Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[C:13](B(O)O)=[CH:12][CH:11]=[CH:10][N:9]=1.Br[C:18]1[CH:31]=[C:30]2[C:21]([O:22][C:23]3[C:24]([F:42])=[CH:25][C:26]([O:40][CH3:41])=[CH:27][C:28]=3[C:29]32[C:35]2=[N:36][CH:37]=[CH:38][N:34]2[C:33]([NH2:39])=[N:32]3)=[CH:20][CH:19]=1>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.O1CCOCC1>[F:42][C:24]1[C:23]2[O:22][C:21]3[C:30](=[CH:31][C:18]([C:13]4[C:8]([F:7])=[N:9][CH:10]=[CH:11][CH:12]=4)=[CH:19][CH:20]=3)[C:29]3([C:35]4=[N:36][CH:37]=[CH:38][N:34]4[C:33]([NH2:39])=[N:32]3)[C:28]=2[CH:27]=[C:26]([O:40][CH3:41])[CH:25]=1
Reactant: OB(O)c1cccnc1F
Reactant: COc1cc(F)c2c(c1)C1(N=C(N)n3ccnc31)c1cc(Br)ccc1O2
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc(F)c2c(c1)C1(N=C(N)n3ccnc31)c1cc(-c3cccnc3F)ccc1O2
Temperature: 100 °C
Yield: 56.6 %

Procedure:
A pressure vessel was charged with potassium carbonate (1M solution) (49 mL, 49 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phospine)dichloropalladium(II) (1.739 g, 2.457 mmol), 2-fluoropyridin-3-ylboronic acid (3.46 g, 24.57 mmol), and 7′-bromo-4′-fluoro-2′-methoxyspiro[imidazo[1,5-a]imidazole-7,9′-xanthen]-5-amine (5.1 g, 12.28 mmol). Dioxane (150 mL) was added and the mixture was capped under argon, sonicated for 1 min and heated at 100° C. for 4 hours. The solution was concentrated. Material was purified via silica gel column chromatography using 50-100% ethyl acetate in hexane to afford 4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-methoxyspiro[imidazo[1,5-a]imidazole-7,9′-xanthen]-5-amine (3 g, 6.95 mmol) as a white solid.
Reaction SMILES: [CH:1](=[C:8]1/[N:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[NH:11][C:12]/1=[O:13])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21](=[O:30])/[CH:22]=[CH:23]/[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([CH:22]1[C:21](=[O:30])[O:13][C:12]2[NH:11][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])=[N:9][C:8]=2[CH:1]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1NC(c2ccccc2F)=N/C1=C\c1ccccc1
Reactant: O=C/C=C/c1ccccc1
Product: O=C1Oc2[nH]c(-c3ccccc3F)nc2C(c2ccccc2)C1Cc1ccccc1
Reaction time: 72 h
Yield: 65 %

Procedure:
Prepared according to the general procedure using (Z)-4-benzylidene-2-(2-fluorophenyl)-1H-imidazol-5(4H)-one and trans-cinnamaldehyde. After 72 h, the unpurified residue was purified by flash chromatography using 15% EtOAc/hexanes to afford 5h as an off-white solid (78 mg, 65%). Analytical data for 5 h: 1H NMR (500 MHz, CDCl3) δ 9.32 (d, J=8.4 Hz, 1H), 8.21 (td, J=8.0, 1.9 Hz, 1H), 7.36-7.21 (m, 8H), 7.12-7.05 (m, 3H), 7.02-6.99 (m, 2H), 4.09 (d, J=6.8 Hz, 1H), 3.62 (ddd, J=10.2, 6.8, 4.6 Hz, 1H), 3.37 (dd, J=14.9, 4.5 Hz, 1H), 2.43 (dd, J=14.8, 10.2 Hz, 1H); 13C NMR (CDCl3, 126 MHz) δ 169.1, 159.5 (d, JCF=244.7 Hz), 148.8, 138.0, 137.5, 137.2, 130.1 (d, JCF=8.9 Hz), 129.2, 129.0, 128.6, 128.5 (d, JCF=3.0 Hz), 128.2, 128.0, 126.7, 125.2 (d, JCF=2.9 Hz), 117.0 (d, JCF=10.2 Hz), 115.8 (d, JCF 22.3 Hz), 110.3 (d, JCF=3.3 Hz), 47.4, 38.4, 32.7; IR (film) cm−1 1771, 1632, 1614, 1528, 1467, 1454, 1428, 1122, 1106, 1073, 909, 762, 732, 698; LRMS (ESI): Mass calcd for [M+H]+ C25H20FN2O2: 399.1. found 399.4; Enantiomeric ratio was measured by chiral phase HPLC (Chiralcel OD-H; 5% IPA/3% MeOH/hexanes 0.5 mL/min, 280 nm), Rt1 (minor)=53.0, Rt2 (major)=63.6 min; er=98:2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:20][C@@H:19]([C:21]2[CH:32]=[CH:31][C:24]3[O:25][C:26]([CH3:30])([CH3:29])[O:27][CH2:28][C:23]=3[CH:22]=2)[O:18][C:17]1=[O:33].[C:37]1([N:43]=[C:44]=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(O)(C)C>ClCCl>[CH3:29][C:26]1([CH3:30])[O:25][C:24]2[CH:31]=[CH:32][C:21]([C@H:19]3[O:18][C:17](=[O:33])[N:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][C:4]4[CH:3]=[C:2]([NH:1][C:44]([NH:43][C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)=[O:45])[CH:36]=[CH:35][CH:34]=4)[CH2:20]3)=[CH:22][C:23]=2[CH2:28][O:27]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(N)c4)C(=O)O3)ccc2O1
Reactant: O=C=Nc1ccccc1
Solvent: CC(C)O
Solvent: ClCCl
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NC(=O)Nc5ccccc5)c4)C(=O)O3)ccc2O1
Temperature: 20 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
A solution of (5R)-3-(6-{2-[(3-aminobenzyl)oxy]ethoxy}hexyl)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (0.057 g) in dichloromethane (2 ml) was treated with phenyl isocyanate (0.020 g) and the mixture stirred under nitrogen at 20° C. for 2 h. Isopropanol (5 ml) was added to quench excess isocyanate, and the mixture stirred for 30 min before leaving to stand for 15 h. The solvents were removed in vacuo to give a residue which was purified by SPE. Elution with a stepped gradient of eluants from cyclohexane to cyclohexane-EtOAc (9:1) and onwards to EtOAc followed by solvent evaporation in vacuo gave the title compound (0.062 g). LCMS RT=3.70 min, ES+ve 618 (MH)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C:10]([NH:14][C:15]2[CH:16]=[C:17]3[C:26](=[CH:27][C:28]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])[O:25][CH2:24][C:23]2[N:18]3[CH:19]([CH3:37])[C:20](=[O:36])[NH:21][N:22]=2)([CH3:13])[CH2:9]1)=O)(C)(C)C.[ClH:38]>>[ClH:38].[F:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:28]1[CH:27]=[C:26]2[C:17]([N:18]3[C:23]([CH2:24][O:25]2)=[N:22][NH:21][C:20](=[O:36])[CH:19]3[CH3:37])=[CH:16][C:15]=1[NH:14][C:10]1([CH3:13])[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: CC1C(=O)NN=C2COc3cc(-c4ccccc4F)c(NC4(C)CCN(C(=O)OC(C)(C)C)C4)cc3N21
Agent: Cl
Product: CC1C(=O)NN=C2COc3cc(-c4ccccc4F)c(NC4(C)CCNC4)cc3N21
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
A mixture of 3-[7-(2-fluoro-phenyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-3-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.008 g, 0.017 mmol) in HCl (4 M in EtOAc, 2 mL) was stirred at ambient temperature for 1 h. The solvent was removed in vacuo to give 7-(2-fluoro-phenyl)-4-methyl-6-(3-methyl-pyrrolidin-3-ylamino)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one hydrochloride acid (0.007 g, 87%) as a white solid. 1H NMR (400 MHz, methanol-d4) δ 7.53-7.42 (m, 1H), 7.41-7.34 (m, 1H), 7.34-7.29 (m, 1H), 7.29-7.22 (m, 1H), 6.89 (s, 1H), 6.70-6.64 (m, 1H), 4.97-4.93 (m, 1H), 4.64-4.57 (s, 2H), 3.60-3.45 (m, 1H), 3.38-3.34 (m, 2H), 3.18-3.07 (m, 1H), 2.20-2.06 (m, 1H), 2.04-1.92 (m, 1H), 1.56-1.47 (m, 3H), 1.39 (m, 3H). LC/MS (Table 1, Method 5) Rt=2.272 min; MS m/z: 410 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:17]2[CH2:20][CH2:19][CH2:18]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][CH2:23][CH2:24][Cl:25].C(N(CC)CC)C>CN(C)C=O>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:22][CH2:23][CH2:24][Cl:25])[CH2:15][CH2:16]2)[CH:8]=[C:7]([CH:17]2[CH2:20][CH2:19][CH2:18]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCCBr
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCNCC2)n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCl)CC2)n1
Temperature: 40 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
3.5 g of 2-tert-butyl-4-(piperazin-1-yl)-6-cyclobutyl-pyrimidine (12.75 mmol), 2.3 g of 1-bromo-3-chloro-propane (14.6 mmol) and 2.8 ml of triethylamine (20.1 mmol) were dissolved in 70 ml of dimethylformamide. The mixture was stirred at room temperature overnight and for further 3 h at 40° C. The reaction mixture was then extracted with water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was then purified by silica gel chromatography (dichloromethane as eluent) to yield 3.0 g (67%) of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]1[C:33](=[O:34])[N:4]2[C:5]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:6]([CH2:9][S:10][C:11]3[N:15]([CH3:16])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12.[Br:35][C:36]([Br:41])([CH2:39][Br:40])[CH:37]=O.CN(C)C1C=CC=CC=1.S(Cl)(Cl)=O.S([O-])(O)(=O)=O.[K+]>C(Cl)Cl>[Br:35][C:36]([Br:41])([CH2:39][Br:40])[CH:37]=[N:1][C@@H:2]1[C:33](=[O:34])[N:4]2[C:5]([C:17]([O:19][CH:20]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:6]([CH2:9][S:10][C:11]3[N:15]([CH3:16])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12
Reactant: O=CC(Br)(Br)CBr
Reactant: Cn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: Cn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N=CC(Br)(Br)CBr)[C@H]2SC1
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 70.5 %

Procedure:
To a solution of benzhydryl 7β-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate (2.473 g, 5.000 mmol) in methylene chloride (35 ml) was added under ice-cooling a solution of 2,2,3-tribromopropanal (1.474 g, 5.000 mmol) in methylene chloride (5 ml) and the mixture was stirred for 20 minutes. The reaction mixture was cooled to -20° C., N,N-dimethylaniline (3.5 ml) was added thereto and then thionyl chloride (0.5 ml, 6.9 mmol) was added dropwise. After stirring under ice-cooling for 2 hours, the reaction mixture was poured into a mixture of a saturated aqueous solution of potassium hydrogen sulfate (100 ml) with ice (100 g) followed by extraction with methylene chloride (400 ml, twice). The methylene chloride layer was washed successively with an ice-cooled saturated aqueous solution of potassium hydrogen sulfate (200 ml) and then ice-water (200 ml). Thereafter, the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was crystallized with the addition of ethyl acetate (20 ml). The crystalline substance was recovered by filtration, washed with a small volume of ice-cooled methylene chloride and dried under reduced pressure to yield 2.720 g (71%) of the title compound as a pale yellow crystal. This product gradually decomposed with coloration at 90° C. and higher.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:13]([N:26]1[CH2:29][CH:28](OS(C)(=O)=O)[CH2:27]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.CCN(C(C)C)C(C)C>CC#N>[CH:13]([N:26]1[CH2:29][CH:28]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[N:8]=[CH:9][CH:10]=[CH:11][N:12]=3)[CH2:2][CH2:3]2)[CH2:27]1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: c1cnc(N2CCNCC2)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: c1ccc(C(c2ccccc2)N2CC(N3CCN(c4ncccn4)CC3)C2)cc1

Procedure:
To a solution of 2-piperazin-1-yl-pyrimidine (2.48 g, 15.10 mmol, Alfa) and methanesulfonic acid 1-benzhydryl-azetidin-3-yl ester (4 g, 12.6 mmol, Oakwood) in CH3CN (40 mL) was added DIPEA (2.63 mL, 15.10 mmol) at room temperature. The resulting mixture was then refluxed for 2 h. The solvent was removed by evaporation and the residue was partitioned between CH2Cl2 and aqueous NaHCO3. The organic layer was washed with aqueous NaHCO3 (2×) and then extracted with 1N HCl (2×). The aqueous layer was cooled and then pH adjusted with 1N NaOH. The resulting mixture was extracted with CH2Cl2 (2×). The organic layer was dried over MgSO4 and concentrated. The resulting residue was purified by MPLC to yield 2-[4-(1-benzhydryl-azetidin-3-yl)-piperazin-1-yl]-pyrimidine.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3([CH2:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([N+:19]([O-])=O)[CH:16]=4)[CH2:11]3)[C:9](=[O:22])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(N(CC)CC)C.[H][H]>CCOC(C)=O.CO.[Pd]>[NH2:19][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C:10]1([C:3]3[CH:2]=[N:7][CH:6]=[N:5][C:4]=3[NH:8][C:9]1=[O:22])[CH2:18]2
Reactant: O=C1Nc2ncnc(Cl)c2C12Cc1ccc([N+](=O)[O-])cc1C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncncc21
Reaction time: 24 h

Procedure:
To a solution of (±)-4′-chloro-5-nitro-1,3-dihydrospiro[indene-2,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′H)-one from Step C (400 mg, 1.26 mmol) in EtOAc (40 mL) and MeOH (10 mL) was added triethylamine (0.88 mL, 6.315 mmol). The mixture was hydrogenated at 50 psi hydrogen over 10% Pd/C (100 mg). After 24 h and 90 h, an additional amount of palladium on carbon (100 mg) was added to the reaction mixture and hydrogenation was continued for a total of 180 h. The reaction mixture was filtered through a pad of Celite and concentrated in vacuo. The residue was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound. MS: m/z=253 (M+1).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)[C:3]=1[C:4]#[N:5].CN(C)C(=O)C.[CH3:27][NH:28][NH2:29]>O>[CH3:27][N:28]1[C:2]2[C:3](=[C:6]([O:10][C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=3)[CH:7]=[CH:8][CH:9]=2)[C:4]([NH2:5])=[N:29]1
Reactant: CNN
Reactant: N#Cc1c(F)cccc1Oc1ccc2ccccc2c1
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cn1nc(N)c2c(Oc3ccc4ccccc4c3)cccc21
Temperature: 130 °C
Yield: 97 %

Procedure:
To a 20 mL vial containing 2-fluoro-6-(naphthalen-2-yloxy)-benzonitrile (966 mg, 3.67 mmol) and a magnetic stir bar was added anhydrous N,N-dimethylacetamide and the mixture was stirred until solution was achieved. Methyl hydrazine (390 uL, 7.34 mmol) was added, the vial was capped, the reaction mixture was placed in an oil bath at 120° C. and stirred at that temperature overnight. The reaction mixture was heated at 130° C. for an additional 3 h. The cooled reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×30 mL). The combined organics were washed with water (3×15 mL), dried (Na2SO4), filtered and concentrated to give 1.03 g of a tan solid. This residue was purified via flash chromatography on silica gel (120 g) utilizing CH2Cl2 and then 9:1 CH2Cl2/EtOAc as eluent to give 770 mg of I-190 an off-white solid. This material was deemed of sufficient purity to be utilized in subsequent reactions. 1H NMR, MS.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.[NH2:14][CH:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]1.C(N(CC)CC)C>C(O)(C)C>[N+:8]([C:7]1[C:2]([NH:14][CH:15]2[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:17][CH2:16]2)=[C:3]2[S:13][CH:12]=[CH:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCC(Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Temperature: 100 °C

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (118 mg, 0.550 mmol), tert-butyl (4-aminocyclohexyl)carbamate (140 mg, 0.66 mmol) and triethylamine (0.23 mL, 1.6 mmol) in isopropyl alcohol (5 mL) was heated at 100° C. for 1 h. The mixture was concentrated to give the desired product as a mixture of cis- & trans-isomer mixtures to be used in the next step directly. LCMS calculated for C18H25N4O4S (M+H)+: m/z=393.2. Found: 393.1.
Reaction SMILES: [ClH:1].Cl.C1(C[N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][N:17]3[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18]3)[CH2:12][CH2:11]2)C=CC=CC=1.C(O)C.C>O>[ClH:1].[ClH:1].[NH:10]1[CH2:11][CH2:12][CH:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18]2)[CH2:14][CH2:15]1
Reactant: c1ccc(CN2CCC(CN3Cc4ccccc4C3)CC2)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: c1ccc2c(c1)CN(CC1CCNCC1)C2
Reaction time: 9 h

Procedure:
56.6 g (149 mmol) of 2-{[1-(phenylmethyl)-4-piperidyl]methyl}-2,3-dihydro-1H-isoindole dihydrochloride, 300 ml of ethanol, 50 ml of water and 5 g of palladinized charcoal (10% palladium) are introduced into a Parr apparatus and a hydrogenolysis is performed under approximately 0.41 MPa for 9 h.
Reaction SMILES: Br[CH2:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:7][CH2:6]1)=O.[C:15]([O:19][C:20](=[O:35])[CH2:21][CH2:22][N:23]([CH2:27][C:28]1[S:29][C:30]([CH2:33][CH3:34])=[CH:31][CH:32]=1)[C:24]([NH2:26])=[S:25])([CH3:18])([CH3:17])[CH3:16]>CO>[C:15]([O:19][C:20](=[O:35])[CH2:21][CH2:22][N:23]([C:24]1[S:25][CH:2]=[C:3]([C@H:5]2[CH2:10][CH2:9][C@H:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:7][CH2:6]2)[N:26]=1)[CH2:27][C:28]1[S:29][C:30]([CH2:33][CH3:34])=[CH:31][CH:32]=1)([CH3:16])([CH3:17])[CH3:18]
Reactant: CCc1ccc(CN(CCC(=O)OC(C)(C)C)C(N)=S)s1
Reactant: CC(C)(C)[C@H]1CC[C@H](C(=O)CBr)CC1
Solvent: CO
Product: CCc1ccc(CN(CCC(=O)OC(C)(C)C)c2nc([C@H]3CC[C@H](C(C)(C)C)CC3)cs2)s1

Procedure:
2-Bromo-1-(trans-4-tert-butyl-cyclohexyl)-ethanone (72 mg, 0.277 mmol) was added to a methanol (about 4 mL) solution of 3-[1-(5-ethyl-thiophen-2-ylmethyl)-thioureido]-propionic acid tert-butyl ester (100 mg, 0.304 mmol) to obtain 3-[[4-(trans-4-tert-butyl-cyclohexyl)-thiazol-2-yl]-(5-ethyl-thiophen-2-ylmethyl)-amino]-propionic acid tert-butyl ester (108 mg, 0.220 mmol) following a method analogous to General Procedure C (and similar to the procedure found in Example 5). Hydrolysis of this ester following a method analogous to General Procedure G1 using 1 N NaOH (aq) solution (2 mL), THF (1 mL) and MeOH (1 mL) gave 3-[[4-(trans-4-tert-butyl-cyclohexyl)-thiazol-2-yl]-(5-ethyl-thiophen-2-ylmethyl)-amino]-propionic acid (37 mg, 0.085 mmol). LC-MS m/z: 435 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.[CH2:15]([O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].CN(C1C=CC=CN=1)C.Cl>ClCCl>[CH2:15]([O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]3)=[O:29])=[CH:26][CH:25]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: CCCCCCCCOc1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(C(=O)Oc2ccc3cc(C(=O)O)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88 %

Procedure:
In 30 ml of dichloromethane, 3 g of 6-hydroxy-2-naphthoic acid and 2.4 g oftriethylamine were dissolved. To this solution were added 4.4 g of 4-octyloxybenzoic acid chloride and 0.2 g of dimethylaminopyridine, and the solution was stirred for about 20 hours at an ambient temperature. A diluted hydrochloric acid solution was added to the solution and the organic layer in the mixed solution was separated by means of a separatingfunnel. After the solvent was distilled off, the residue was washed with n-hexane and dried to obtain 5.9 g of 6-(4-octyloxyphenylcarbonyloxy)-2-naphthoic acid. The compound was added in 10 g of thionyl chloride to dissolve, and a very small amount of N,N-dimethyl formamide was added to the solution and the solution was refluxed for 4 hours. An excess amount of thionyl chloride was distilled off to obtain 5.7 g of the titled compound.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][CH2:20][CH2:21][CH2:22][OH:23].[OH-].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1>[CH2:1]([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH2:10][O:23][CH2:22][CH2:21][CH2:20][F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCF
Reactant: ClCCN(Cc1ccccc1)Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Product: FCCCOCCN(Cc1ccccc1)Cc1ccccc1
Yield: 67.6 %

Procedure:
Dibenzyl-[2-(3-fluoro-propoxy)-ethyl]-amine (770 mg) was prepared by following General Procedure S starting from dibenzyl-(2-chloro-ethyl)-amine (1 g), 3-fluoro-propan-1-ol (295 mg), 50% (w/w) KOH solution (4.25 mL) and tetrabutylammonium bromide (130 mg) in dioxane (4.25 mL).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:13]=[C:12]2I.[Cl:29][C:30]1[CH:35]=[CH:34][N:33]=[C:32]([Sn](CCCC)(CCCC)CCCC)[N:31]=1.N#N>CN(C=O)C.[Cu]I.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>[Cl:29][C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[C:9]([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])[CH:10]=3)[N:14]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:13]=2)[N:31]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4c(F)cccc4F)ccc32)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccc(Cl)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nccc(Cl)n3)c3cc(-c4c(F)cccc4F)ccc32)cc1
Temperature: 80 °C
Yield: 25.7 %

Procedure:
To a solution of 5-(2,6-difluorophenyl)-3-iodo-1-tosyl-1H-indole (2.0 g, 3.92 mmol) and 4-chloro-2-tributylstannanyl-pyrimidine (2.38 g, 5.98 mmol) in DMF (60 mL) was bubbled N2 for 15 min and added CuI (0.898 g, 4.71 mmol) and Pd(PPh3)4 (0.226 g, 0.196 mmol). The reaction mixture was heated at 80° C. for 1 h and cooled to RT. The reaction mixture was quenched with water and precipitate was formed. The resulting precipitate was collected by filtration, washed with water, and dried to yield crude product. Purification by silica gel column chromatography, eluting with 10% EtOAc in hexanes obtained the title compound (0.50 g, 26%). MS (ESI, pos. ion) m/z: 496.0 (M+1).
Reaction SMILES: [C:1]1([C:7]2[C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:12][C:11]=3[C:10]([C:20]#[N:21])=[C:9]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1C[O:32]CC1>>[O:32]=[C:12]1[C:11]2[C:10]([C:20]#[N:21])=[C:9]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)[CH:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2
Reactant: N#Cc1c(N2CCCC2)cc(-c2ccccc2)c2c1Cc1ccccc1-2
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCC2)cc(-c2ccccc2)c2c1C(=O)c1ccccc1-2
Temperature: 2.5 °C

Procedure:
A solution of 4-phenyl-2-(pyrrolidin-1-yl)-9H-fluorene-1-carbonitrile (336 mg) in THF was added sodium hydride (25 mg) and was stirred at 0-5° C. for less than five minutes. After completion, the reaction solvent was evaporated under vacuum and the crude solid obtained was quenched with ice water and subsequently neutralized by dilute HCl. The precipitate thus obtained was filtered and purified on a silica gel column using ethyl acetate-hexane as eluent. Light red solid; mp 166-168° C.; ESIMS 351 (M++1); IR (KBr) 2215 (CN), 1717 cm−1 (CO); 1H NMR (300 Hz, CDCl3) δ 1.97-2.10 (m, 4H, CH2), 3.67-3.73 (m, 4H, 2CH2), 6.43-6.48 (m, 1H, ArH), 6.59 (s, 1H, ArH), 7.04-7.12 (m, 2H, ArH), 7.40-7.47 (m, 2H, ArH), 7.48-7.54 (m, 3H, ArH), 7.55-7.59 (m, 1H, ArH); 13C NMR (75.53 MHz, CDCl3): δ 24.50, 49.37, 88.60, 115.58, 11927, 120.14, 123.11, 126.0, 127.12, 127.33, 127.49, 129.34, 132.13, 133.40, 136.26, 137.69, 141.23, 142.34, 149.32, 189.94.