Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C(C)=CC=CC=1.[OH-].[K+].[F:32][C:33](F)=[C:34]([F:39])[C:35]([F:38])([F:37])[F:36]>O1CCCC1.O>[F:32][C:33]([O:14][C:10]1[CH2:9][C:8]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:13]=[CH:12][CH:11]=1)=[C:34]([F:39])[C:35]([F:38])([F:37])[F:36]
Reactant: OC1=CC=CC(Oc2ccccc2)(Oc2ccccc2)C1
Reactant: FC(F)=C(F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1C
Product: FC(OC1=CC=CC(Oc2ccccc2)(Oc2ccccc2)C1)=C(F)C(F)(F)F
Temperature: 25 °C
Yield: 75 %

Procedure:
Five g (0.018 mole) of 3-phenoxy-3-phenoxyphenol, 100 ml of xylene and 1.2 g of KOH are placed into a flask equipped with a Dean-Stark trap. This mixture is stirred at reflux until water of reaction ceases to evolve. The mixture is cooled and 100 ml of tetrahydrofuran (THF) are added and the mixture is further cooled in a dry ice/acetone bath while 15 g of perfluoropropene are bubbled into the reaction mixture. The mixture is stirred for three hours while warming to room temperature. Next, 100 ml of water are added and the mixture is stirred. The product phase is separated, dried over sodium sulfate, filtered and distilled. The product propene is an oil obtained in a yield of 75 percent. The oil has a pour point below -27° C., a boiling point of 150° C. at 1.0 mm Hg and a DSC of 373° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([P:16]([OH:18])[OH:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[C@@H](N)C1C=CC=CC=1>C(O)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([P:16]([OH:17])[OH:18])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(NC(=O)OCc1ccccc1)P(O)O
Agent: CC[C@@H](N)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)P(O)O
Yield: 32.4 %

Procedure:
A solution of 1-(benzyloxycarbonylamino)-2-methylpropylphosphonous acid (3.4 g, 12.5 mmol) in 20 mL of absolute ethanol was heated to reflux and (R)-(+)-methylbenzylamine (96% ee, 1.5 g, 12.5 mmol) was added. The resulting mixture was diluted with 120 mL of ethyl acetate. The precipitate was filtered off, washed with 100 mL of ethyl acetate and 100 mL of ether, dried in vacuo to afford (R)-1-(benzyloxycarbonylamino)-2-methylpropylphosphonous acid as a white solid (1.1 g) with a rotation [α]D=−10.87° (c=10 mg/mL 9:1 DMF-H2O). This material was found to be 93% ee by chiral HPLC.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[C:11]([CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]>O1CCCC1.[Pd]>[CH3:1][C:2]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: Cc1cc(C=Cc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)ccc1OCC(=O)O
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cc(CCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)ccc1OCC(=O)O

Procedure:
A solution of {2-methyl-4-[2-(4′-trifluoromethyl-biphenyl-4-yl)-vinyl]-phenoxy}-acetic acid (0.98 g, 2.4 mmol) in 100 ml of tetrahydrofuran was hydrogenated over 0.16 g of 20% palladium on carbon catalyst. The catalyst was removed by filtration, and the filtrate was evaporated. The crude product was recrystallized from aqueous acetonitrile. mp 174-176° C.; IR (thin film) cm−1: 1747, 1711, 1500, 1318, 1160, 1123; 400 MHz 1H NMR (DMSO-d6) δ 7.83 (d, 2H, J=8.1 Hz), 7.74 (d, 2H, J=8.3 Hz), 7.60 (d, 2H, J=6.5 Hz), 7.32 (d, 2H, J=8.3 Hz), 7.01 (d, 1H, J=2.0 Hz), 6.94 (dd, 1H, J=2.0, 8.3 Hz), 6.66 (d, 1H, J=8.3 Hz), 4.59 (s, 2H), 2.83 (m, 2H), 2.76 (m, 2H), 2.11 (s, 3H); MS m/z 413 (M−1). Anal. Calc'd for C24H21F3O3: C, 69.56; H, 5.11. found: C, 69.28; H, 4.96.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]([OH:9])[C:6]2[CH:10]=[CH:11][S:12][C:5]=2[CH2:4]1)[CH3:2].[Cl:13][C:14]1[CH:15]=[C:16](F)[CH:17]=[CH:18][C:19]=1[Cl:20]>>[ClH:13].[Cl:13][C:14]1[CH:15]=[C:16]([O:9][CH:7]2[CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][C:5]3[S:12][CH:11]=[CH:10][C:6]2=3)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: Fc1ccc(Cl)c(Cl)c1
Reactant: CCN1Cc2sccc2C(O)C1
Product: CCN1Cc2sccc2C(Oc2ccc(Cl)c(Cl)c2)C1
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 7) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](=[O:20])[N:10]([CH2:21][CH2:22][CH2:23]Cl)[N:9]=1.[CH2:34]([CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](=[O:20])[N:10]([CH2:21][CH2:22][CH2:23][N:44]2[CH2:45][CH2:46][CH:41]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:42][CH2:43]2)[N:9]=1
Reactant: O=c1n(CCCCl)nc(CCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1Cc1ccccc1
Reactant: c1ccc(CC2CCNCC2)cc1
Product: O=c1n(CCCN2CCC(Cc3ccccc3)CC2)nc(CCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1Cc1ccccc1

Procedure:
Prepared as for Example 6 using 3-(3,5-bis(tri-fluoromethyl)phenethyl)-4-benzyl-1-(3-chloropropyl)-5-oxo-1,2,4-triazole (Description 2) and 4-benzylpiperidine. MS m/e (CI+) 631 (100%, M+1).
Reaction SMILES: [CH2:1]([O:4][CH:5]([CH3:11])[CH2:6][CH2:7][CH:8]([OH:10])[CH3:9])[CH:2]=[CH2:3].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][O:10][CH:8]([CH2:7][CH2:6][CH:5]([O:4][CH2:1][CH:2]=[CH2:3])[CH3:11])[CH3:9]
Reactant: C=CCOC(C)CCC(C)O
Reactant: BrCCCCBr
Product: C=CCOC(C)CCC(C)OCCCCBr

Procedure:
Using 5-allyloxy-2-hexanol and 1,4-dibromo-butane, the above compound is produced.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[N:12]=[N:11]2)=[CH:6][CH:5]=1)([O-])=O.O.O.[Sn](Cl)Cl>C1COCC1.CCO>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:13]1[N:12]=[N:11][N:10]([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH:14]=1
Reactant: O=[N+]([O-])c1ccc(-n2cc(-c3ccccn3)nn2)cc1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(-n2cc(-c3ccccn3)nn2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 31.4 %

Procedure:
To a stirred solution of 2-[1-(4-nitro-phenyl)-1H-[1,2,3]triazol-4-yl]-pyridine (0.149 g, 0.556 mmol) in 1:1 THF/EtOH (8 mL) is added tin (II) dichloride dihydrate (0.439 g, 1.95 mmol) and the mixture is stirred at room temperature for 22 hours. The solvent is removed in vacuo and 2N NaOH (3 mL) added to the residue. The mixture is stirred for 1 hour, diluted with water and extracted with DCM (3×40 mL). The organic layers are dried over Na2SO4, filtered and evaporated to give a crude product purified by Isolute FlashSilicaII Cartridge chromatography, eluting with 98:2 DCM:MeOH. The fractions containing the title compound are combined and evaporated to afford the desired compound as a yellow solid (41.4 mg, 31%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[N:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([Sn]([N:29]=[N+:30]=[N-:31])(CCCC)CCCC)CCC>O1CCOCC1>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:31][N:30]=[N:29][N:15]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2nnn[nH]2)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 0.513 g of N-Boc 4-cyanopiperidine in 5 mL of dioxane was added 0.71 mL of tri-n-butyl tin azide. The reaction was heated at 100° C. for 4 days and was then evaporated to a viscous oil. The residue was taken up in 5 mL of ether and treated with 10 mL of 2N hydrochloric acid in ether. The reaction was stirred for 1 hour and then the precipitate was filtered, washed well with ether and dried to afford 0.54 g the title compound as a tan solid.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[CH3:33][CH:34]([CH3:65])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56](=[O:63])[C:57]4[CH:62]=[CH:61][CH:60]=[N:59][CH:58]=4)=[CH:51][CH:50]=3)=[CH:45][CH:46]=2)[C:41]1=[O:64])[C:36]([O:38]C)=[O:37]>>[CH3:33][CH:34]([CH3:65])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56](=[O:63])[C:57]4[CH:62]=[CH:61][CH:60]=[N:59][CH:58]=4)=[CH:51][CH:50]=3)=[CH:45][CH:46]=2)[C:41]1=[O:64])[C:36]([OH:38])=[O:37]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4cccnc4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4cccnc4)cc3)cc2C1=O
Yield: 51.63 %

Procedure:
The compound of example 207 was prepared analogous to compound of example 98 by hydrolysis of compound of example 206.
Reaction SMILES: [CH2:1]([C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH:2]=C.I([O-])(=O)(=O)=[O:17].[Na+]>C1COCC1.O.O=[Os](=O)(=O)=O.CC(O)(C)C>[C:10]1([C:4]2([CH2:1][CH:2]=[O:17])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=CCC1(c2ccccc2)CCCCC1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)(C)O
Product: O=CCC1(c2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (1-allylcyclohexyl)benzene (210 mg, 1.048 mmol) in THF (5 mL) were added a solution of sodium periodate (538 mg, 2.52 mmol) in water (5.00 mL) and 0.105 ml of 2.5% OsO4 in t-BuOH. The mixture was stirred at room temperature for 18 hrs. The mixture was extracted with EtOAc and washed with brine. The combined aqueous layers were back extracted with EtOAc and combined. The resulting material was dried over Na2SO4 and evaporated to give an oily residue. 1H NMR (400 MHz, CDCl3) δ ppm 9.36 (2 H, t, J=3.08 Hz), 7.18-7.42 (5 H, m), 2.58 (2 H, d, J=3.30 Hz), 1.34-1.81 (10 H, m).
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])=[O:13].C(OCC)(=O)C.Cl>O1CCCC1.[Zn].O>[Cl:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])([OH:13])[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(F)(F)C(O)(CCl)c1ccc(Cl)cc1Cl
Yield: 52.6 %

Procedure:
In 20 ml of dried tetrahydrofuran was suspended 0.97 g of zinc. To the suspension was dropwise added 3.0 g of ethyl bromodifluoroacetate under reflux. Then, 10 ml of a solution of 2.2 g of 2,2',4'-trichloroacetophenone dissolved in dried tetrahydrofuran was dropwise added under reflux. The resulting mixture was refluxed for 10 minutes. The insolubles were removed by filtration. The solvent was removed by distillation under reduced pressure. To the residue obtained were added 20 ml of ethyl acetate and 20 ml of water. The resulting solution was adjusted to pH 1.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluant: n-hexane/toluene=1/2) to obtain 1.8 g of oily ethyl 4-chloro-3-(2,4-dichlorophenyl)-2,2-difluoro-3-hydroxybutyrate.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:47]2[CH:52]=[CH:51][C:50]([OH:53])=[CH:49][CH:48]=2)[CH2:10][NH:11][C:12]2[N:20]=[C:19]([N:21]3[CH2:25][CH2:24][C@@H:23]([NH:26][C:27](=[O:34])[C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH2:22]3)[N:18]=[C:17]3[C:13]=2[N:14]=[CH:15][N:16]3[C@@H:35]2[CH2:39][C@H:38]([NH:40][C:41](=[O:44])[CH2:42][CH3:43])[C@@H:37]([OH:45])[C@H:36]2[OH:46])=[CH:5][CH:4]=1.[CH3:54][N:55]1[C:59]2C=CC(C([Cl:66])=O)=CC=2N=[N:56]1>>[ClH:66].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:47]2[CH:48]=[CH:49][C:50]([OH:53])=[CH:51][CH:52]=2)[CH2:10][NH:11][C:12]2[N:20]=[C:19]([N:21]3[CH2:25][CH2:24][C@@H:23]([NH:26][C:27]([C:28]4[CH:33]=[CH:32][C:54]5[N:55]([CH3:59])[N:56]=[N:31][C:30]=5[CH:29]=4)=[O:34])[CH2:22]3)[N:18]=[C:17]3[C:13]=2[N:14]=[CH:15][N:16]3[C@@H:35]2[CH2:39][C@H:38]([NH:40][C:41](=[O:44])[CH2:42][CH3:43])[C@@H:37]([OH:45])[C@H:36]2[OH:46])=[CH:5][CH:4]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccc(O)cc4)c4ccc(O)cc4)nc(N4CC[C@@H](NC(=O)c5ccncc5)C4)nc32)[C@H](O)[C@@H]1O
Reactant: Cn1nnc2cc(C(=O)Cl)ccc21
Agent: Cl
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccc(O)cc4)c4ccc(O)cc4)nc(N4CC[C@@H](NC(=O)c5ccc6c(c5)nnn6C)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
This compound is prepared analogously to N-{(R)-1-[6-[2,2-Bis-(4-hydroxy-phenyl)-ethylamino]-9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-9H-purin-2-yl]-pyrrolidin-3-yl}-isonicotinamide hydrochloride (Example 158) by replacing isonicotinoyl chloride hydrochloride with 1-methyl-1H-1,2,3-benzotriazole-5-carbonyl chloride. (MH+ 762.4)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][C:6](=[O:22])[N:7]2[CH3:21].[Br:23][C:24]1[CH:25]=[N:26][CH:27]=[C:28](Br)[CH:29]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:23][C:24]1[CH:29]=[C:28]([C:11]2[C:3]([O:2][CH3:1])=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH3:21])[C:6](=[O:22])[CH2:5]3)[CH:27]=[N:26][CH:25]=1
Reactant: COc1c(B2OC(C)(C)C(C)(C)O2)ccc2c1CC(=O)N2C
Reactant: Brc1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: COc1c(-c2cncc(Br)c2)ccc2c1CC(=O)N2C
Temperature: 120 °C

Procedure:
To 4-methoxy-1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one (80 mg, 0.264 mmol) was added 3,5-dibromopyridine (CAS#625-92-3, 188 mg, 0.792 mmol), 1,2-dimethoxyethane (3.0 mL), and 2 M aqueous sodium carbonate (0.320 mL, 0.63 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.11 mmol/g loading, (144 mg, 0.016 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 120° C. for 2 hours. The reaction mixture was then cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 10 to 75%) to furnish 5-(5-bromo-pyridin-3-yl)-4-methoxy-1-methyl-1,3-dihydro-indol-2-one; HRMS: (ESI) tilt 333.0246 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 3.24 (s, 3H), 3.75 (s, 3H), 3.78 (s, 2H), 4.71 (s, 2H), 6.84 (d, J=8.1 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.94 (d, J=2.0 Hz, 1H), 8.45 (d, J=1.8 Hz, 1H), 8.55 (d, J=2.0 Hz, 1H)
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:23])[O:17][CH2:18][CH2:19][C:20]#[C:21][CH3:22])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:24]([N:23]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH2:19][C:20]#[C:21][CH3:22])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC#CCCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=C(Cl)c1ccccc1
Product: CC#CCCOC(=NC(=O)c1ccccc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 3-pentynyl 5,7-dihydro-6H-dibenz[c,e]-azepine-6-carboximidate and benzoyl chloride, there is obtained 3-pentynyl N-(benzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, mass spectrum m/e: M+ 408 (3), 407 (4), 341 (8), 194 (100), 105 (57);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=O)[CH2:15][N:16]=1)=[CH:8]2.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1>O.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([N:54]3[CH2:59][CH2:58][O:57][CH2:56][CH2:55]3)=[O:20])[CH2:15][N:16]=1)=[CH:8]2
Reactant: C1COCCN1
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)N4CCOCC4)S3)[nH]c12
Temperature: 25 °C
Reaction time: 72 h
Yield: 43.5 %

Procedure:
A mixture of [2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (500 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (330 mg), 1-hydroxybenzotriazole (230 mg), morpholine (190 mg) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 3 days. Water was added to the mixture and the resultant was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:methanol=100:0 to 95:5, volume ratio) to give pale yellow crystals. The crystals were recrystallized from acetone-hexane and then recrystallized from acetone-methanol to give the title compound (250 mg, 43%) as colorless prisms. MS 531 (MH+). mp 148-149° C.
Reaction SMILES: [C:1]([C:6]1[C:18]([CH3:19])=[CH:17][C:9]2[N:10]([CH3:16])[C:11]([CH:13](Cl)Cl)=[N:12][C:8]=2[CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].C([O-])(=[O:22])C.[Na+]>C(O)C>[C:1]([C:6]1[C:18]([CH3:19])=[CH:17][C:9]2[N:10]([CH3:16])[C:11]([CH:13]=[O:22])=[N:12][C:8]=2[CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)[O-]
Reactant: CCCC(=O)c1cc2nc(C(Cl)Cl)n(C)c2cc1C
Agent: [Na+]
Solvent: CCO
Product: CCCC(=O)c1cc2nc(C=O)n(C)c2cc1C

Procedure:
2.0 g of 5-butyryl-2-dichloromethyl-1,6-dimethylbenzimidazole are dissolved in 100 ml of ethanol. 50 ml of a 4 N sodium acetate solution are added and the solution is refluxed for 5 hours. The solution is evaporated to dryness under reduced pressure and recrystallised from ethyl acetate/cyclohexane. 5-butyryl-1,6-dimethylbenzimidazole-2-carboxaldehyde having a melting point of 116°-118° is obtained.
Reaction SMILES: [CH2:1]([Li])CCC.[I-].C[S+](C)(C)=O.[CH2:12]([O:14][C:15]([C:17]1([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4[O:36][N:35]=[C:34]([CH3:37])[C:33]=4[CH:38]=[O:39])=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:19][CH2:18]1)=[O:16])[CH3:13]>CS(C)=O>[CH2:12]([O:14][C:15]([C:17]1([C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4[O:36][N:35]=[C:34]([CH3:37])[C:33]=4[CH:38]4[CH2:1][O:39]4)=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)[CH2:19][CH2:18]1)=[O:16])[CH3:13]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C=O)cc3)cc2)CC1
Reactant: [Li]CCCC
Agent: C[S+](C)(C)=O
Agent: [I-]
Solvent: CS(C)=O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C4CO4)cc3)cc2)CC1
Reaction time: 0.08 h

Procedure:
n-Butyllithium (1.6M in hexanes, 2.30 mL, 3.69 mmol) was placed in a flask along with DMSO (8 mL) and the solution was placed under N2 atmosphere. Trimethyl sulfoxonium iodide (0.963 g, 4.29 mmol) was added and stirred for 5 minutes. 1-[4′-(4-Formyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.46 g, 1.23 mmol) in DMSO (8 mL) was then added and the reaction was stirred. After 40 minutes the reaction was quenched with ice then submitted to standard aqueous workup and purified on silica gel (0-40% EtOAc in hexanes) to afford the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[CH:10]([NH:19][C:20](=[O:22])[CH3:21])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N(C(F)(F)F)S([S:34]([C:37]([F:40])([F:39])[F:38])(=[O:36])=[O:35])(=O)=O)C=CC=CC=1.ClCCl.C(N(CC)CC)C>C(OCC)(=O)C>[CH2:1]([O:8][C:9](=[O:23])[CH:10]([NH:19][C:20](=[O:22])[CH3:21])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][S:34]([C:37]([F:40])([F:39])[F:38])(=[O:36])=[O:35])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(N(c1ccccc1)C(F)(F)F)S(=O)(=O)C(F)(F)F
Reactant: CC(=O)NC(Cc1cccc(O)c1)C(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC(Cc1cccc(OS(=O)(=O)C(F)(F)F)c1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
A solution of 8.30 g (0.026 mol) of rac.-2-acetamido-3-[3-hydroxyphenyl)propanoic acid benzyl ester and 10.0 g (0.028 mol) of N-phenyl-N-trifluoromethyl 1,1,1-trifluoromethyl sulfonyl sulfonamide in 110 mL of freshly distilled dichloromethane was cooled in an ice bath and 4.10 mL (0.029 mol) of triethylamine was added dropwise. The resulting mixture was stirred 1 hour at 0° C. and was allowed to warm to room temperature over 2 hours. The mixture was diluted with 250 mL of ethyl acetate and was washed with successive 50 mL portions of water. 1N sodium hydroxide, 1N hydrochloric acid, water, and brine and was dried over magnesium sulfate. Filtration and concentration afforded an oil which was purified by preparative chromatography on a Waters Prep 500 liquid chromatograph fitted with two Prep-Pak silica gel cartridges, eluting with 40% ethyl acetate-hexane to give 10.02 g (85%) of rac.-2-acetamido-3-[3-[(trifluoromethylsulfonyl)oxy]phenyl]propanoic acid benzyl ester.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([S:8](Cl)(=[O:10])=[O:9])=[C:5]([CH3:7])[N:6]=1.Cl.[NH:13]1[CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C>C(Cl)Cl>[N:13]1([S:8]([C:4]2[S:3][C:2]([Cl:1])=[N:6][C:5]=2[CH3:7])(=[O:10])=[O:9])[CH2:16][CH2:15][CH2:14]1
Reactant: Cc1nc(Cl)sc1S(=O)(=O)Cl
Reactant: C1CNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)sc1S(=O)(=O)N1CCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-chloro-4-methylthiazole-5-sulphonylchloride (462 mg; 2.0 mmol) in DCM (5 mL) was added to an ice-cold solution of azetidine hydrochloride (196 mg; 2.1 mmol) and triethylamine (1.0 mL; 7.2 mmol) in DCM (15 mL) and the mixture stirred at 0° C. for 30 minutes. The DCM was removed in vacuo to give a residue which was partitioned between water (50 mL) and ethyl acetate (75 mL). The organic layer was washed with brine, dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with 10% ethyl acetate in isohexane, to give the desired material as a solid which was crystallised from ethyl acetate and isohexane (100 mg).