Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=[O:17])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][CH3:16])[CH:9]=1)([CH3:7])[CH3:6].[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1.CCN(CC)CC>C(Cl)Cl>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]([CH3:7])([CH3:6])[C:4](=[O:17])[CH2:3][NH:2][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)=[S:27])=[CH:9][C:10]=1[O:15][CH3:16]
Reactant: Fc1ccc(N=C=S)cc1
Reactant: COc1cc(C(C)(C)C(=O)CN)ccc1F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(C)(C)C(=O)CNC(=S)Nc2ccc(F)cc2)ccc1F
Temperature: 25 °C
Yield: 88.1 %

Procedure:
To a mixture of 1-amino-3-(4-fluoro-3-methoxyphenyl)-3-methylbutan-2-one hydrochloride (35.4 g, 0.135 mol) and 4-fluorophenyl isothiocyanate (21.75 g, 0.142 mol) in DCM (500 mL) was added Et3N (37.6 ml, 0.27 mol) at 0° C., and the reaction mixture was warm to room temperature over 1 h. The reaction mixture was washed with 1N HCl (500 mL), satd NaHCO3 (500 mL) and brine (500 mL) successively, dried over MgSO4, filtered and concentrated under reduced pressure give a residue, which was triturated with Hex-EtOAc to afford 1-(3-(4-fluoro-3-methoxyphenyl)-3-methyl-2-oxobutyl)-3-(4-fluorophenyl)thiourea (45 g, 88%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.85 (b, 1H), 7.25 (m, 2H), 7.15 (m, 2H), 7.05 (m, 1H), 6.79 (m, 2H), 6.67 (b, 1H), 3.88 (s, 3H), 1.54 (s, 6H).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH:11]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]4[O:22][CH2:23][O:24][C:18]=4[CH:17]=3)[C:12](O)=O)=[CH:4][C:3]=2[O:2]1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N([OH:49])N=NC=2C=1.[CH3:50][NH:51][C@@:52]([CH3:66])([C:63]([OH:65])=[O:64])[CH2:53][C:54]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[NH:56][CH:55]=1>CN(C=O)C.CCOC(C)=O>[CH3:12][C:11]([CH2:10][C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1)([CH2:15][C:16]1[CH:21]=[CH:20][C:19]2[O:22][CH2:23][O:24][C:18]=2[CH:17]=1)[C:50]([NH:51][C@@:52]([CH3:66])([C:63]([OH:65])=[O:64])[CH2:53][C:54]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[NH:56][CH:55]=1)=[O:49]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)C(Cc1ccc2c(c1)OCO2)Cc1ccc2c(c1)OCO2
Reactant: CN[C@](C)(Cc1c[nH]c2ccccc12)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(Cc1ccc2c(c1)OCO2)(Cc1ccc2c(c1)OCO2)C(=O)N[C@](C)(Cc1c[nH]c2ccccc12)C(=O)O
Reaction time: 72 h
Yield: 47.9 %

Procedure:
A solution of 1.0 g (3.0 mmol) of bis-(3,4-methylenedioxyphenylmethyl)acetic acid in 20 mL DMF was treated with 0.68 g (3.3 mmol) of DCC and 0.45 g (3.3 mmol) of HOBt. A solution of 0.73 g (3.15 mmol) of methyl α-methyl-D-tryptophan in 20 mL EtOAc was then added and the solution left stirring for 3 days. The mixture was filtered and the solvent removed under reduced pressure. The residue was taken up in EtOAc and washed with 1N HCl, then saturated NaCl. Drying over MgSO4 and removal of the solvent under reduced pressure left the crude product. Chromatography on silica gel, eluting with a gradient of 10% EtOAc in hexane to 50% EtOAc in hexane gave 0.78 g (48.8% yield) of the product as a white foam. The structure was confirmed by NMR spectroscopy.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:21]=[CH:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=O)[C:11]=2[CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:23]12[CH2:32]C3C[CH:29]([CH2:31][CH:25]([CH2:26]3)[C:24]1=O)[CH2:30]2.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(N([CH2:45][CH3:46])CC)C>C1COCC1>[Si:1]([O:8][C:9]1[CH:21]=[CH:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[C:26]3[CH:25]4[CH2:24][CH:23]5[CH2:30][CH:29]([CH2:45][CH:46]3[CH2:32]5)[CH2:31]4)[C:11]=2[CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)C(=O)c1ccccc1-2
Reactant: CCN(CC)CC
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)C(=C1C3CC4CC(C3)CC1C4)c1ccccc1-2

Procedure:
A solution of 2-tert-butyldimethylsilyloxy-9H-fluoren-9-one (0.689 g, 2.2 mmol) and adamantanone (0.66 g, 4.4 mmol) in 30 mL of dry THF was added dropwise over a period of 7 h to a refluxing mixture of TiCl3 (6.8 g, 44 mmol), LAH (0.8 g, 21 mmol) and triethylamine (3 mL) in 80 mL of dry THF. The reaction was refluxed for an additional 12 h. The alkene was then isolated and purified as described above for 1a to give 0.65 g (68%) of 3b: mp 102°-105° C.; 1H NMR (CDCl3) delta 7.832-6.785 (m, 7H), 4.038 (s, 1H), 3.972 (s, 1H), 2.095-1.990 (m, 12H), 1.006 (s, 9H), 0.225 (s, 6H); 13C NMR (CDCl3) delta 159.91, 155.06, 140.64, 139.89, 139.13, 133.61, 126.29, 125.65, 124.31, 119.87, 118.71, 118.43, 116.35, 39.49, 39.40, 36.90, 35.99, 35.90, 27.83, 25.81, 25.73, 18.35, -4.33. ##STR33##
Reaction SMILES: II.[CH:3]1(Br)[CH2:5][CH2:4]1.[C:7]([O-:11])(=[O:10])[CH:8]=[O:9].[CH2:12]1COC[CH2:13]1>>[OH:9][CH:8]([CH:3]1[CH2:4][CH2:5]1)[C:7]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: C1CCOC1
Reactant: BrC1CC1
Reactant: O=CC(=O)[O-]
Agent: II
Product: CCOC(=O)C(O)C1CC1
Temperature: -20 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
A flame dried two-neck round bottom flask fitted with a reflux condenser and N2 outlet was charged with anhydrous THF, freshly activated Mg (120 mg, 4.95 mmol) and a catalytic amount of iodine. A small portion of cyclopropyl bromide dissolved in THF was added. After initiation of reflux, the reaction mixture was cooled to −20° C. and the remaining cyclopropyl bromide (500 mg, 4.13 mmol) was gradually added. After 30 min a freshly distilled solution of glyoxylate 45 (549 mg, 5.37 mmol) in THF was added over a 10 min period and the resulting solution was stirred at −20° C. for 2 h before being quenched with a small amount of water. After 10 min the reaction mixture was further diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic extracts were combined, dried over anhydrous MgSO4, filtered, concentrated in vacuo and purified by column chromatography eluting with ethyl acetate/n-hexane (a gradient of 10-20%) to furnish ethyl α-hydroxycyclopropaneacetate (422 mg, 71%) as a viscous oil. The oil (350 mg, 2.43 mmol) was dissolved in anhydrous DCM and cooled to 0° C. Then Ph3P (2.04 gm, 7.78 mmol) was added followed by CBr4 (1.20 gm, 3.64 mmol). The reaction mixture was stirred at 0° C. for 2 h and then concentrated in vacuo. The Ph3PO was precipitated by addition of n-hexane and removed by filtration. The crude reaction mixture was purified by flash column chromatography to furnish ethyl α-bromocyclopropaneacetate (46, R=c-Pr): (311 mg, 62% yield).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[O:11]1[C:15]2([CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1.F[C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[N+:30]([O-:32])=[O:31]>C1COCC1>[F:29][C:27]1[CH:26]=[CH:25][C:24]([N+:30]([O-:32])=[O:31])=[C:23]([CH:28]=1)[O:21][CH:18]1[CH2:19][CH2:20][C:15]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:16][CH2:17]1
Reactant: OC1CCC2(CC1)OCCO2
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1OC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
63 ml LiHMDS (1 M in THF) were added dropwise to a stirred solution of 10 g 1,4-dioxa-spiro[4.5]decan-8-ol in THF (60 ml) at 0° C. and the reaction stirred for 30 min. A solution of 2,4-difluor-1-nitro-benzene in THF (20 ml) was than added over 5 min and the reaction warmed to rt and stirred for 16 h. The reaction was quenched with sat. ammonium chloride solution and adjusted to pH 7 with 2N HCl. The solvent was removed under vacuum and the residue portioned between EtOAc (200 ml) and water (100 ml). The organic layer was separated and the aqueous phase washed with EtOAc (2×50 ml). The combined organic phases were washed with brine (50 ml) and separated. The organic phase was evaporated to give a solid that was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][O:10][CH3:11])[CH:6]=[C:5]([O:12][CH3:13])[C:4]=1[C:14]1[N:19]2[N:20]=[C:21]([CH2:31][O:32][CH3:33])[C:22]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[C:18]2[CH:17]=[CH:16][CH:15]=1.[H-].[Na+].Br[CH2:37][CH:38]1[CH2:40][CH2:39]1.O>CN(C)C=O.C(OCC)(=O)C>[CH:38]1([CH2:37][N:23]([C:22]2[C:21]([CH2:31][O:32][CH3:33])=[N:20][N:19]3[C:14]([C:4]4[C:5]([O:12][CH3:13])=[CH:6][C:7]([CH2:9][O:10][CH3:11])=[CH:8][C:3]=4[O:2][CH3:1])=[CH:15][CH:16]=[CH:17][C:18]=23)[C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])[CH2:40][CH2:39]1
Reactant: BrCC1CC1
Reactant: COCc1cc(OC)c(-c2cccc3c(NC(=O)OC(C)(C)C)c(COC)nn23)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COCc1cc(OC)c(-c2cccc3c(N(CC4CC4)C(=O)OC(C)(C)C)c(COC)nn23)c(OC)c1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl N-[7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-(methoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]carbamate (170 mg) dissolved in N,N-dimethylformamide (4 mL) was added sodium hydride (60% in oil; 22 mg) and (bromomethyl)cyclopropane (0.043 mL), and the reaction mixture was stirred for 30 minutes at 40° C. Water was added to the obtained reaction mixture, extraction was performed with ethyl acetate and the organic extract was washed with brine. The obtained organic extract was dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure to afford a crude product of tert-butyl N-cyclopropylmethyl-N-[7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-(methoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]carbamate.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH:20](OC(=S)C)[C:21]([O:23]C)=O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.O.O.O.O.O.O.O.O.O.O.[S:49]([O-])([O-])(=O)=O.[Na+].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>ClCCl.CC(C)=O>[Si:1]([O:18][CH2:19][CH:20]([SH:49])[CH2:21][OH:23])([C:14]([CH3:16])([CH3:15])[CH3:17])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=S(=O)([O-])[O-]
Reactant: COC(=O)C(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)OC(C)=S
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](OCC(S)CO)(c1ccccc1)c1ccccc1
Temperature: -50 °C
Reaction time: 1.5 h
Yield: 35.6 %

Procedure:
To a solution of methyl 3-t-butyldiphenylsilyloxy-2-thioacetoxypropionate (example 40) (14.3 g, 34.4 mmol) in dichloromethane (1.0 L) was added diisobutylaluminium hydride (96 mL of 1.5 M solution in toluene, 144 mmol, 4.2 eq) at −78° C. The solution was stirred at −78° C. for 1 hr and at −50° C. for another 1.5 hr. Sodium sulfate decahydrate (15 g) was added and the mixture was warmed at room temperature for 2 hr. Acetone was added and the solution was stirred overnight. Anhydrous sodium sulfate was added and the solution was stirred for 30 min and filtered over CELITE diatomeceous earth. The solid was washed several times with acetone and the solvents were evaporated under reduced pressure. The crude material was purified by flash chromatography with a mixture of hexane and ethyl acetate (85:15) to give the desired compound (4.25 g) in 36% yield.
Reaction SMILES: [Br-].[Li+].[F:3][C:4]([F:16])([C:9]1([C:12]([F:15])([F:14])[F:13])[CH2:11][O:10]1)[C:5]([F:8])([F:7])[F:6].[C:17](=[O:19])=[O:18]>CN1CCCC1=O>[C:17]1(=[O:18])[O:10][CH2:11][C:9]([C:12]([F:15])([F:14])[F:13])([C:4]([F:16])([F:3])[C:5]([F:8])([F:7])[F:6])[O:19]1
Reactant: O=C=O
Reactant: FC(F)(F)C(F)(F)C1(C(F)(F)F)CO1
Agent: [Br-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Product: O=C1OCC(C(F)(F)F)(C(F)(F)C(F)(F)F)O1
Temperature: 100 °C
Yield: 72 %

Procedure:
73 mL N-methylpyrrolidone (NMP) was introduced into a 500-mL autoclave; 1.5 g (17 mmol) lithium bromide and 132 g (575 mmol) 2-pentafluoroethyl-2-trifluoromethyloxirane were charged; and the interior of the system was replaced with CO2 5 times. The reaction solution was heated to 100° C. and pressurization with CO2 at 0.8 MPa was performed until the starting epoxide had disappeared. After the reaction was finished, the reaction solution was returned to room temperature; quenching was performed with 300 mL 1 N aqueous hydrochloric acid; separation was carried out and the organic layer was dried over magnesium sulfate; and suction filtration was performed. The filtrate was subjected to rectification under reduced pressure using a 10-stage Oldershaw column to obtain 113 g (isolated yield=72%, purity=99.7%) 1-trifluoromethyl-1-pentafluoroethylethylene carbonate (=4-pentafluoroethyl-4-trifluoromethyl-1,3-dioxolan-2-one). Molecular Sieve 3A (Wako Pure Chemical Industries, Ltd.) was then introduced and the water content was reduced to 30 ppm.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:11].II.[Br:15]Br>C(Cl)(Cl)(Cl)Cl.[Fe]>[Br:15][C:8]1[CH:9]=[CH:10][C:5]2[O:4][C:3](=[O:11])[C:2]([CH3:12])([CH3:1])[C:6]=2[CH:7]=1
Reactant: CC1(C)C(=O)Oc2ccccc21
Reactant: BrBr
Agent: [Fe]
Agent: II
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)C(=O)Oc2ccc(Br)cc21

Procedure:
2,3-Dihydro-3,3-dimethylbenzofuran-2-one (1.62 g, 0.01 mole), in carbon tetrachloride (25 ml) containing catalytic amounts of iron filings and iodine was treated with bromine (1.6 g, 0.01 mole) and the mixture boiled under reflux for 1 hour. The solvent was removed under vacuum and the residue taken up in petroleum ether (b.p. 60°-80° C.). The solution was decanted from a little insoluble residue and washed with aqueous sodium metabisulphite and water, dried over magnesium sulphate and run down. The title product was obtained as a white solid m.p. 49°-53° C. and was shown by NMR to be a slightly impure sample of the product obtained in Example 3(b).
Reaction SMILES: C([Si]([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=1)(C)C)(C)(C)C.C([Li])(CC)C.CN(C)[CH:24]=[O:25].Cl>O1CCCC1.O.CCOCC>[Cl:16][C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[C:13]([Cl:15])[C:12]=1[CH:24]=[O:25]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Cl)cc(Cl)c1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: O=Cc1c(Cl)cc(O)cc1Cl
Temperature: -68 °C

Procedure:
Dissolve tert-butyl-(3,5-dichloro-phenoxy)-dimethyl-silane (425 g, 1.5 mol) in 4 L dry tetrahydrofuran and cool to −68° C. Slowly add 1.1 equivalents of sec-butyl lithium (103.1 g, 1.61 mol) at −68° C. (˜1.75 hr). After addition is complete, stir the reaction at −70° C. for 30 min. Add dimethylformamide (168.5 g, 2.3 mol) and stir the reaction at −70° C. for 1 hr. Add 1 M hydrochloric acid in water (3.5 L) and allow the reaction to warm to room temperature. Pour the reaction mixture into ether (5 L), wash with water then brine. Dry over sodium sulfate and concentrate under vacuum to an orange solid. Triturate with cold dichloromethane and filter to recover 250 g (80%) pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[C:9]([C@@H:11]3[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]3)=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C@@H:30]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31][C:32](O)=[O:33])=[CH:25][CH:24]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C@@H:30]([NH:35][C:36](=[O:37])[O:38][C:39]([CH3:41])([CH3:40])[CH3:42])[CH2:31][C:32]([N:13]2[CH2:14][CH2:15][CH2:16][C@@H:11]([C:9]3[N:8]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[C:7]4[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=4[N:10]=3)[CH2:12]2)=[O:33])=[CH:25][CH:24]=1
Reactant: COCCCn1c([C@@H]2CCCNC2)nc2cccc(Cl)c21
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc(Br)cc3)NC(=O)OC(C)(C)C)C2)nc2cccc(Cl)c21

Procedure:
((R)-7-Chloro-1-(3-methoxypropyl)-2-(piperidin-3-yl)-1H-benzo[d]imidazole (30E) (0.111 mmol, crude oil) prepared according to the procedure described in Example 30, Steps A-E was added to a 15 mL round-bottomed flask equipped for stirring under nitrogen. DMF (2 mL), (R)-4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoic acid (0.122 mmol, 0.032 g) and N-methylmorpholine (0.555 mmol, 0.061 mL) were then added and the solution was allowed to stir at rt for 5 min. HATU (0.122 mmol, 0.046 g) was added and the resultant solution was stirred at room temperature for 3 hrs. The reaction solution was then directly purified by preparative LC/MS (20-85% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording tert-butyl (R)-1-(4-bromophenyl)-4-((R)-3-(7-chloro-1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutan-2-ylcarbamate (31A) as a clear oil that was used directly onto the next step. EST-MS: m/z 647.3 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[C:18]([CH3:19])=[C:17]([C:20](O)=[O:21])[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[C:5]([O:23][CH:24]([CH2:27][F:28])[CH2:25][F:26])[CH:4]=1)#[N:2].CN(C(ON1N=N[C:39]2[CH:40]=[CH:41][CH:42]=[N:43][C:38]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C[N:54](C)[CH2:55][CH2:56]CN>CN(C=O)C.O>[N:43]1([CH2:38][CH2:56][CH2:55][NH:54][C:20]([C:17]2[S:16][C:12]3[N:13]=[CH:14][N:15]=[C:10]([NH:9][C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=4[O:23][CH:24]([CH2:27][F:28])[CH2:25][F:26])[C:11]=3[C:18]=2[CH3:19])=[O:21])[CH2:39][CH2:40][CH2:41][CH2:42]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(C#N)cc3OC(CF)CF)c12
Reactant: CN(C)CCCN
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)NCCCN2CCCC2)sc2ncnc(Nc3ccc(C#N)cc3OC(CF)CF)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-[4-Cyano-2-(2-fluoro-1-fluoromethyl-ethoxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (100 mg), HATU (114 mg) and TEA (52 μl) were dissolved in DMF (4 ml). N,N-dimethyl-1,3-propanediamine (31 μl) was added. The mixture was stirred for 1 hour at rt. Then the mixture was poured in water and filtrated. The solid was washed with water and dried in an oven at 70° C.
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:23][CH2:24][C:25](OC)=[O:26])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>CCCCCC.O1CCCC1.[Cl-].[Na+]>[O:26]=[C:25]([CH2:24][CH2:23][C:17]1[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:15]([O:14][CH3:13])[CH:16]=1)[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: COP(C)(=O)OC
Reactant: COC(=O)CCc1ccc(OC)c(OC)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(CCC(=O)CP(=O)(OC)OC)cc1OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 28.5 %

Procedure:
To a mixture cooled at -78° C. of 50 ml of 2.1M n-butyl lithium solution in hexane and 100 ml of tetrahydrofuran, was added dropwise 12.4 g of dimethyl methylphosphonate. The mixture was stirred at -78° C. for 30 minutes, and thereafter 22.4 g of methyl 3-(3,4-dimethoxyphenyl)propionate [synthesized from 3,4-dimethoxycinnamic acid in 2 steps: (a) esterification (HCl--CH3OH) and (b) reduction (Pd/C--H2)] and 100 ml of tetrahydrofuran were added dropwise to the mixture. Then, the reaction was continued at -78° C. for 22 hours. The reaction mixture was poured in 500 ml of saturated aqueous sodium chloride solution. After neutralization and extraction with dichloromethane, the extract was dried and concentrated to give crude product. By purification of the crude product by means of column chromatography (silica gel/hexane:ethyl acetate=1:4), 9.0 g of the above caption compound was obtained.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]([C:6]([OH:8])=O)[C:4]=1[C:12]([OH:14])=O.Cl.[NH2:16][C@@H:17]1[CH2:22][NH:21][C:20](=[O:23])[CH2:19][CH2:18]1.C(N(CC)CC)C>CN(C=O)C>[NH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]2[C:4]=1[C:12](=[O:14])[N:16]([C@H:17]1[CH2:18][CH2:19][C:20](=[O:23])[NH:21][CH2:22]1)[C:6]2=[O:8]
Reactant: Nc1cccc(C(=O)O)c1C(=O)O
Reactant: N[C@H]1CCC(=O)NC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1cccc2c1C(=O)N([C@H]1CCC(=O)NC1)C2=O
Temperature: 80 °C
Yield: 46.5 %

Procedure:
To a mixture of 3-amino phthalic acid hydrochloride (0.144 g, 0.664 mmol) and (S)-5-aminopiperidin-2-one hydrochloride (0.100 g, 0.664 mmol) in dry DMF (2.2 mL) was added triethylamine (0.933 mL, 6.64 mmol) and the reaction mixture was heated at 80° C. over 18 h. The crude mixture was quenched by the addition of a saturated aqueous NaHCO3 solution (30 mL) and extracted using DCM (3×20 mL). Combined organic phases were dried over MgSO4, filtered and concentrated. The crude residue was purified by preparative reverse phase HPLC to give the desired product 30 (0.08 g, 47%) as an off-white powder. 1H NMR (400 MHz, DMSO) δ 7.56 (s, 1H), 7.42 (dd, J=7.7, 7.7 Hz, 1H), 6.94 (m, 2H), 6.48 (br s, 2H), 4.32 (m, 1H), 3.60 (app t, J=11.3 Hz, 1H), 3.23-3.02 (m, 1H), 2.62-2.42 (obsc m, 1H), 2.42-2.21 (m, 2H), 1.86 (m, 1H). MS (ESI) m/z calcd for C13H14N3O3 [M+H]+ 260.3, found: 260.7.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH:6]([C:12]([O:14][CH3:15])=[O:13])[CH2:5]2.C([O:20]O)(C)(C)C>C1(C)C=CC=CC=1.C(#N)C.CC(C)[O-].[Zr+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[C:6]([OH:20])([C:12]([O:14][CH3:15])=[O:13])[CH2:5]2
Reactant: COC(=O)C1Cc2cc(Cl)ccc2C1=O
Reactant: CC(C)(C)OO
Agent: [Zr+4]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: COC(=O)C1(O)Cc2cc(Cl)ccc2C1=O
Temperature: 30 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
To a solution of methyl 5-chloro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate (also known as methyl 5-chloro-1-oxo-2,3-dihydroindene-2-carboxylate) (0.500 g, 2.23 mmol) (Formula IIa wherein R1 is OCH3 and R4 is Cl) and zirconium(IV) isopropoxide (0.0086 g, 0.022 mmol) in toluene (1.34 g, 1.56 mL) at 30° C. was added an aqueous solution of tert-butyl hydroperoxide (70%, 0.316 g, 2.46 mmol). The reaction mixture was stirred for 24 hours at 30° C. and then diluted with acetonitrile (about 6 mL). Quantitative HPLC analysis showed 92% conversion of methyl 5-chloro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate, forming racemic methyl 5-chloro-2,3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylate in 89% yield (97% chemoselectivity).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=O)=[CH:4]1)[CH3:2].C(Cl)(=O)C(Cl)=O.[Cl:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:25]=[CH:26][C:27]=1[NH2:28].C(N(CC)CC)C>C(Cl)Cl>[Cl:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:25]=[CH:26][C:27]=1[NH:28][C:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:3]([CH2:1][CH3:2])[CH:4]=1)=[O:14]
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Reactant: CCn1cc(C(=O)O)c2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCn1cc(C(=O)Nc2ccc(CC(=O)OC)cc2Cl)c2ccccc21
Temperature: 15 °C
Yield: 88.4 %

Procedure:
To 1-ethylindole-3-carboxylic acid (160.2 mg, 0.847 mmol) were added methylene chloride (3.5 ml) and oxalyl chloride (108.9 μl, 1.270 mmol) under stirring at 15° C. The reaction mixture was stirred for 2.5 hours at room temperature. The solvent was then distilled off under reduced pressure. To the residue was added methylene chloride (3.5 ml). Under stirring at room temperature, a solution of methyl 3-chloro-4-aminophenylacetate (177.5 mg, 0.889 mmol) in methylene chloride (3.5 ml) and triethylamine (0.37 ml, 2.667 mmol) were added and the mixture was heated under reflux for 18 hours. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform. The resulting solution was washed with 1N HCl ad saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give methyl 3-chloro-4-((1-ethyl-3-indolylcarbonyl)amino)phenylacetate (277.7 mg, 88%) as a brown amorphous substance. The resulting compound was provided for the subsequent reaction without further purification.