Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[NH:8][N:7]=[C:6]([NH:9][C:10]2[C:11]3[CH2:26][CH2:25][CH2:24][C:12]=3[N:13]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH:17]3[C:21](O)=[O:22])[N:15]=2)[CH:5]=1)([CH3:3])[CH3:2].Cl.CN.[CH3:30][N:31](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH:1]([C:4]1[NH:8][N:7]=[C:6]([NH:9][C:10]2[C:11]3[CH2:26][CH2:25][CH2:24][C:12]=3[N:13]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH:17]3[C:21]([NH:31][CH3:30])=[O:22])[N:15]=2)[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)c1cc(Nc2nc(N3CCCC3C(=O)O)nc3c2CCC3)n[nH]1
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)C1CCCN1c1nc2c(c(Nc3cc(C(C)C)[nH]n3)n1)CCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 6.4 %

Procedure:
To a solution of 1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylic acid (300 mg, 0.842 mmol) in DMF (5 mL) was added methylamine hydrochloride (284 mg, 4.207 mmol), HATU (320 mg, 0.842 mmol), diisopropylethylamine (163 mg, 1.263 mmol). The reaction mixture was stirred at RT for 16 h. The progress of reaction was monitored by LCMS. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×30 mL). The organic layer was washed with water (8×40 mL) and dried over anhydrous sodium sulfate. Removal of solvent under vacuum gave a crude product which was purified by reverse HPLC to obtain pure 1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-methylpyrrolidine-2-carboxamide (20 mg) as racemate. The enantiomers were separated by chiral HPLC to afford (R)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-methylpyrrolidine-2-carboxamide (5 mg). 1H NMR (400 MHz, CD3OD, freebase) δ (ppm): 1.30 (d, 6H), 1.95-2.25 (m, 6H), 2.68 (s, 3H), 2.74 (t, 2H), 2.78 (t, 2H), 2.93-3.03 (m, 1H), 3.59 (brs, 1H), 3.80 (brs, 1H), 4.54 (d, 1H), 6.40 (brs, 1H). The other enantiomer was made using the chiral (R) starting material.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[N:7]=1)=O)C.[NH3:16].CO>>[CH3:15][O:14][C:8]1[CH:9]=[C:10]([O:12][CH3:13])[N:11]=[C:6]([C:4]([NH2:16])=[O:3])[N:7]=1
Reactant: N
Reactant: CCOC(=O)c1nc(OC)cc(OC)n1
Solvent: CO
Product: COc1cc(OC)nc(C(N)=O)n1
Yield: 100 %

Procedure:
Ethyl-4,6-dimethoxy-pyrimidin-2-carboxylate (25 g, 1 eq.) in NH3/MeOH (7 M, 15 mL) was irradiated in a microwave reactor at 100° C. for 15 min. The solution was concentrated in vacuo to yield compound 286 as a beige solid in 100% yield. MS (ESI, EI+): m/z=184 (MH+).
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16]([OH:18])=O)(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.[CH3:24][CH:25]([NH2:34])[CH:26]([OH:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16]([NH:34][C@H:25]([CH3:24])[C@@H:26]([OH:33])[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:18])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: CC(N)C(O)c1ccccc1
Product: C[C@@H](NC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12)[C@@H](O)c1ccccc1

Procedure:
2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chlorobenzoic acid was coupled with (1S,2R)-(+)-norephedrine as in EXAMPLE 1, Part C. HPLC: RT=10.13 min. MS (ESI−): mass calcd. for C22H19ClN4O4S2, 502.05; m/z found, 501 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.69 (s, 1H), 8.37 (dd, J=7.0, 1.0, 1H), 8.22 (dd, J=8.8, 1.0, 1H), 7.73 (d, J=2.0, 1H), 7.72 (dd, J=8.8, 7.0, 1H), 7.41-7.29 (m, 5H), 7.24 (d, J=8.4, 1H), 6.93 (dd, J=8.4, 2.0, 1H), 6.28 (br d, J=8.3, 1H), 4.98 (d, J=3.0, 1H), 4.45 (ddq, J=8.3, 6.9, 3.0, 1H), 2.60 (br s, 1H), 1.05 (d, J=6.9, 3H).
Reaction SMILES: CCN(C(C)C)C(C)C.[O:10]=[C:11]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH2:12][NH:13][C:14](=[O:28])[C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[Br:57][C:58]1[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][C:59]=1[C:60](O)=[O:61]>CN(C=O)C.O>[Br:57][C:58]1[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][C:59]=1[C:60]([N:32]1[CH2:31][CH2:30][N:29]([C:11](=[O:10])[CH2:12][NH:13][C:14](=[O:28])[C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:19][CH:20]=2)[CH2:34][CH2:33]1)=[O:61]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(Oc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Br)c(C(=O)N2CCN(C(=O)CNC(=O)c3ccc(Oc4ccccc4)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 84.5 %

Procedure:
DIPEA (85.5 mg, 0.114 mL, 0.66 mmol) was added to a stirred solution of N-(2-Oxo-2-piperazin-1-yl-ethyl)-4-phenoxy-benzamide (60 mg, 0.176 mmol) in DMF (2 mL). HOBT (21.89 mg, 0.16 mmol) and EDCI.HCl (70.5 mg, 0.36 mmol) were then added at room temperature. After 2 minutes, 2-Bromo-5-methoxy benzoic acid (33.9 mg, 0.15 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was then diluted with cold water, and the resulting precipitate was filtered, washed with water then hexane and dried to afford 70 mg (86.5% yield) of N-{2-[4-(2-Bromo-5-methoxy-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-4-phenoxy-benzamide as a pale yellow solid. LCMS Purity: 95.76%, HPLC Purity: 96.07%. 1H NMR (CDCl3): δ 8.5 (bs, 1H), 7.9 (d, 2H), 7.5 (m, 1H), 7.4 (m, 2H), 7.2 (m, 1H), 6.9 (m, 5H), 4.2 (m, 2H), 3.8 (s, 3H), 3.5 (m, 6H), 3.2 (m, 2H), 2.1 (s, 1H), 2.0 (m, 1H), 1.3 (s, 3H), 0.8 (m, 1H).
Reaction SMILES: [CH3:1][NH:2][NH2:3].[CH3:4][O:5][C:6](=[O:20])[CH:7]([C:17](=O)[CH3:18])[C:8](=O)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCO>[CH3:4][O:5][C:6]([C:7]1[C:17]([CH3:18])=[N:3][N:2]([CH3:1])[C:8]=1[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:20].[CH3:4][O:5][C:6]([C:7]1[C:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:3][N:2]([CH3:1])[C:17]=1[CH3:18])=[O:20]
Reactant: COC(=O)C(C(C)=O)C(=O)Cc1ccccc1
Reactant: CNN
Solvent: CCO
Product: COC(=O)c1c(C)nn(C)c1Cc1ccccc1
Product: COC(=O)c1c(Cc2ccccc2)nn(C)c1C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
MeNHNH2 (0.42 mL. 7.9 mmol) is added to a solution of 2-acetyl-3-oxo-4-phenyl-butyric acid methyl ester (1.84 g, 7.85 mmol) in EtOH (15 mL) at RT. The mixture is stirred for 14 h at RT. The solvent is removed and crude material is purified by column chromatography using 10-25% EtOAc in hexane to afford 5-benzyl-1,3-dimethyl-1H-pyrazole-4-carboxylic acid methyl ester (less polar) and 3-benzyl-1,5-dimethyl-1H-pyrazole-4-carboxylic acid methyl ester (more polar).
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:11][C:12]1N=C(C=O)S[CH:16]=1.O(C)[Na].[CH2:22]1[CH2:26]O[CH2:24][CH2:23]1>>[C:12]1([CH:11]=[CH:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:4])[CH:16]=[CH:24][CH:23]=[CH:22][CH:26]=1
Reactant: Cc1csc(C=O)n1
Reactant: O=C(CO)c1ccccc1
Reactant: C1CCOC1
Agent: CO[Na]
Product: O=C(C=Cc1ccccc1)c1ccccc1
Yield: 17 %

Procedure:
2.27 g (16.7 mmol) of 2-hydroxyacetophenone, 2.0 g of 4-methylthiazole-2-carbaldehyde (15.7 mmol), and 10 ml of 25% wt NaOCH3 were reacted in 50 ml of dry THF to give 0.67 g (17%) of chalcone after purification. 1H NMR (300 MHz, CDCl3): δ 12.67 (s, 1H), 7.98-7.95 (m, 1H), 7.80 (d, J=15.3 Hz, 1H), 7.89 (d, J=15.0 Hz, 1H), 7.53 (d, d, J=8.4, 8.4 Hz, 1H), 7.11 9 s, 1H), 7.05 (d, J=8.4 Hz, 1H), 6.97 (d, d, J=7.5, 7.8 Hz, 1H), 2.56 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:20])=[CH:4][C:5]([Cl:19])=[C:6]([CH:18]=1)[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH2:14])[C:9]=1[N+:15]([O-:17])=[O:16].[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1>>[NH2:14][C:10]1[C:9]([N+:15]([O-:17])=[O:16])=[C:8]([O:7][C:6]2[C:5]([Cl:19])=[CH:4][C:3]([Cl:20])=[C:2]([NH:1][C:30]([NH:29][C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([C:22]([F:21])([F:32])[F:33])[CH:24]=3)=[O:31])[CH:18]=2)[CH:13]=[CH:12][N:11]=1
Reactant: Nc1cc(Oc2ccnc(N)c2[N+](=O)[O-])c(Cl)cc1Cl
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Product: Nc1nccc(Oc2cc(NC(=O)Nc3cccc(C(F)(F)F)c3)c(Cl)cc2Cl)c1[N+](=O)[O-]
Yield: 58 %

Procedure:
Method G was used with 4-(5-amino-2,4-dichlorophenoxy)-2-amino-3-nitropyridine and 3-trifluoromethylphenyl isocyanate to afford the title compound as a yellow solid (92 mg, 58%). 1H-NMR (δ, ppm, DMSO-d6): 6.01 (d, 1H, HPy,5, J=5.6 Hz), 7.26 (s, 2H, NH2,Py), 7.35-7.37 (m, 1H, Harom), 7.53-7.55 (m, 2H, Harom), 7.90 (s, 1H, Harom), 7.98 (s, 1H, Harom), 8.03 (d, 1H, HPy,6, J=5.6 Hz), 8.24 (s, 1H, Harom), 8.62 (s, 1H, NHurea), 9.86 (s, 1H, NHurea). 13C-NMR (δ, ppm, DMSO-d6): 99.6 (C-4); 113.9 (C-11); 114.1 (C-14); 118.4 (C-2); 118.7 (C-16); 119.4 (C-7); 121.0 (C-18); 121.9 (C-9); 125.1 (C-15); 129.5 (C-19); 130.0 (C-17); 130.4 (C-8); 136.3 (C-10); 139.7 (C-13); 147.3 (C-6); 151.7 (C-12); 153.4 (C-5); 153.8 (C-1); 157.6 (C-3). LC-MS (m/z): 501 (M+H, 100).
Reaction SMILES: [S:1]1[CH2:5][C@@H:4]([C:6]([OH:8])=[O:7])[NH:3][CH2:2]1.CCN(C(C)C)C(C)C.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>CN(C=O)C>[CH2:22]([O:21][C:19]([N:3]1[C@H:4]([C:6]([OH:8])=[O:7])[CH2:5][S:1][CH2:2]1)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)[C@@H]1CSCN1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)[C@@H]1CSCN1C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
(R)-Thiazolidine-4-carboxylic acid (309.9 mg, 2.33 mmol) was dissolved in DMF (10 mL) and distilled water (10 mL). The solution was cooled to 0° C., and DIEA (0.590 mL, 3.39 mmol) was added followed by benzyl chloroformate (0.485 mL, 3.40 mmol). The reaction was stirred at 0° C. and allowed to warm to ambient temperature overnight. The reaction was filtered and purified by reverse phase HPLC to give the desired product.
Reaction SMILES: [Br:1]P(Br)Br.O[CH:6]([C:8]1[CH:9]=[C:10]([C:25]([N:27]([CH3:29])[CH3:28])=[O:26])[CH:11]=[C:12]2[C:17]=1[O:16][C:15]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[CH:14][C:13]2=[O:24])[CH3:7]>C(Cl)Cl>[BrH:1].[Br:1][CH:6]([C:8]1[CH:9]=[C:10]([C:25]([N:27]([CH3:29])[CH3:28])=[O:26])[CH:11]=[C:12]2[C:17]=1[O:16][C:15]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[CH:14][C:13]2=[O:24])[CH3:7]
Reactant: CC(O)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: Br
Product: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Temperature: 25 °C
Reaction time: 96 h
Yield: 82 %

Procedure:
A solution of tribromophosphine 1M in CH2Cl2 (0.346 mL, 0.35 mmol) at 25° C., was added dropwise to 8-(1-hydroxyethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (120 mg, 0.35 mmol) suspended in DCM (1 mL). The resulting suspension was stirred at 25° C. for 4 days. The resulting gum was triturated in ether to give a precipitate which was collected by filtration, washed with ether and dried to a constant weight to afford 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (140 mg, 82%) as a white solid, which was used without further purification. Mass Spectrum: M+H+ 409.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].C(OC([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[C:25]([O:30][CH2:31][CH2:32]O)=[N:26][CH:27]=[CH:28][N:29]=2)[CH2:20][CH2:19]1)=O)(C)(C)C.N(C(OCC)=O)=NC(OCC)=O>>[N:21]1([C:24]2[C:25]([O:30][CH2:31][CH2:32][O:10][C:3]3[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=3[Cl:1])=[N:26][CH:27]=[CH:28][N:29]=2)[CH2:22][CH2:23][NH:18][CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Reactant: COc1ccc(O)c(Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Product: COc1ccc(OCCOc2nccnc2N2CCNCC2)c(Cl)c1

Procedure:
The title compound was prepared starting from 2-chloro-4-methoxyphenol (103 mg, 0.65 mmol) and 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (0.61 mmol; prepared in Example 52, Step 2) according to the procedure described in Example 52, Step 3, but utilizing diethyl azodicarboxylate (DEAD) instead of TMAD. Yield 50 mg (21%). HRMS m/z calcd for C17H21ClN4O3 (M)+ 364.1302, found 364.1307
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([CH2:11][C:12]([OH:14])=[O:13])[C:9]=2[CH:10]=1.[CH2:15](Br)[CH:16]=[CH2:17].C(=O)([O-])[O-].[K+].[K+].Cl.C(OCC)(=O)C>CN(C)C=O>[CH2:17]([O:13][C:12](=[O:14])[CH2:11][C:8]1[C:9]2[CH:10]=[C:2]([CH3:1])[NH:3][C:4]=2[CH:5]=[CH:6][CH:7]=1)[CH:16]=[CH2:15]
Reactant: C=CCBr
Reactant: Cc1cc2c(CC(=O)O)cccc2[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)Cc1cccc2[nH]c(C)cc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 2-methylindole-4-acetic acid (53 g) in N,N-dimethylformamide (500 ml) was added dropwise allyl bromide (31 ml), and added anhydrous potassium carbonate (59 g). The mixture was stirred at 50° C. for 1 hour. After cooling to room temperature, the reaction mixture was poured into a mixture of 2N hydrochloric acid-ethyl acetate and then extracted with ethyl acetate. The extraction was washed with water and a saturated aqueous solution of sodium chloride, successively, dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane-ethyl acetate) to give the title compound (43.5 g) having the following physical data.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl.[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][N:30]([C:8]([NH:7][C:2]4[CH:3]=[N:4][CH:5]=[CH:6][N:1]=4)=[O:15])[CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Nc1cnccn1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cnccn1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 36.4 %

Procedure:
A solution of 2,2,2-trichloroethyl pyrazin-2-ylcarbamate (150 mg, 0.556 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (137 mg, 0.556 mmol), diisopropylethylamine (0.0968 ml, 0.556 mmol) and dimethylsulfoxide (3 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and a solid was collected by filtration and washed with water. This was recrystallized from a mixed solvent of tetrahydrofuran and ethyl acetate to obtain the desired product (74.3 mg, 36.4%) as a solid.
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([C@@:7]2(O)[CH2:11][N:10]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C@H:9]([C:22]([O:24][CH3:25])=[O:23])[CH2:8]2)=[CH:3][CH:2]=1.[CH3:33][Si:34]([CH2:37][SH:38])([CH3:36])[CH3:35]>C(#N)C.FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([C@:7]2([S:38][CH2:37][Si:34]([CH3:36])([CH3:35])[CH3:33])[CH2:11][N:10]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C@H:9]([C:22]([O:24][CH3:25])=[O:23])[CH2:8]2)=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)CS
Reactant: COC(=O)[C@@H]1C[C@@](O)(c2ccc(-c3ccccc3)cc2)CN1C(=O)OCc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: CC#N
Product: COC(=O)[C@@H]1C[C@](SC[Si](C)(C)C)(c2ccc(-c3ccccc3)cc2)CN1C(=O)OCc1ccccc1
Reaction time: 26 h
Yield: 43.7 %

Procedure:
To a clear solution of (2S,4R)-1-benzyl 2-methyl 4-(biphenyl-4-yl)-4-hydroxypyrrolidine-1,2-dicarboxylate (2.59 g, 6.00 mmol) and trimethylsilylmethanethiol (1.019 mL, 7.20 mmol) in Acetonitrile (30 mL) was added Scandium(III) trifluoromethanesulfonate (0.295 g, 0.600 mmol) as solid by one portion at room temperature. The formed pink solution was stirred at this temperature for 26 h. TLC analysis showed starting material was completely consumed. Quenched with sat. ammonium chloride, extracted with EtOAc. Washed the organic with brine, dried over MgSO4, filtered, evaporated in vacuo. The residue was purified by BIOTAGE® column, eluted with gradient 5˜40% EtOAc-hexane to afford the mixture of diastereomers 3.10 g (97%). This oily mixture was purified by BIOTAGE® again, eluted with gradient 0˜20% EtOAc-toluene to yield the by-product (2S,4S)-1-benzyl 2-methyl 4-(biphenyl-4-yl)-4-((trimethylsilyl)methylthio)pyrrolidine-1,2-dicarboxylate (1.40 g, 2.62 mmol, 43.7% yield) as a wax and the desired product (2S,4R)-1-benzyl 2-methyl 4-(biphenyl-4-yl)-4-((trimethylsilyl)methylthio)pyrrolidine-1,2-dicarboxylate (1.25 g, 2.108 mmol, 35.1% yield) as a white foam. 1H NMR (500 MHz, CHLOROFORM-d) ppm −0.03 (s, 9H), 1.33 (dd, J=28.08, 11.29 Hz, 1H), 1.49 (dd, J=17.70, 11.29 Hz, 1H), 2.62-2.85 (m, 2H), 3.62, 3.77 (s, 3H), 3.97 (t, J=11.60 Hz, 1H), 4.16 (dd, J=74.62, 11.44 Hz, 1H), 4.35-4.56 (m, 1H), 4.99-5.19 (m, 1H), 5.17-5.27 (m, 1H), 7.27-7.40 (m, 8H), 7.39-7.49 (m, 2H), 7.49-7.67 (m, 4H). LC-MS (retention time: 3.62 mm, method B), MS m/z 534 (M+H).
Reaction SMILES: Br.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[C:6](=[O:14])[N:5]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:4]1=[O:21].Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[C:25]([CH2:37][CH2:38][CH3:39])[N:24]=1.C(O)(C)C>CO>[CH3:34][O:33][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][C:29]=1[O:35][CH3:36])[N:26]=[C:25]([CH2:37][CH2:38][CH3:39])[N:24]=[C:23]2[N:18]1[CH2:19][CH2:20][CH:15]([N:5]2[C:6](=[O:14])[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=3)[N:3]([CH3:2])[C:4]2=[O:21])[CH2:16][CH2:17]1
Reactant: Cc1ccc2c(c1)c(=O)n(C1CCNCC1)c(=O)n2C
Reactant: CCCc1nc(Cl)c2cc(OC)c(OC)cc2n1
Agent: Br
Solvent: CC(C)O
Solvent: CO
Product: CCCc1nc(N2CCC(n3c(=O)c4cc(C)ccc4n(C)c3=O)CC2)c2cc(OC)c(OC)cc2n1
Yield: 35 %

Procedure:
The procedure similar to that described in Example 40 was repeated, except that 354.0 mg (1.0 mmol) of 1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)quinazoline hydrobromide (Compound v) obtained in Example 41 was used, 4-chloro-6,7-dimethoxy-2-propylquinazoline was used in place of 4-chloro-6,7-dimethoxyquinazoline, and isopropyl alcohol was used as a reaction solvent in place of methanol. As a result, 174.3 mg (yield: 35%) of Compound 82 was obtained as white crystals.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[NH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C=O)C>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][N:6]1[C:7]2[C:12](=[C:11]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:10]=[CH:9][CH:8]=2)[C:4]([N+:1]([O-:3])=[O:2])=[CH:5]1)[CH3:29]
Reactant: CC(C)(C)OC(=O)Cc1cccc2[nH]cc([N+](=O)[O-])c12
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc([N+](=O)[O-])c2c(CC(=O)OC(C)(C)C)cccc21
Reaction time: 0.08 h

Procedure:
To a solution of tert-butyl [3-nitro-1H-indol-4-yl]acetate from Step D (385 mg, 1.39 mmol) in DMF (5 mL) at ambient temperature was added sodium hydride (60 mg of a 60% dispersion in mineral oil, 1.50 mmol). The reaction mixture was stirred for 5 min, then ethyl bromoacetate (256 mg, 1.53 mmol) was added and stirring was continued for 10 min. The reaction was quenched with saturated aqueous NaHCO3 (5 mL) and extracted with CHCl3 (2×25 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—90:10 to 40:60, to give the title compound. MS: m/z=307 (M-C4H7).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[F:5][C:6]([F:23])([F:22])[CH2:7][N:8]=[C:9]([NH2:21])[NH:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][S:17][CH2:18][CH2:19][NH2:20])[N:15]=1>CO>[F:23][C:6]([F:5])([F:22])[CH2:7][N:8]=[C:9]([NH2:21])[NH:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][S:17][CH2:18][CH2:19][NH:20][C:3]([NH:2][CH3:1])=[S:4])[N:15]=1
Reactant: CN=C=S
Reactant: NCCSCc1csc(NC(N)=NCC(F)(F)F)n1
Solvent: CO
Product: CNC(=S)NCCSCc1csc(NC(N)=NCC(F)(F)F)n1
Reaction time: 18 h
Yield: 22.8 %

Procedure:
Methyl isothiocyanate (80 mg.) was added to 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazole (320 mg.) dissolved in methanol (5 ml.) and the solution kept at room temperature for 18 hours and then evaporated to dryness. The residual gum was purified by preparative thin layer chromatography using ethyl acetate/methanol/ammonia 6:1:0.5 v/v/v as developing solvent to give 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[2-(3-methylthioureido)ethylthiomethyl]thiazole (90 mg.), characterised as the hydrogen maleate, m.p. 137°139° (decomp.) (after crystallisation from acetonitrile.).
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:25][C:4]=1[CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[Na+].O=[C:36]1[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:37]1>CN(C)C=O>[Cl:2][C:3]1[CH:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:25][C:4]=1[CH:5]=[C:36]1[CH2:37][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39]1
Reactant: COC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C=C2CN(C(=O)OC(C)(C)C)C2)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 42.7 %

Procedure:
(2-Chloro-4-(methoxycarbonyl)benzyl)triphenylphosphonium bromide (1.04 g, 1.98 mmol) was dissolved in N,N-dimethylformamide (DMF, 20 mL) and the solution was cooled to 0° C. A 60% suspension of NaH in paraffin oil (80 mg, 2.00 mmol) was added and the reaction mixture was stirred at 0° C. for 15 mins. A solution of tert-butyl 3-oxoazetidine-1-carboxylate (0.32 g, 1.87 mmol) in anhydrous DMF (5 mL) was added and the reaction mixture was heated overnight at 65° C. After completion of the reaction as indicated by HPLC/MS, the cooled reaction mixture was diluted with EtOAC (20 mL) and quenched with a saturated NH4Cl solution (10 mL). The organic layer was washed with water (3×20 mL) and brine (15 mL). It was then dried over anhydrous Na2SO4, filtered and evaporated to get the crude product. This crude was purified by silica gel column chromatography using 50-80% EtOAc in Hexanes as eluent to provide tert-butyl 3-(2-chloro-4-(methoxycarbonyl)benzylidene)azetidine-1-carboxylate (0.27 g) as a white solid. ES+(M+Na)+360.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH2:24][CH3:25])[CH:16]=2)[CH2:13][CH2:12][CH:11]([O:26][C:27](=[O:29])[CH3:28])[CH2:10]1)=O)(C)(C)C>Cl.O1CCOCC1>[NH2:8][CH:9]1[CH:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH2:24][CH3:25])[CH:16]=2)[CH2:13][CH2:12][CH:11]([O:26][C:27](=[O:29])[CH3:28])[CH2:10]1
Reactant: CCOc1cc(C2CCC(OC(C)=O)CC2NC(=O)OC(C)(C)C)ccc1OC
Agent: Cl
Solvent: C1COCCO1
Product: CCOc1cc(C2CCC(OC(C)=O)CC2N)ccc1OC
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
3.0 g (7.36 mmol) of acetic acid (1SR,3RS,4RS)-3-tert-butoxycarbonylamino-4-(3-ethoxy-4-methoxy-phenyl)-cyclohexyl ester (compound C6) are dissolved in 6 ml of 4 M HCl in dioxane and stirred for 30 min. After removal of the solvent the residue is dissolved in dichloromethane and 25 ml of sat. Na—HCO3 solution are added carefully. After phase separation, reextraction of the water layer and drying of the combined organic layers (Na2SO4) the solvent is removed to give 2.25 g of the title compound.