Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[CH:13]=2)[CH:11]=1)[C:6](O)=[O:7].[CH3:24][NH2:25]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[CH:13]=2)[CH:11]=1)[C:6]([NH:25][CH3:24])=[O:7]
Reactant: CN
Reactant: COc1cc(C(=O)O)cc(-c2ccc3cc(OC)ccc3c2)c1
Product: CNC(=O)c1cc(OC)cc(-c2ccc3cc(OC)ccc3c2)c1
Yield: 28 %

Procedure:
The compound was prepared by reaction of 3-methoxy-5-(6-methoxy-naphthalene-2-yl)benzoic acid (500 mg, 1.62 mmol, 1 eq) with 33% methylamine solution (1 eq) according to method D. Purification by column chromatography with hexane/ethyl acetate 1/1 as the eluent yielded the desired product in a yield of 28%, 148 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[NH:13][CH:12]=[N:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH3:16][Si:17]([CH2:20][CH2:21][O:22][CH2:23]Cl)([CH3:19])[CH3:18]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:13]([CH2:23][O:22][CH2:21][CH2:20][Si:17]([CH3:19])([CH3:18])[CH3:16])[CH:12]=[N:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COc1cccc(-c2cnc[nH]2)c1
Agent: [H-]
Agent: [Na+]
Product: COc1cccc(-c2cncn2COCC[Si](C)(C)C)c1
Yield: 57.8 %

Procedure:
Reaction of 5-(3-methoxy-phenyl)-1H-imidazole (500 mg, 2.87 mmol), NaH (60%, 112 mg, 2.79 mmol), and SEMCl (598 uL, 3.35 mmol) followed by column chromatography on silica gel (hexane/EtOAC 3:2) gave the title compound (505 mg, 60%) as a brown oil. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 0.93 (t, 2H, J=7.5 Hz), 3.52 (t, 2H, J=9.0 Hz), 3.87 (s, 3H), 5.30 (s, 2H), 6.80–6.83 (m, 1H), 7.26–7.39 (m, 3H), 7.40 (s, 1H), 7.63 (s, 1H).
Reaction SMILES: ClC1C=C(NC2C=CC(F)=CC=2F)C=CC=1C(C1C=C(C2N=NN(CCOC3CCCCO3)C=2)C=CC=1C)=O.[Cl:40][C:41]1[CH:46]=[C:45]([NH:47][C:48]2[CH:53]=[CH:52][C:51]([F:54])=[CH:50][C:49]=2[F:55])[CH:44]=[CH:43][C:42]=1[C:56]([C:58]1[CH:63]=[C:62]([C:64]2[N:65]=[N:66][N:67]([CH2:69][CH2:70][O:71]C3CCCCO3)[CH:68]=2)[CH:61]=[CH:60][C:59]=1[O:78][CH3:79])=[O:57]>>[Cl:40][C:41]1[CH:46]=[C:45]([NH:47][C:48]2[CH:53]=[CH:52][C:51]([F:54])=[CH:50][C:49]=2[F:55])[CH:44]=[CH:43][C:42]=1[C:56]([C:58]1[CH:63]=[C:62]([C:64]2[N:65]=[N:66][N:67]([CH2:69][CH2:70][OH:71])[CH:68]=2)[CH:61]=[CH:60][C:59]=1[O:78][CH3:79])=[O:57]
Reactant: COc1ccc(-c2cn(CCOC3CCCCO3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Agent: Cc1ccc(-c2cn(CCOC3CCCCO3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Product: COc1ccc(-c2cn(CCO)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 101, using compound 119 (0.11 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 20:80 to 100:0 as the eluent to afford the title compound as yellow foam.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH:19]=O)[CH:13]=1)[CH:8]1[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:22]1([NH2:25])[CH2:24][CH2:23]1.[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:21])[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH2:19][NH:25][CH:22]2[CH2:24][CH2:23]2)[CH:13]=1)[CH:8]1[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CC1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(Cl)c(C=O)c1)C1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1ccc(Cl)c(CNC2CC2)c1)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
A mixture of (4-chloro-3-formyl-benzyl)-cyclopropyl-carbamic acid tert-butyl ester (563 mg, 1.82 mmol) and cyclopropylamine (0.195 mL, 2.73 mmol) in MeOH (18 mL) was heated to reflux for 4 h. The mixture was allowed to cool to rt, and NaBH4 (103 mg, 2.73 mmol) was added in portions. The mixture was stirred for 1 h, and the solvents were removed under reduced pressure. The resulting oil was diluted with EtOAc (100 mL), and the resulting mixture was washed with aq. sat. NaHCO3 and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC(CH2Cl2/MeOH 95:5) yielded the title compound (343 mg, 54%). LC-MS: tR=0.78 min; ES+: 351.39.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:7]2[C:3]=1[CH2:4][N:5]([CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[C:25]([O:33][CH2:34][CH3:35])[CH:24]=1)[CH2:19][C:20]([OH:22])=O)[C:6]2=[O:17].C1N=C[N:38](C(N2C=NC=C2)=O)C=1.[NH4+].[OH-]>C1COCC1>[C:20]([CH2:19][CH:18]([N:5]1[C:6](=[O:17])[C:7]2[C:3](=[C:2]([Cl:1])[CH:10]=[CH:9][C:8]=2[NH:11][C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])[CH2:4]1)[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:31])[F:32])=[C:25]([O:33][CH2:34][CH3:35])[CH:24]=1)(=[O:22])[NH2:38]
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC(F)F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(N)=O)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC(F)F
Yield: 17.9 %

Procedure:
Cyclopropanecarboxylic acid {2-[2-carbamoyl-1-(4-difluoromethoxy-3-ethoxy-phenyl)-ethyl]-7-chloro-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide was prepared by the procedure of Example 6 from 3-[4-chloro-7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (0.55 g, 1.1 mmol), CDI (0.26 g, 1.6 mmol) and NH4OH (0.35 ml, 3.3 mmol) in THF (15 ml) to give cyclopropanecarboxylic acid {2-[2-carbamoyl-1-(4-difluoromethoxy-3-ethoxy-phenyl)-ethyl]-7-chloro-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as white solid (0.10 g, 20%): mp 198-200° C.; 1H NMR (CDCl3): δ 0.89-0.93 (m, 2H, c-CH2), 1.10-1.20 (m, 2H, c-CH2), 1.44 (t, J=7.5 Hz, 3H, OCH2CH3), 1.66-1.68 (m, 1H, c-CH), 2.98 (dd, J=5, 15 Hz, 1H, CH2), 3.43 (dd, J=10, 15 Hz, 1H, CH2), 4.09 (q, J=7.5 Hz, 2H, OCH2CH3), 4.18 (d, J=17.5 Hz, 1H, CHHN), 4.37 (d, J=17.5 Hz, 1H, CHHN), 5.48 (br, 1H, NHH), 5.57-5.53 (m, 1H, CHN), 5.92 (br, 1H, NHH), 6.86 (t, JH-F=75 Hz, 1H, CF2H), 6.94-7.02 (m, 3H, Ar), 7.16 (d, J=10 Hz, 1H, Ar), 7.38 (t, J=8 Hz, 1H, Ar), 8.45 (d, J=8 Hz, 1H, Ar), 10.40 (s, 1H, NHCO). 13C NMR (CDCl3): δ 8.5, 14.6, 16.2, 38.6, 47.9, 54.1, 64.9, 101.57, 102.3, 113.2, 116.0, 119.2, 119.8, 121.8, 123.0, 133.2, 136.8, 137.1, 139.1, 150.9, 169.4, 171.1, 172.6; Anal Calcd for C24H26ClF2N3O5: C, 56.75; H, 4.76; N, 8.27. Found: C, 56.68; H, 4.63; N, 8.04.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])/[C:5](/Br)=[CH:6]/[CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:2].[CH3:15][S:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1(P([Pd-4](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)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:14])/[C:5](/[C:20]1[CH:21]=[CH:22][C:17]([S:16][CH3:15])=[CH:18][CH:19]=1)=[CH:6]/[CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:2]
Reactant: CCOC(=O)/C(Br)=C/C1CCCCC1
Reactant: CSc1ccc(B(O)O)cc1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)/C(=C/C1CCCCC1)c1ccc(SC)cc1
Yield: 87.6 %

Procedure:
Dissolve (Z)-2-bromo-3-cyclohexyl-acrylic acid ethyl ester (76.4 g, 300 mmol) and 4-(methylthio)benzene boronic acid (60.5 g, 360 mmol) in a mixture of 1500 mL toluene, 500 mL ethanol and 2M aqueous sodium carbonate solution (500 mL). Add tetrakis(triphenylphosphino)palladium(0) (10.4 g, 3mol %) and heat the mixture at reflux for 5 h. Cool and remove the ethanol under vacuum. Partition the residue between water (250 mL) and dichloromethane (4×250 mL). Combine the extracts and dry over magnesium sulfate, filter and concentrate. Pass through a silica gel pad with a mix of iso-hexane:dichloromethane:diethyl ether (92:4:4) to give the title compound as a hazy oil (80 g). GC-MS (m/e): 304 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[CH:14]=[CH:13][C:12]([NH2:15])=[N:11]1.C(N(CC)CC)C.[F:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:25]=1[C:26](Cl)=[O:27]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[CH:14]=[CH:13][C:12]([NH:15][C:26](=[O:27])[C:25]2[C:24]([F:23])=[CH:32][CH:31]=[CH:30][C:29]=2[F:33])=[N:11]1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Nc1ccn(Cc2ccc(Cl)cc2Cl)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccn(Cc2ccc(Cl)cc2Cl)n1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
1-[(2,4-Dichlorophenyl)methyl]-1H-pyrazol-3-amine (40 μl, 0.23 mmol, Art-Chem GmbH) was dissolved in dichloromethane (2 ml). Triethylamine (64 μl, 0.46 mmol) and then 2,6-difluorobenzoyl chloride (49 mg, 0.28 mmol, Aldrich) were added and the reaction was stirred at room temperature for 2 h. The reaction was quenched by addition of water (5 ml). The organic phase was separated (by hydrophobic frit) and concentrated under a flow of nitrogen. The residue was purified by MDAP (supelcosil ABZ+Plus column) eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN:Water 95:5+0.05% Formic acid) (Method A). The appropriate fractions were concentrated in vacuo then under nitrogen flow. The sample was dissolved in methanol and applied to a 5 g aminopropyl ion exchange cartridge (prewashed with MeOH) and eluted with MeOH. The relevant fractions were combined and concentrated to give the title compound as a colourless solid (36 mg); LCMS: (System 1) MH+=382/384, tRET=3.47 min.
Reaction SMILES: Br[C:2]1[N:23]=[C:5]2[N:6]=[C:7]([CH3:22])[C:8]([C:18]([O:20][CH3:21])=[O:19])=[C:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])[N:4]2[N:3]=1.[NH:24]1[CH2:29][CH2:28][S:27][CH2:26][CH2:25]1>O1CCOCC1>[Cl:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[C:9]1[N:4]2[N:3]=[C:2]([N:24]3[CH2:29][CH2:28][S:27][CH2:26][CH2:25]3)[N:23]=[C:5]2[N:6]=[C:7]([CH3:22])[C:8]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1c(C)nc2nc(Br)nn2c1-c1ccc(Cl)cc1Cl
Reactant: C1CSCCN1
Solvent: C1COCCO1
Product: COC(=O)c1c(C)nc2nc(N3CCSCC3)nn2c1-c1ccc(Cl)cc1Cl
Temperature: 75 °C
Yield: 91.3 %

Procedure:
To a stirred solution of methyl 2-bromo-7-(2,4-dichlorophenyl)-5-methyl-[1,2,4]-triazolo[1,5-a]pyrimidine-6-carboxylate (30 mg, 0.07 mmol) in dioxane (2 mL) was added thiomorpholine (15 μL, 0.14 mmol). After heating to 75° C. for 16 h, the reaction was concentrated under reduced pressure and diluted with EtOAc. The organic layer was washed with satd aq NH4Cl and brine prior to drying over anhydrous MgSO4. Filtration, concentration under reduced pressure and purification by silica gel chromatography afforded methyl 7-(2,4-dichlorophenyl)-5-methyl-2-thiomorpholino-[1,2,4]-triazolo[1,5-a]pyrimidine-6-carboxylate (28 mg, 90%) as a yellow solid.
Reaction SMILES: [Si](O[CH2:9][CH2:10][CH2:11][N:12]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH:19]([O:22]C)OC)[C:13]1=[O:24])(C(C)(C)C)(C)C.Cl.[NH:26]1[CH2:31][CH2:30][CH:29]([O:32][C:33](=[O:47])[NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:28][CH2:27]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(#N)C>[OH:22][CH2:19][CH2:18][CH2:17][N:14]1[CH2:15][CH2:16][N:12]([CH2:11][CH2:10][CH2:9][N:26]2[CH2:27][CH2:28][CH:29]([O:32][C:33](=[O:47])[NH:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:30][CH2:31]2)[C:13]1=[O:24]
Reactant: O=C(Nc1ccccc1-c1ccccc1)OC1CCNCC1
Reactant: COC(CCN1CCN(CCCO[Si](C)(C)C(C)(C)C)C1=O)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: O=C(Nc1ccccc1-c1ccccc1)OC1CCN(CCCN2CCN(CCCO)C2=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
To crude 1-[3-(tert-butyldimethylsilanyloxy)propyl]-3-(3,3-dimethoxypropyl)imidazolidin-2-one (11.4 g, 32 mmol; prepared as described in Preparation 2) was added to a 1:1 mixture of 1N aqueous HCl (32 mL, 32 mmol, 1.0 eq) in ACN (32 mL). The reaction was allowed to stir at room temperature for 2 hours. To the reaction mixture was added biphenyl-2-ylcarbamic acid piperidin-4-yl ester (9.4 g, 32 mmol; prepared as described in Preparation 3) and was allowed to stir for 30 minutes, followed by the addition of NaBH(OAc)3 (20.3 g, 96 mmol). The reaction mixture was allowed to stir overnight. After overnight, the solution was concentrated in vacuo. The crude mixture was taken up in DCM (400 mL) and washed with 1N NaOH (200 mL), water (200 mL) and brine (200 mL). The organic phase was dried over MgSO4, filtered and concentrated then purified via silica gel chromatography (10% MeOH in DCM with 1% NH3(aq)) to afford the title compound (7.98 g, 16.6 mmol) in 52% yield.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=1)[O:26][CH2:27][C:28](O)=[O:29].C(Cl)(=O)C([Cl:37])=O>C(Cl)(Cl)Cl.CN(C)C=O>[O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=1)[O:26][CH2:27][C:28]([Cl:37])=[O:29]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)COc1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)COc1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of {3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]phenoxy}acetic acid (0.22 g, 0.5 mmol) in dry chloroform (5 mL) was added at ambient temperature oxalyl chloride (0.43 mL, 5.0 mmol) followed by 1 drop of N,N-dimethylformamide. The mixture was stirred at ambient temperature for 2 h and evaporated to dryness in vacuo to afford crude {3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]phenoxy}acetyl chloride. The crude product was dissolved in dry dichloromethane (5 mL), and used in the next step. To a solution of methylamine hydrochloride (0.07 mg, 1.0 mmol) in dry dichloromethane (5 mL) containing triethylamine (0.35 mL, 2.5 mmol) was added at 0° C. 5.0 mL (0.50 mmol) of the stock solution of {3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]phenoxy}acetyl chloride. The mixture was stirred at ambient temperature for 16 h, diluted with dichloromethane (20 mL), washed with 7% aqueous solution of citric acid (10 mL), water (10 mL), and brine (10 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (hexanes/ethyl acetate 1:3) to afford N-methyl-2-{3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]phenoxy}acetamide (0.09 g, 40%) as a colorless solid: mp 175-176° C.; 1H NMR (300 MHz, CDCl3) δ 7.34-7.17 (m, 3H), 7.09-6.98 (m, 2H), 6.90 (s, 1H), 6.87-6.76 (m, 2H), 6.55 (br s, 1H), 6.48 (s, 1H), 6.44 (s, 1H), 5.09-4.96 (m, 2H), 4.88-4.79 (m, 1H), 4.75-4.69 (m, 1H), 4.60-4.51 (m, 2H), 4.47 (s, 2H), 3.11-2.92 (m, 2H), 2.92-2.88 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 177.9, 168.4, 161.9, 161.3, 157.6, 142.0, 137.9, 132.7, 130.3, 128.7, 123.9, 123.5, 121.0, 120.1, 120.0, 118.8, 113.9, 113.6, 109.1, 93.3, 80.6, 72.4, 67.2, 57.7, 43.9, 29.0, 25.7; MS (ES+) m/z 457.0 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5](=[O:9])[C:4]([O:10]CC2C=CC=CC=2)=[C:3]1[CH2:18][O:19][CH2:20][CH3:21].[ClH:22].[CH2:23](O)C>[Pd]>[ClH:22].[CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5](=[O:9])[C:4]([OH:10])=[C:3]1[CH:18]([O:19][CH2:20][CH3:21])[CH3:23]
Reactant: CCOCc1c(OCc2ccccc2)c(=O)cc(C)n1C
Reactant: CCO
Agent: [Pd]
Agent: Cl
Product: CCOC(C)c1c(O)c(=O)cc(C)n1C
Yield: 83.3 %

Procedure:
1,6-Dimethyl-2-(1-ethoxymethyl)-3-benzyloxy-pyridin4(1H)-one (3.65 g, 12 mmol) was dissolved in 40 ml of ethanol and adjusted to pH 1 with concentrated hydrochloric acid prior to hydrogenolysis for 4 hours in the presence of 5% Pd/C catalyst (0.8 g). Filtration followed by rotary evaporation gave the crude product as a white solid. Recrystallization from ethanol/diethyl ether gave the pure title compound (2.48 g, 83.3%) as a white crystalline solid. m.p. 195-199° C.
Reaction SMILES: [CH2:1]([PH:9](=[O:11])[OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(O)C>[CH2:1]([P:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:10])[OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC[PH](=O)O
Reactant: C=CCCCCCC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCO
Product: CCCCCCCCP(=O)(O)CCCCCCCC
Yield: 32.8 %

Procedure:
To a stirred mixture of 46.5 g (0.261 mol) of n-octylphosphinic acid in 250 mL 95% ethanol, 1-octene (58.6 g, 0.5218 mol) was added followed by 9.042 g (0.026 mol) of 70% benzoyl peroxide. The resulting mixture was refluxed for 8 hs, and then another 6.758 g (0.0196 mol) of benzoyl peroxide was added and the reaction continued to reflux for an extra 8 hs. A third 4.244 g of benzoyl peroxide was added (0.01305 mol) and refluxing continued for an extra 8 hs. The resulting mixture was cooled in the refrigerator, filtered, and 11.8 g of di-n-octylphosphinic acid was recovered using a rotary evaporator. The solid was washed with 100 mL of cooled 95% ethanol and the filtrate was concentrated on the rotary vacuum and replaced in the refrigerator. Another 24.9 g di-n-octylphosphinic acid was obtained on cooling to attain a total of 36.7 g (48.4% yield).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[N+](C1C=CC(S(O[CH2:25][C@H:26]2[CH2:28][C:27]2([F:30])[F:29])(=O)=O)=CC=1)([O-])=O>>[F:29][C:27]1([F:30])[CH2:28][C@@H:26]1[CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@H]2CC2(F)F)cc1
Reactant: COC(=O)c1ccc(O)cc1
Product: COC(=O)c1ccc(OC[C@H]2CC2(F)F)cc1

Procedure:
Using methyl 4-hydroxybenzoate and ((1R)-2,2-difluorocyclopropyl)methyl 4-nitrobenzenesulfonate, and in the same manner as in Example 5, the title compound was obtained. 1H NMR (300 MHz, DMSO-d6) δ 1.41-1.61 (1H, m), 1.66-1.84 (1H, m), 2.13-2.38 (1H, m), 3.81 (3H, s), 3.99-4.14 (1H, m), 4.18-4.31 (1H, m), 7.00-7.15 (2H, m), 7.85-7.97 (2H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[N:8]=[C:7]2[C:32]1[CH:33]=[N:34][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:36]=1)([O-])=O.CO.CCOC(C)=O>[Pd].CCOC(C)=O.CCCCCC>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[N:8]=[C:7]2[C:32]1[CH:33]=[N:34][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:36]=1
Reactant: CC(C)(C)OC(=O)n1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc([N+](=O)[O-])cc23)cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)n1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(N)cc23)cn1
Reaction time: 8 h
Yield: 95.9 %

Procedure:
Into a Round bottom flask was added tert-butyl 4-(5-nitro-1-trityl-1H-indazol-3-yl)-1H-pyrazole-1-carboxylate (0.440 g, 0.770 mmol) and 10 mL of MeOH and 5 mL of EtOAc followed by Palladium (0.100 g, 0.000470 mmol). The r×n was degassed under Hydrogen (2000 mL, 90 mmol) in balloon, was stirred overnight. TLC (20% EtOAc/Hexane) and MS showed r×n complete. The r×n was filtered through Celite and was rotovaped to dryness to give tert-butyl 4-(5-amino-1-trityl-1H-indazol-3-yl)-1H-pyrazole-1-carboxylate (0.400 g; Yield=95.9%)
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:6][CH2:5]1)=[O:3].C[O-].[Na+].[C:10](OC)(=[O:15])[C:11]([O:13][CH3:14])=[O:12]>CO>[CH3:14][O:13][C:11](=[O:12])[C:10](=[O:15])[CH2:1][C:2]([CH:4]1[CH2:6][CH2:5]1)=[O:3]
Reactant: CC(=O)C1CC1
Reactant: COC(=O)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(=O)CC(=O)C1CC1
Reaction time: 0.25 h
Yield: 49.5 %

Procedure:
To a solution of cyclopropyl methyl ketone (5 g, 59.4 mmol) in MeOH (75 mL) was added sodium methoxide (4.8 g, 54.0 mmol) at rt. After a 15 min stirring, dimethyl oxalate (7 g, 59.4 mmol) was added. The reaction mixture was stirred for 16 h at rt and concentrated. The residue was taken up in a saturated aqueous solution of ammonium chloride and extracted with EtOAc. The organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane/EtOAc, 95:5) to provide 5 g of the title compound. Rf=0.59 (hexane/EtOAc, 4:1); 1H NMR (300 MHz, CDCl3) δ ppm 1.00-1.30 (m, 4H), 1.80-1.95 (m, 1H), 3.85 (s, 3H), 6.48 (s, 1H), 14.2-15.0 (br. s, 1H).
Reaction SMILES: N[CH:2]1[CH2:6][C@@:5]([CH:26]([CH3:28])[CH3:27])([C:7]([NH:9][CH2:10][C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=2[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:8])[CH:4]=[CH:3]1.[O:29]=C(C(OCC)=O)C(OCC)=O.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[C:22]([O:21][C:12]1[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=1[CH2:10][NH:9][C:7]([C@:5]1([CH:26]([CH3:28])[CH3:27])[CH2:6][C:2](=[O:29])[CH:3]=[CH:4]1)=[O:8])([CH3:25])([CH3:24])[CH3:23]
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: CC(C)[C@]1(C(=O)NCc2cc(C(F)(F)F)ccc2OC(C)(C)C)C=CC(N)C1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)[C@]1(C(=O)NCc2cc(C(F)(F)F)ccc2OC(C)(C)C)C=CC(=O)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
A mixture of (1S)-4-amino-N-[2-tert-butoxy-5-(trifluoromethyl)benzyl]1-isopropylcyclopent-2-ene-1-carboxamide (35 g, 88 mmol) and diethyl oxomalonate (31 g, 176 mmol) in toluene (350 mL) was refluxed until no more starting material left as judged by HPLC. The reaction mixture was cooled to 0° C. and 1,8-diazabicyclo[5.4.0]undec-7-ene (27 g, 176 mmol) was added. The reaction mixture was then warmed to r.t. and stirred at this temperature for 1 hr before being quenched with 1M HCl and vigorously stirred for 1 hr. The reaction mixture was diluted with EtOAc and the two layers were separated. The aqueous phase was then extracted with EtOAc (5×). The organics were combined, dried over sodium sulfate and evaporated to dryness. The crude was purified by column chromatography on silica gel eluting with hexane:EtOAc (11:1) to yield 32 g of (1S)—N-[2-tert-butoxy-5-(trifluoromethyl)benzyl]-1-isopropyl-4-oxocyclopent-2-ene-1-carboxamide as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][N:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.[CH:43]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45][C:44]=1[CH2:53][CH2:54][O:55][CH2:56][C:57]([NH2:59])=[NH:58]>CN(C=O)C.ClCCl>[NH:58]=[C:57]([NH:59][C:8]([C:3]1[C:2]([Cl:1])=[N:7][CH:6]=[CH:5][N:4]=1)=[O:10])[CH2:56][O:55][CH2:54][CH2:53][C:44]1[CH:45]=[CH:46][C:47]2[C:52](=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:43]=1
Reactant: O=C(O)c1nccnc1Cl
Reactant: N=C(N)COCCc1ccc2ccccc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N=C(COCCc1ccc2ccccc2c1)NC(=O)c1nccnc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under an atmosphere of nitrogen, 3-chloro-2-pyrazinecarboxylic acid (Tyger, 250 mg), TBTU (532 mg), and diisopropylethylamine (1.34 ml) were added to a solution of 2-(2-naphthalen-2-yl-ethoxy)-acetamidine hydrochloride (417 mg) in DMF (5 ml). The reaction mixture was stirred for 2 h at r.t., diluted with dichloromethane and washed with water. The organic layer was dried (Na2SO4), filtered, and the solvent was evaporated. The obtained, crude title compound (567 mg) was used without further purification in the next step.