Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:23]=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)[C:3]=1[CH2:24][C:25]([O:27][CH3:28])=[O:26].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:39]1[CH2:43]OC[CH2:40]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:23]=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)[C:3]=1[CH:24]([CH2:40][CH2:39][CH3:43])[C:25]([O:27][CH3:28])=[O:26]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc2c(c1)OCO2)CCCC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc2c(c1)OCO2)CCCC3
Yield: 82.6 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(benzo[d][1,3]dioxol-5-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.328 g; 0.83 mmol), LHMDS 1N in THF (1.24 mL; 1.24 mmol), 1-iodopropane (0.162 mL; 1.66 mmol) in DMF (4.1 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-40%) in heptane furnished 0.300 g (83%) of the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[C:21]1[O:25][CH:24]=[N:23][CH:22]=1)[NH2:17]>ClCCl>[Cl:1][C:2]1[C:7]([C:8]([NH:17][C:16]2[CH:18]=[CH:19][C:20]([C:21]3[O:25][CH:24]=[N:23][CH:22]=3)=[C:14]([O:13][CH3:12])[CH:15]=2)=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)c1c(Cl)ncnc1Cl
Reactant: COc1cc(N)ccc1-c1cnco1
Solvent: ClCCl
Product: COc1cc(NC(=O)c2c(Cl)ncnc2Cl)ccc1-c1cnco1
Reaction time: 0.5 h
Yield: 71 %

Procedure:
4,6-Dichloropyrimidine-5-carbonyl chloride (600 mg, 2.84 mmol, prepared according to E. V. Tarasov et al. Synlett 2000, 5, 625-626) was dissolved in dichloromethane (5 ml) and TEA (395 μl, 2.83 mmol) was added. To this solution, 3-methoxy-4-(oxazol-5-yl)aniline (540 mg, 2.84 mmol, prepared according to S. H. Watterson et al. Bio. Med. Chem. Lett. 12 (2002) 2879-2882) in 5 ml DCM was dropwise added and the mixture was stirred for 30 min. The reaction mixture was then diluted with dichloromethane, washed with 4% sodium bicarbonate solution, dried over magnesium sulphate, filtered and evaporated. The crude (844 mg, 87% purity, 71% yield) was used in the next synthetic step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:15]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:22]([NH2:26])(=[O:25])[CH:23]=[CH2:24].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CC#N>CCOC(C)=O.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:15]1(=[C:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:5]2[CH:6]=[CH:7][C:2](/[CH:24]=[CH:23]/[C:22]([NH2:26])=[O:25])=[CH:3][CH:4]=2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: C=CC(N)=O
Reactant: Brc1ccc(C(=C2CCCCCC2)c2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: NC(=O)/C=C/c1ccc(C(=C2CCCCCC2)c2ccccc2)cc1
Yield: 33.7 %

Procedure:
A suspension of [(4-Bromophenyl)(phenyl)methylene]cycloheptane (1) (0.50 g, 1.47 mmol), TEA (1.21 mL, 8.71 mmol), acrylamide (0.62 g, 8.73 mmol), Pd(OAc)2 (0.080 g, 0.36 mmol), P(o-tolyl)3) (0.19 g, 0.63 mmol) and CH3CN was stirred at reflux under N2. After 2 h heating was discontinued and the reaction diluted with EtOAc (50 mL) and water (50 mL). The mixture was filtered through a celite pad and the filtrate transferred to a separatory funnel. The organic fraction was washed with brine (50 mL), dried (MgSO4), filtered and concentrated to an amber oil. This oil was purified by column chromatography on silica gel (50 g) using a hexanes to 25% EtOAc:hexanes to 100% EtOAc gradient to afford a pale yellow solid. Trituration of the solid with EtOAc (25 mL) yielded 164 mg (33%) of the title compound (4) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 1.54 (s, 8H), 2.24 (br s, 4H), 6.55 (d, J=15.9 Hz, 1H), 7.07 (br, 1H), 7.14-7.20 (m, 7H), 7.25 (d, J=15.9 Hz, 1H), 7.49 (d, J=8.1 Hz, 2H), 7.50 (br, 1H). LRMS (APCI): m/z 332 (M+H)+. Anal. Calcd for C23H25NO.0.1H2O: C, 82.67; H, 7.63; N, 4.19. Found: C, 82.75; H, 7.56; N, 4.20.
Reaction SMILES: NC(=O)[C@@H:3]([NH:8][C:9](=[O:37])[C@@H:10]([NH:15][C:16]([N:18]1[C:26]2[CH2:25][CH2:24][N:23]([CH3:27])[CH2:22][C:21]=2[C:20]([C:28]2[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=2[F:36])=[N:19]1)=[O:17])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4]C(C)C.N1CC[CH:42]([C:45]([NH2:47])=[O:46])[CH2:41][CH2:40]1>>[C:45]([CH:42]1[CH2:41][CH2:40][N:8]([C:9](=[O:37])[C@@H:10]([NH:15][C:16]([N:18]2[C:26]3[CH2:25][CH2:24][N:23]([CH3:27])[CH2:22][C:21]=3[C:20]([C:28]3[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=3[F:36])=[N:19]2)=[O:17])[C:11]([CH3:14])([CH3:12])[CH3:13])[CH2:3][CH2:4]1)(=[O:46])[NH2:47]
Reactant: NC(=O)C1CCNCC1
Reactant: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C)C2)C(C)(C)C)C(N)=O
Product: CN1CCc2c(c(-c3cc(F)c(F)cc3F)nn2C(=O)N[C@H](C(=O)N2CCC(C(N)=O)CC2)C(C)(C)C)C1

Procedure:
Compound 79 was prepared according to the procedure described for the synthesis of compound 72 by replacing leucine amide with piperidine-4-carboxamide. LCMS (+ESI) m/z=535.4 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1)[CH2:26]Br>>[CH3:32][O:31][C:29]1[CH:28]=[C:25]([CH:24]=[C:23]([O:22][CH3:21])[CH:30]=1)[CH2:26][N:8]1[C:9]([S:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19]
Reactant: COc1cc(CBr)cc(OC)c1
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: COc1cc(Cn2c(Sc3cc(C)cc(C)c3)c(C(C)C)c(=O)[nH]c2=O)cc(OC)c1
Yield: 53.1 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 3,5-dimethoxybenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (234 mg, yield: 53.1%).
Reaction SMILES: [CH2:1]1[O:9][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(#N)C.[NH2:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[C:24]([F:27])([F:26])[F:25])[NH:20][C:19](=[O:28])[N:18]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:17]2=[O:34]>>[OH:9][CH2:1][CH:2]([NH:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[C:24]([F:26])([F:25])[F:27])[NH:20][C:19](=[O:28])[N:18]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:17]2=[O:34])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(N)cc2c1=O
Reactant: c1ccc(C2CO2)cc1
Solvent: CC#N
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(NC(CO)c3ccccc3)cc2c1=O
Reaction time: 0.25 h
Yield: 17.7 %

Procedure:
To a solution of 0.101 ml (0.887 mmol) of styrene oxide in 1 ml acetonitril 242 mg (1.77 mmol) zinc chloride are added and the mixture is stirred for 15 minutes. To the resulting white suspension 50 mg (0.148 mmol) of N-(6-amino-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide are added and the mixture is stirred at 70° C. for 90 minutes. Another 0.017 ml (0.147 mmol) of styrene oxide are added and the mixture is stirred for another 30 minutes at 70° C. The solvent is evaporated by rotavapor evaporation. The residue is dissolved in ethyl acetate and washed with an aqueous solution of potassium carbonate (1M) and with an aqueous solution of citric acid (10%). The crude product is purified by reversed phase (C18) chromatography using an acetonitril-water gradient. Upon lyophilisation 12 mg (18%) of N-[6-(2-hydroxy-1 -phenyl-ethylamino)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl]-methanesulfonamide are obtained as a yellowish solid. MS (ES+): m/e =459 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:6]=[CH:5][C:4]=1[OH:18].[C:19]([N:26]1[CH2:31][CH2:30][CH:29](O)[CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOC(C)=O>[C:22]([O:21][C:19]([N:26]1[CH2:31][CH2:30][CH:29]([O:18][C:4]2[CH:5]=[CH:6][C:7]([B:9]3[O:10][C:11]([CH3:17])([CH3:16])[C:12]([CH3:14])([CH3:15])[O:13]3)=[CH:8][C:3]=2[O:2][CH3:1])[CH2:28][CH2:27]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 45 h
Yield: 71.5 %

Procedure:
To a solution of 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.8 g, 3.2 mmol, 1 eq), 1-boc-4-hydroxypiperidine (0.97 g, 4.8 mmol, 1.5 eq) and triphenylphosphine (1.26 g, 4.8 mmol, 1.5 eq) in anhydrous THF (8 mL) was added DIAD (0.94 mL, 4.8 mmol, 1.5 eq) dropwise at 0° C. The solution was stirred at RT for 45 h. The solvent was removed, and the resulting light orange oily residue was treated with 20% AcOEt/c-hexane to give white crystals (PPh3O) which were filtered off and washed with the same mixture. The filtrate was evaporated to give an oily residue which was treated with c-hexane and a few drops of AcOEt to give a white precipitate that was removed by filtration and an oily residue that solidified upon standing. The crude product (1.93 g containing some c-hexane) was used as it was in the subsequent step. The remainder was purified by column chromatography (Isolute Flash Si II column, 25 g silica gel, 0-8% AcOEt in c-hexane) to give the pure desired product (0.991 g). HPLC-MS (10-95% B in 4 min at 0.5 mL+2 min 100% B, flow 0.8 mL/min, 50° C.): tR=5.10 min, [M+H]+ m/z 334.3.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:9][C:10]([C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[NH2:19])=[O:11])[C:6]([OH:8])=O)(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:32][C@H:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:34][OH:35]>CN(C=O)C>[C:1]([NH:4][CH:5]([CH2:9][C:10]([C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[NH2:19])=[O:11])[C:6]([NH:32][CH:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:34][OH:35])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(CC(=O)c1cc(Cl)ccc1N)C(=O)O
Reactant: N[C@@H](CO)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(=O)NC(CC(=O)c1cc(Cl)ccc1N)C(=O)NC(CO)c1ccccc1
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 2-acetamido-4-(2-amino-5-chlorophenyl)-4-oxo-butyric acid (0.569 g; 2 mmol) in dry DMF (8 ml), 1,1'-carbonyldiimidazole (0.34 g; 2.1 mmol) was added portionwise at 5°-8° C. under nitrogen. After stirring at 5° C. for 1.5 h, (R)-(-)-2-amino-2-phenylethanol (0.33 g; 2.4 mmol) in dry DMF (6 ml) was added dropwise at 3°-5° C. The reaction was then stirred for 2 h in an ice bath and 16 h at room temperature, quenched with water and extracted with ethyl acetate. The organic layer was washed with water, dried with an. sodium sulfate and concentrated to dryness. The residue was purified by flash-chromatography on silica gel (ethyl acetate:methanol=98:2) to yield 2-acetylamino-4-(2-amino-5-chlorophenyl)-N-(2-hydroxy-1-phenyl-ethyl)-4-oxobutyramide as a yellow solid (0.18 g; 22%; m.p. 212°-215° C.) (pure diastereoisomer with Rf<).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][C@@:5]1([N:28]=[N+:29]=[N-:30])[C:16]([O:18][CH2:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])[CH:2]=[CH2:3].[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>C(Cl)Cl>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[CH2:1]([C@H:4]1[CH2:8][NH:7][CH2:6][C@@:5]1([N:28]=[N+:29]=[N-:30])[C:16]([O:18][CH2:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])[CH:2]=[CH2:3]
Reactant: C=CC[C@H]1CN(C(=O)OC(C)(C)C)C[C@@]1(N=[N+]=[N-])C(=O)OCC(=O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC[C@H]1CNC[C@@]1(N=[N+]=[N-])C(=O)OCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
While under nitrogen, a solution of racemic 1-tert-butyl 3-(2-oxo-2-phenylethyl) (3R,4S)-4-allyl-3-azidopyrrolidine-1,3-dicarboxylate (0.425 g, 1.02 mmol) in methylene chloride (4 mL) was treated with trifluoroacetic acid (1.2 mL, 15 mmol) quickly dropwise, and the resulting homogeneous mixture was stirred at room temperature. After 40 min, the mixture was concentrated under reduced pressure and dried under high vacuum for several hours to give crude racemic 2-oxo-2-phenylethyl (3R,4S)-4-allyl-3-azidopyrrolidine-3-carboxylate trifluoroacetate as a dark amber viscous oil which was used immediately in the next step. LC-MS ESI+MS found for C16H18N4O3 m/z 315.2 (M+H). 1H NMR (CDCl3, 400 MHz) δ 7.92 (m, 2 H), 7.69 (m, 1 H), 7.55 (m, 2 H), 5.75 (m, 1 H), 5.62 (m, 2 H), 5.24 (d, J=17 Hz, 1 H), 5.20 (d, J=10.2 Hz, 1 H), 4.08 (m, 1 H), 3.80 (m, 1 H), 3.55 (m, 2 H), 2.80 (m, 1 H), 2.63 (m, 1 H), 2.27 (m, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[C:5]([Cl:12])=[CH:4][C:3]=1[F:13].Cl[C:15](OC(Cl)(Cl)Cl)=[O:16]>C1(C)C=CC=CC=1>[Cl:12][C:5]1[C:6]2[O:7][CH2:8][CH2:9][O:10][C:11]=2[C:2]([N:1]=[C:15]=[O:16])=[C:3]([F:13])[CH:4]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1c(F)cc(Cl)c2c1OCCO2
Solvent: Cc1ccccc1
Product: O=C=Nc1c(F)cc(Cl)c2c1OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2.25 g (0.011 mole) of 5-amino-8-chloro-6-fluoro-1,4-benzodioxane in 50 mL of toluene was added slowly 0.67 mL (1.09 g, 0.0055 mole) of trichloromethyl chloroformate. This mixture was stirred at ambient temperature for one hour and then was heated at reflux for approximately 16 hours. At the conclusion of this period the solvent was evaporated from the reaction mixture under reduced pressure, leaving 8-chloro-6-fluoro-1,4-benzodioxan-5-yl isocyanate as a residue which was used in the next step without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:18]([O:20]CC3C=CC([N+]([O-])=O)=CC=3)=[O:19])=[C:14]([F:17])[CH2:15][S:16][C@H:11]12)=[O:8]>[Pd].CO>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:18]([OH:20])=[O:19])=[C:14]([F:17])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(F)CS[C@H]12
Agent: [Pd]
Solvent: CO
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)O)=C(F)CS[C@H]12
Reaction time: 1 h

Procedure:
To 110 ml. of methanol and 83 mg. of pre-reduced 5 percent palladium on carbon were added 83 mg. of p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-fluoro-3-cephem-4-carboxylate. The mixture was hydrogenated at 53 psig. for one hour. The resulting mixture was filtered, the filtered catalyst was washed with methanol, and the methanol washings were added to the filtrate. The filtrate was then evaporated in vacuo. The residue was dissolved in ethyl acetate, and the ethyl acetate solution was extracted with dilute aqueous sodium bicarbonate. The sodium bicarbonate solution was washed with ethyl acetate, layered with ethyl acetate, and dilute aqueous HCl was added. The layered ethyl acetate was separated and evaporated to recover 7-[2-(2-thienyl)acetamido]-3-fluoro-3-cephem-4-carboxylic acid, shown by bioautogram to be biologically active.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:13]O[C:11](=[O:14])[C:10]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[CH3:33][NH2:34]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH2:13][N:34]([CH3:33])[C:11](=[O:14])[C:10]=2[C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)=[CH:19][CH:20]=2)=[CH:7][CH:8]=1
Reactant: CN
Reactant: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)OC2)cc1
Product: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)N(C)C2)cc1
Yield: 29 %

Procedure:
A stirred solution of 4-(4-methoxyphenyl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (500 mg, 1.18 mmol) in 2N methanolic MeNH2 (50 mL) was refluxed for 3 h. The reaction mixture was then concentrated in vacuo and the residue was dissolved in 4N HCl in dioxane The reaction mixture was refluxed for 16 h, then basified with aqueous NaHCO3 solution and extracted with EtOAc (2×30 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 4-(4-methoxyphenyl)-1-methyl-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one (150 mg, 29%) as a solid. 1H NMR (500 MHz, d6-DMSO): δ 8.43-8.39 (m, 1H), 8.04-7.98 (m, 2H), 7.82-7.56 (m, 3H), 7.18-7.09 (m, 4H), 7.04 (d, J=7.2 Hz, 2H), 6.82 (d, J=7.2 Hz, 2H), 5.39 (s, 2H), 4.38 (s, 2H), 3.78 (s, 3H), 2.99 (s, 3H). MS: M+H: m/z=437.1; M+Na: m/z=459.2; M+K: m/z=475.2 and HPLC: 87%, (Condition-B).
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]1[C:7]([CH3:14])=[N:8][C:9]([CH3:13])=[CH:10][C:11]=1[CH3:12])=O.[NH2:15][C:16]([NH2:18])=[S:17]>CCO>[CH3:14][C:7]1[C:6]([C:4]2[N:15]=[C:16]([NH2:18])[S:17][CH:3]=2)=[C:11]([CH3:12])[CH:10]=[C:9]([CH3:13])[N:8]=1
Reactant: NC(N)=S
Reactant: Cc1cc(C)c(C(=O)CBr)c(C)n1
Agent: Br
Solvent: CCO
Product: Cc1cc(C)c(-c2csc(N)n2)c(C)n1
Yield: 62.1 %

Procedure:
A mixture of 2-bromo-1-(2,4,6-trimethylpyridin-3-yl)ethanone hydrobromide (9.00 g, 27.9 mmol) and thiourea (2.12 g, 27.9 mmol) in 95% EtOH (39.8 mL) was heated at reflux for 120 min. The solution was concentrated and added with water (50 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(2,4,6-trimethylpyridin-3-yl)thiazol-2-amine (3.80 g) as yellow solids in 62% yield: 1H NMR (500 MHz, CDCl3) δ 6.87 (s, 1H), 6.31 (s, 1H), 5.07 (bs, 2H), 2.49 (s, 3H), 2.38 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: [F:1][C:2]1[N:3]=[C:4]([C:22]2[CH:23]=[N:24][CH:25]=[C:26]([F:28])[CH:27]=2)[S:5][C:6]=1[N:7](C(OC(C)(C)C)=O)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].FC(F)(F)C(O)=O>ClCCl>[C:11]([O:10][C:8](=[O:9])[NH:7][C:6]1[S:5][C:4]([C:22]2[CH:23]=[N:24][CH:25]=[C:26]([F:28])[CH:27]=2)=[N:3][C:2]=1[F:1])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1sc(-c2cncc(F)c2)nc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1sc(-c2cncc(F)c2)nc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.8 %

Procedure:
To a solution of di(tert-butyl) 4-fluoro-2-(5-fluoropyridin-3-yl)-1,3-thiazol-5-ylimidodicarbonate (320 mg, 0.77 mmol) in DCM (7 mL) was added trifluoroacetic acid (TFA) (0.7 mL). The solution was stirred at room temperature for 10 minutes, before quenched slowly with saturated NaHCO3 solution. The organic layer was separated and the aqueous layer was extracted with dichloromethane (DCM). The combined organic layer was dried over Na2SO4, filtered and purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to give product as a pale yellow solid (166 mg, 68%): mp 188-191° C.; 1H NMR (300 MHz, CDCl3) δ 8.84 (s, 1H), 8.46 (d, J=2.7 Hz, 1H), 7.85 (ddd, J=9.1, 2.6, 1.7 Hz, 1H), 6.92 (br s, 1H), 1.55 (s, 9H); ESIMS m/z 312 (M−1).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=C(N)[CH:8]=2)[N:3]=1.[H-].[Na+].CI.[CH3:17][N:18]([CH:20]=O)[CH3:19]>O>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[CH:8]=[C:20]([N:18]([CH3:19])[CH3:17])[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc2cc(N)ccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: Cc1ccc2cc(N(C)C)ccc2n1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
A mixture of 2-methylquinolin-6-amine (2.4 g, 15.2 mmol) and NaH (2.4 g, 60.8 mmol) in DMF (60 mL) was stirred at 40° C. for 3 hrs. Then CH3I (3.8 mL, 60.8 mmol) was added by syringe. The reaction mixture was stirred at 40° C. overnight and then cooled to room temperature. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water and brine and dried over anhydrous Na2SO4. After purified by column chromatography (hexane/EtOAc=25:1), compound 3 was obtained (1.1 g, 39%). MS [M++1]=187, LC-MS: tR=0.775 min.
Reaction SMILES: Br[C:2]1[C:3](=[O:27])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:8][CH:7]=[C:6]([O:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:5]=2.[Cu][C:29]#[N:30].[Cl-].[NH4+]>CN(C)C=O>[O:27]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([O:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:5]=2)[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:2]1[C:29]#[N:30]
Reactant: N#C[Cu]
Reactant: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: N#CC1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1=O
Temperature: 150 °C
Reaction time: 3 h
Yield: 83.3 %

Procedure:
2-Bromo-3-phenyl-6-(3-phenylpropoxy)indene-1-one (1.0 g, 2.3 mmol) was dissolved in N,N-dimethylformamide (10 ml). Copper (I) cyanide (617 mg, 6.9 mmol) was added thereto and the mixture was stirred for 3 hours at 150° C. The mixture was cooled, and saturated ammonium chloride was added thereto. The organic layer was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated, and the resulting residue was purified by column chromatography (ethyl acetate:hexane=1:3) to obtain the title compound (700 mg, yield 80%) as a red solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH3:26][C:27]([NH2:31])([CH3:30])[CH2:28][NH2:29]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:29][CH2:28][C:27]([CH3:30])([NH2:31])[CH3:26])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: CC(C)(N)CN
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC(C)(C)N)c2c1

Procedure:
The title compound was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2-methylpropane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 425, 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (d, J=7.83 Hz, 1 H), 7.85 (d, J=7.58 Hz, 1 H), 7.70 (s, 1 H), 7.60 (t, J=7.33 Hz, 1 H), 7.48-7.38 (m, 2 H), 7.29-7.27 (m, 1 H), 6.09 (s, 1 H), 5.15 (brs, 2 H), 3.57 (brs, 2 H), 3.26 (s, 2 H), 2.43 (s, 3 H), 1.34-1.20 (m, 6 H).
Reaction SMILES: [Br-].[C:2]1([P+:8]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:14][C:13]3[CH:15]=[CH:16][C:17]4[C:22]([C:12]=3[C:11]3[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=5[CH:29]=[CH:30][C:10]=3[CH2:9]2)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1(C)C=CC=CC=1>[C:2]1([P:8]([CH2:9][C:10]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:11]=2[C:12]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][C:13]=2[CH3:14])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc([P+]2(c3ccccc3)Cc3ccc4ccccc4c3-c3c(ccc4ccccc34)C2)cc1
Agent: [Al+3]
Agent: [Br-]
Agent: [H-]
Solvent: Cc1ccccc1
Product: Cc1ccc2ccccc2c1-c1c(CP(c2ccccc2)c2ccccc2)ccc2ccccc12
Reaction time: 5 h

Procedure:
4 g (7.3 mmol) of 4,4-diphenyl-4,5-dihydro-3H-dinaphtho-[2,1-c:1',2'-e]phosphepinium bromide are suspended under a protective gas in 70 ml of absolute toluene. 500 mg (14.3 mmol) of lithium aluminum hydride are added to this suspension and the reaction solution is heated to boiling for 5 hours. Unreacted lithium aluminum hydride is subsequently filtered off. The organic phase is extracted with 20 ml of 1N sodium hydroxide solution and subsequently with 20 ml portions of water until the aqueous phase has a pH of from 6 to 7. The organic phase is dried over sodium sulfate and the toluene is drawn off at 12 torr/40° C. The wax-like residue is admixed with 15 ml of oxygen-free isopropanol, boiled and crystallized.