the reaction was allowed to warm to ambient temperature. After 45 minutes at ambient temperature the reaction was cooled to 0° C. prior to the introduction of a chilled (0° C.), DCM (1 mL) solution of triethylamine (19.1 mg, 0.189 mmol) and N-(3,5-difluorobenzyl)-2-{[(4S)-3-methyl-2,5-dioxo-1′,3′-dihydrospiro[imidazolidine-4,2′-inden]-5′-yl]amino}-2-oxoethanaminium chloride (85.0 mg, 0.189 mmol, Intermediate 1). The ice bath was allowed to slowly melt overnight as the reaction warmed to ambient temperature. The reaction was then diluted with EtOAc (50 mL) and then washed with 1M HCl (50 mL, twice), half-saturated brine (50 mL) and saturated brine (50 mL). After drying over sodium sulfate, filtration and concentration in vacuo gave a residue which was applied to a silica gel column for purification, eluting with DCM:MeOH—99:1 to 90:10. The product containing factions were pooled and concentrated in vacuo to give a residue that was not of sufficient purity. This residue was applied to a second silica gel column for purification, eluting with DCM:MeOH—99:1 to 95:5. The product containing factions were pooled and concentrated in vacuo to give 30 mg of the title compound. MS: m/z=550 (M+23(Na+)). HRMS: m/z=528.2428; calculated m/z=528.2417 for C27H32N5O4F2.
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[C:5](I)[S:4][C:3]=1[CH:9]1[O:13]CCO1.C[O:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[C:18]([CH3:25])[CH:17]=1.C[O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[OH:15][C:16]1[CH:21]=[CH:20][C:19]([C:5]2[S:4][C:3]([CH:9]=[O:13])=[C:2]([C:31]3[CH:32]=[CH:33][C:28]([OH:27])=[CH:29][CH:30]=3)[C:6]=2[CH3:7])=[C:18]([CH3:25])[CH:17]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1c(I)sc(C2OCCO2)c1Br
Reactant: COc1ccc(B(O)O)c(C)c1
Product: Cc1cc(O)ccc1-c1sc(C=O)c(-c2ccc(O)cc2)c1C
Yield: 91 %

Procedure:
Starting from 2-(3-bromo-5-iodo-4-methylthien-2-yl)-1,3-dioxolane (2.5 g, 6.7 mmol) and 4-methoxy-2-methylphenylboronic acid (1.2 g, 7.2 mmol) in place of 4-methoxyphenylboronic acid (Step 1), and substituting 4-methoxyphenylboronic acid in place of 3-methoxyphenylboronic acid (Step 2), the title compound (0.50 g, 91%) was synthesized in essentially the same manner as described in Example 1.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[Li].BrC1C(F)=CC=CC=1F.[Li]CCCC>C1COCC1>[CH2:15]([O:14][C:12]([N:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]1[C:24]1[C:23]([F:22])=[CH:28][CH:27]=[CH:26][C:25]=1[F:29])=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc2cnccc2c1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: [Li]c1c(F)cccc1F
Agent: Fc1cccc(F)c1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1C=Cc2ccccc2C1c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of isoquinoline (645 mg; 5 mmol) in THF (20 mL) is treated with benzyl chloroformate (853 mg; 5 mmol) at 0° C., and the mixture stirred at 0° C. for 1 hour. 2,6-Difluorophenyllithium (prepared from 1-bromo-2,6-difluorobenzene (1.37 g; 7.1 mmol) and n-BuLi (2.5M in hexanes, 2.7 mL; 6.8 mmol at -78° C.) are added to this mixture and the resulting solution stirred at 0° C. for 1 hour and then at room temperature for 2 hours. The reaction is quenched with saturated NH4Cl solution, extracted with ether, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash chromatography over silica gel (elution with hexanes/ether 5;1) to give the product as a colorless oil (0.62 g) LC-MS [MH+] 378.2, RT=3.00 min.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])C.[C:35]([C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)(=[O:37])[CH3:36]>>[C:35]([C:38]1[CH:43]=[CH:42][C:41]([C:27]2[CH:26]=[C:25]([C:28]([F:30])([F:31])[F:29])[CH:24]=[CH:23][C:22]=2[O:21][C:16]2[CH:15]=[C:14]([CH:19]=[C:18]([CH3:20])[CH:17]=2)[O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([OH:34])=[O:3])=[C:8]([CH3:33])[CH:9]=2)=[CH:40][CH:39]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Product: CC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2Oc2cc(C)cc(Oc3ccc(CCC(=O)O)c(C)c3)c2)cc1
Yield: 26 %

Procedure:
The compound of 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-methyl-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester is reacted with 4-acetyl phenyl boronic acid as in Example 38 to afford 0.056 g (26%) of the title compound. 1H NMR (400 MHz, CDCl3); HRMS (ES+) m/z exact mass calculated for C32H28O5F3 549.1888, found 549.1888.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:10]3[NH:11][C:12](=[S:15])[NH:13][CH2:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:17].[Na+].I[CH3:20]>C(O)C>[CH3:20][S:15][C:12]1[NH:13][C:14](=[O:17])[N:9]2[N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:16]=[C:10]2[N:11]=1
Reactant: S=C1NCn2nc(-c3ccccc3)cc2N1
Reactant: [OH-]
Reactant: CI
Agent: [Na+]
Solvent: CCO
Product: CSc1nc2cc(-c3ccccc3)nn2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.3 %

Procedure:
7-Phenyl-2-thioxo-2,3-dihydropyrazolo[1,5-a][1,3,5]triazin-4(1H-one (6.4 g, 26.2 mmol) was dissolved in absolute ethanol (150 mL). To this solution was added aqueous sodium hydroxide (2.1 g, 53 mmol in 50 mL of water) and finally iodomethane (1.7 mL, 27.3 mmol) was added dropwise. The resulting solution was stirred at room temperature for 3 hours and then concentrated to a white solid. This solid was suspended in water and the mixture acidified (to pH=1) with concentrated sulfuric acid. The resulting precipitate was collected by filtration, washed with water and dried to give 2-(methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4(3H)-one (5.5 g, 81%) as a white solid. 1H-NMR (DMSO-d6): δ 7.99 (d, 2H), 7.5 (m, 3H), 6.93 (s, 1H), 2.58 (s, 3H); MS m/z 259 (M+1).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5](Cl)=[CH:4]N=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:19]1C[O:22][CH2:21][CH2:20]1>>[CH2:21]([OH:22])[CH3:20].[CH3:2][CH2:7][CH2:6][CH2:5][CH2:4][CH2:19][CH3:20]
Reactant: Nc1ccc(Cl)cn1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CCCCCCC
Product: CCO
Temperature: 1 °C
Yield: 85 %

Procedure:
13.94 g of 2-amino-5-chloropyridine (1.5 equiv.) and 30 g mono ester mono amide (70.85 mmol, 1 equiv.) were dissolved in 240 ml THF. The solution was cooled to 0-2° C. and 212.6 ml 1M LiHMDS solution in THF (3 equiv.) was added over 20 min. After 1.5 h reaction (in process control by HPLC), 245 ml 2M HClaq were added over 15 min keeping the temperature between 0-10° C. (pH of resulting mixture: 3.2). The resulting mixture was extracted twice with 350 ml ethyl acetate. The organic phases were washed sequentially with 200 ml half saturated NaClaq, combined, dried over Na2SO4, filtered and concentrated under reduced pressure to give crude product which was then purified by crystallized from a 1:2 ethanol/heptane mixture (85% yield).
Reaction SMILES: [Na+].[S:2]([O-:17])([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][S:13]([O-:16])(=[O:15])=[S:14])(=[O:4])=[S:3].[Na+].Cl.[C:20]1([NH:26][C:27](=[NH:35])[NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[C:6]1([N+:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:27]([NH2:35])[NH2:28])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:6]1([N+:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[C:27]([NH2:26])[NH2:35])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[S:2]([O-:17])([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][S:13]([O-:16])(=[O:15])=[S:14])(=[O:4])=[S:3]
Reactant: N=C(Nc1ccccc1)Nc1ccccc1
Agent: Cl
Agent: O=S([O-])(=S)OCCCCCCOS(=O)([O-])=S
Agent: [Na+]
Solvent: O
Product: NC(N)=[N+](c1ccccc1)c1ccccc1

Procedure:
A solution of hexamethylene bis (thiosulphate) sodium salt (100 g. 0.282 mol) in 500 ml of water at 70° C. was added slowly to a stirred solution of 133 g (0.568 mol) of diphenylguanidine hydrochloride in 700 ml water. The mixture was cooled and the solid which separated was collected. Recrystallisation from a mixture of equal parts by volume of methanol and toluene gave 154 g (77.1%) of hexamethylene bis (thiosulphate) bis (diphenylguanidinium) salt, m.p. 151°-153° C.
Reaction SMILES: [CH2:1]([C:3]1[S:29][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][C:15]=3[F:28])[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([F:42])[CH:35]=1)=[O:33].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:3]1[S:29][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][C:15]=3[F:28])[C:8](=[O:12])[N:9]([CH2:31][C:32]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([F:42])[CH:35]=3)=[O:33])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: COc1ccc(C(=O)CBr)cc1F
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3F)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)c(F)c3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3F)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.8 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile (1 g), 2-bromo-1-(3-fluoro-4-methoxyphenyl)ethanone (0.67 g) and N,N-dimethylformamide (10 mL) was added 60% sodium hydride (0.15 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (0.9 g, 64%).
Reaction SMILES: C([O:3][C:4](=[O:18])[CH:5]([O:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=1)[O:6][CH2:7][CH3:8])C.[OH-].[K+].O.Cl>C(O)C>[Cl:16][C:14]1[CH:15]=[C:10]([CH:11]=[C:12]([Cl:17])[CH:13]=1)[O:9][CH:5]([O:6][CH2:7][CH3:8])[C:4]([OH:18])=[O:3]
Reactant: CCOC(=O)C(OCC)Oc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(Oc1cc(Cl)cc(Cl)c1)C(=O)O
Temperature: 45 °C
Yield: 62.1 %

Procedure:
A solution of 50.0 g (0.17 mole) of the ethyl-2-(3,5-dichlorophenoxy)-2-ethoxyacetate in 50 ml ethanol was added slowly to a solution of 13.2 g (0.20 mole) 85% KOH in 150 ml 2B ethanol. The mixture was heated at 45° C for one-half hour, then cooled to room temperature and poured into 300 ml H2O. The pH of the resulting mixture was adjusted to 2 with dilute HCl. An oil separated which was removed by two 150 ml extractions with chloroform. The chloroform extracts were combined, washed with three 150 ml portions of water, and dried over magnesium sulfate. Removal of the solvent in vacuum left 41.7 g of a solid which was recrystallized from hexane to give 28.0 g 2-(3,5-dichlorophenoxy)-2-ethoxyacetic acid, m.p. 83.5°-86.5° C, characterized by infrared spectroscopy.
Reaction SMILES: CN(C=O)C.[CH:6]1([C:9]([NH:11][C:12]2[N:29]=[C:15]3[CH:16]=[CH:17][CH:18]=[C:19]([C:20]4[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=4)[N:14]3[N:13]=2)=[O:10])[CH2:8][CH2:7]1.C(Cl)(=O)C([Cl:33])=O>C(Cl)Cl>[CH:6]1([C:9]([NH:11][C:12]2[N:29]=[C:15]3[CH:16]=[CH:17][CH:18]=[C:19]([C:20]4[CH:28]=[CH:27][C:23]([C:24]([Cl:33])=[O:25])=[CH:22][CH:21]=4)[N:14]3[N:13]=2)=[O:10])[CH2:8][CH2:7]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(-c2cccc3nc(NC(=O)C4CC4)nn23)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(-c2cccc3nc(NC(=O)C4CC4)nn23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2 Drops of DMF are added to a solution of 4-[2-(cyclopropanecarbonyl-amino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl]-benzoic acid (1 eq) obtained by Method A using 4-carboxyphenylboronic acid in DCM under N2 atmosphere. Then oxalyl chloride (2 eq) is added dropwise to this resulting solution (gas release). The mixture is stirred at room temperature for 2 hours. After completion of the reaction by LCMS, the solvent is removed. The crude acid chloride is used without further purification in next step.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1[C:25](=[O:26])[CH2:24]CC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:49][CH:50]2[CH2:54][CH2:53][CH2:52][CH2:51]2)[C:40]([NH:42][C:43]2[CH:47]=[CH:46][N:45]([CH3:48])[N:44]=2)=[O:41])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].N1C(C)=CC=CC=1C.C(OCC)(=[O:65])C>C(Cl)Cl>[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:49][CH:50]2[CH2:51][CH2:52][CH2:53][CH2:54]2)[C:40]([NH:42][C:43]2[CH:47]=[CH:46][N:45]([CH2:48][C@H:25]([OH:26])[CH2:24][OH:65])[N:44]=2)=[O:41])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36]
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(C)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(C[C@H](O)CO)n2)cc1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 23 %

Procedure:
Triphenylphosphine (202 mg, 0.77 mmol) was dissolved in methylene chloride (3 mL) and cooled to 0° C. To this solution was added N-bromosuccinimide (156 mg, 0.88 mmol) and was stirred at 0° C. until it was completely dissolved and became light purple in color. The 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 171 mg, 0.52 mmol) was then added and it was stirred at 0° C. for 15 min and then warmed to 25° C. and stirred for 30 min. The reaction was chilled to 0° C. and the combined solution of 3-(3-amino-pyrazol-1-yl)-propane-(S)-1,2-diol (81 mg, 0.52 mmol) and 2,6-lutidine (180 μL, 1.55 mmol) in methylene chloride (4 mL) was added. The mixture was continued to stir at 0° C. for 30 min and then at 25° C. for 3 h. The reaction was diluted with ethyl acetate (50 mL), washed with water (3×20 mL) and saturated aqueous brine solution (2×20 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 15% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-((S)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-propionamide (56 mg, 23%) as a pale pink powder: ESI-LRMS m/e calcd for C21H28ClN3O5S [M+] 469.1, found 470.1 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.05-1.20 (m, 2H, CH2), 1.32-1.91 (m, 8H, 4×CH2), 2.10-2.33 (m, 1H, CH), 3.24 (s, 3H, SO2CH3), 3.34 (dd, J=11.5, 5.3 Hz, 1H, CH of OCH2), 3.43 (dd, J=11.5, 3.2 Hz, 1H, CH of OCH2), 3.48-3.99 (br.s., 2H, 2×OH), 3.68 (t, J=7.5 Hz, 1H, CH), 3.81-3.97 (m, 3H, OCH and NCH2), 6.57 (d, J=2.2, 1H, Ar), 7.22 (d, J=2.2, 1H, Ar), 7.46 (dd, Jo=8.2, Jm=1.4 Hz. 1H, Ar), 7.59 (d, Jm=1.4 Hz, 1H, Ar), 8.00 (d, Jo=8.2, 1 H, Ar), 9.12 (s, 1H, NH).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH:2]([C:7]2[CH:12]=[CH:11][C:10]([S:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])=[CH:24][CH:23]=1
Reactant: COC(=O)C(Br)c1ccc(Sc2ccc(Cl)cc2)cc1
Reactant: Oc1ccc(Cl)cc1
Product: COC(=O)C(Oc1ccc(Cl)cc1)c1ccc(Sc2ccc(Cl)cc2)cc1
Yield: 62 %

Procedure:
In a manner similar to Example 16, 7.43 g of methyl α-bromo-α-[p-(p-chlorophenylthio)phenyl]acetate was reacted with 3.21 g of p-chlorophenol. Ether workup, chromatography and recrystallization from 150 ml of hexane:chloroform (15:1) yielded 5.2 g of a white solid, mp 90.5°-94.5° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[S:4][CH:5]=[C:6]([CH:8]=[O:9])[N:7]=1.[CH3:12][Mg]Br>CCCCCC.C(OCC)(=O)C>[F:11][C:2]([F:1])([F:10])[C:3]1[S:4][CH:5]=[C:6]([CH:8]([OH:9])[CH3:12])[N:7]=1
Reactant: O=Cc1csc(C(F)(F)F)n1
Reactant: C[Mg]Br
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(O)c1csc(C(F)(F)F)n1

Procedure:
Using the procedure of Example 1, 2-trifluoromethyl-4-thiazolecarboxaldehyde and methyl magnesium bromide were reacted to obtain the desired product with a Rf=0.17 [hexane-ethyl acetate (7-3)].