Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.[C:12]([C:16]1[CH:46]=[CH:45][C:19]([C:20]([C:22]2[C:23]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)=[C:24]3[C:29](=[CH:30][C:31]=2[CH:32]([CH3:34])[CH3:33])[O:28][C:27]([CH3:36])([CH3:35])[CH2:26][C:25]3=[O:37])=[O:21])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].CO>O1CCCC1>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([C:20]([C:22]2[C:23]([C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)=[C:24]3[C:29](=[CH:30][C:31]=2[CH:32]([CH3:34])[CH3:33])[O:28][C:27]([CH3:35])([CH3:36])[CH2:26][C@@H:25]3[OH:37])=[O:21])=[CH:45][CH:46]=1)([CH3:14])([CH3:15])[CH3:13]
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(=O)c1ccc(C(C)(C)C)cc1)C(=O)CC(C)(C)O2
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(=O)c1ccc(C(C)(C)C)cc1)[C@@H](O)CC(C)(C)O2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
78 μl (540 μmol) of borane/N,N-diethylaniline complex are added slowly to a solution of 2.46 mg (20 μmol) of (1R,2S)-1-aminoindan-2-ol in 2 ml of tetrahydrofuran. The mixture is then cooled to 0° C., and a solution of 52 mg (110 μmol) of 6-(4-tert-butylbenzoyl)-5-(4-fluorophenyl)-7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (Example 29A) in 3 ml of tetrahydrofuran are slowly added dropwise. The mixture is then allowed to thaw slowly and stirred at room temperature overnight. Methanol is then added, and the solvent is removed under reduced pressure. The residue is taken up in ethyl acetate and washed in each case twice with 1 M hydrochloric acid and saturated sodium bicarbonate solution and once with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. Purification of the residue by preparative HPLC (method 1) and subsequent chiral HPLC (method 2) gives the target compound.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH2:20][CH2:21][NH2:22])[CH:17]=[CH:18][CH:19]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:23]([O:30][C:31]1[CH:32]=[CH:33][C:34]([C@@H:42]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH2:43]Br)=[C:35]2[C:40]=1[NH:39][C:38](=[O:41])[CH:37]=[CH:36]2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+].[I-].[Na+]>CS(C)=O.O>[C:1]12([CH2:11][CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH2:20][CH2:21][NH:22][CH2:43][C@@H:42]([C:34]4[CH:33]=[CH:32][C:31]([O:30][CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[C:40]5[C:35]=4[CH:36]=[CH:37][C:38](=[O:41])[NH:39]5)[O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH:17]=[CH:18][CH:19]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reactant: NCCc1cccc(OCCC23CC4CC(CC(C4)C2)C3)c1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCc1cccc(OCCC23CC4CC(CC(C4)C2)C3)c1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a solution of Intermediate 31 (0.51 g, 1.7 mmol) in dimethyl sulfoxide (1.5 mL) and (R)-8-(benzyloxy)-5-(2-bromo-1-(tert-butyldimethylsilyloxy)ethyl)quinolin-2(1H)-one (1.06 g, 2.17 mmol) in dimethyl sulfoxide (2 mL) was added sodium hydrogen carbonate (0.53 g, 6.37 mmol) and sodium iodide (0.970 g, 6.47 mmol). The reaction mixture was stirred at 120° C. for 2 hours. The reaction was poured into water and filtered. The crude was purified by column chromatography with silica gel, eluting by methylen chloride giving the title compound as a solid (0.84 g, 63%). MS (M+): 708.
Reaction SMILES: [CH3:1][C:2]1[C:3](=O)[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][NH:6][CH:7]=1.[N-:14]=[N+:15]=[N-:16].[Na+]>P(Cl)(Cl)(Cl)=O>[N:14]([C:3]1[C:2]([CH3:1])=[CH:7][N:6]=[CH:5][C:4]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N+:15]=[N-:16]
Reactant: CCOC(=O)c1c[nH]cc(C)c1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cncc(C)c1N=[N+]=[N-]
Temperature: 95 °C
Yield: 74 %

Procedure:
A slurry of 14.1 g (78 mmol) of ethyl 1,4-dihydro-5-methyl-4oxo-3-pyridinecarboxylate (prepared according to Horvath, G.; Dvortsak, P. J. Heterocycl. Chem. 1980, 359) in 30 mL of phosphorous oxychloride was refluxed for 1 hour. After cooling, the volatiles were removed with a rotary evaporator. The residue was poured into cold saturated aqueous sodium bicarbonate. Dichloromethane was added and the mixture was filtered through celite. The layers were separated. The organic layer was dried (sodium sulfate) and the solvent was removed with a rotary evaporator. The residue was dissolved in 150 mL of dimethylformamide. 15.2 g (234 mmol) of sodium azide was added. The mixture was heated at 95° C. for 1 hour. After cooling, the solvent was removed with a rotary evaporator. The residue was partitioned between ethyl acetate and water. The organic layer was dried (sodium sulfate) and the solvent was removed with a rotary evaporator. The residue was passed through a plug of silica gel with 25% ethyl acetate in hexanes as eluant to afford 11.9 g of the title compound as a cream colored solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH3:10].C(Cl)(Cl)(Cl)Cl.C1C(=O)N([Br:23])C(=O)C1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][Br:23]
Reactant: COc1ccc(Br)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(Br)c(CBr)c1
Temperature: 25 °C

Procedure:
To a solution of 173 g (0.86 mol) of 1-bromo-4-methoxy-2-methylbenzene in 850 ml of CCl4 153 g (0.86 mol) of NBS and 1.0 g of (PhCOO)2 were added at room temperature. This mixture was refluxed for 16 h, cooled to room temperature, and then filtered through glass frit (G2). The precipitate was additionally washed by 2×150 ml of CCl4. The combined filtrate was evaporated to dryness, and the residue was triturated with 600 ml of n-hexane. The precipitate was filtered off (G3 glass frit), washed by 50 ml of n-hexane, and dried in vacuum. This procedure gave 121 g of the title product. Additional amount of the product was obtained by evaporation of a mother liquor followed by crystallization of the residue from 200 ml of n-hexane at −25° C. In total, 157 g (65%; or 56% overall yield for two stages) of 1-bromo-2-(bromomethyl)-4-methoxybenzene has been isolated.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[C:7]([F:15])[CH:6]=1)=O.[C:16]([NH:19][C:20]([NH2:22])=[NH:21])(=[O:18])[CH3:17]>C(#N)C.C(OCC)(=O)C.O>[F:15][C:7]1[CH:6]=[C:5]([C:3]2[N:21]=[C:20]([NH:19][C:16](=[O:18])[CH3:17])[NH:22][CH:2]=2)[CH:10]=[CH:9][C:8]=1[C:11]([F:14])([F:13])[F:12]
Reactant: CC(=O)NC(=N)N
Reactant: O=C(CBr)c1ccc(C(F)(F)F)c(F)c1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)Nc1nc(-c2ccc(C(F)(F)F)c(F)c2)c[nH]1
Temperature: 25 °C
Yield: 25.5 %

Procedure:
To a stirred solution of 2-bromo-1-[3-fluoro-4-(trifluoromethyl)phenyl]ethanone (4.5 g, 15.73 mmol) in acetonitrile (45 ml) was added acetyl guanidine (2.38 g, 23.60 mmol) at room temperature. After refluxing for 4 h the reaction mixture was cooled to room temperature and diluted with ethyl acetate and water. The layers were separated. The aqueous layer was extracted 2-3 times with ethyl acetate and the combined organic layers were washed with water, followed by brine, dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure. The residue obtained after the evaporation of the solvent was purified by silica gel column chromatography using 2% methanol in chloroform to obtain 1.15 g of the product as a yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 2.07 (s, 3H), 7.58 (s, 1H), 7.69-7.78 (m, 3H), 11.31 (br s, 1H), 11.91 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH2:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.[CH2:27]([N:29]=[C:30]=[O:31])[CH3:28]>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH:26][C:30]([NH:29][CH2:27][CH3:28])=[O:31])[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: CCN=C=O
Reactant: CCC(N)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Product: CCNC(=O)NC(CC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Yield: 37.6 %

Procedure:
To a solution of crude 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-amine (100 mg) in tetrahydrofuran (2.3 mL) was added ethyl isocyanate (0.0222 mL, 0.280 mmol) at 0° C. The resultant mixture was stirred at room temperature for 30 min and concentrated in vacuo. The residue was washed with ethyl acetate to give the title compound as a colorless solid (44.1 mg, 0.0917 mmol).
Reaction SMILES: IC1C([N+]([O-])=O)=CC(Cl)=CN=1.C1([Mg]Cl)C=CC=CC=1.[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=[O:25]>>[F:20][C:21]1[CH:22]=[C:23]([CH2:24][OH:25])[CH:26]=[CH:27][CH:28]=1
Reactant: O=Cc1cccc(F)c1
Agent: Cl[Mg]c1ccccc1
Agent: O=[N+]([O-])c1cc(Cl)cnc1I
Product: OCc1cccc(F)c1
Reaction time: 0.5 h
Yield: 44.4 %

Procedure:
A freshly oven dried 250 mL round-bottom flask was charged with 2-iodo-3-nitro-5-chloro-pyridine (1.41 g, 5.0 mmol). The resultant solution was cooled to −78° C. under N2 and PhMgCl (2 M, 3 mL, 6.0 mmol) added and then stirred at the same temperature for 30 min. 3-Fluorobenzaldehyde (1.24 g, 10 mmol) was added and the resulting mixture stirred at −78° C. for two hours and then at room temperature for 24 h. The reaction was quenched with NH4Cl (sat), extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was further purified through automated normal-phase chromatography to afford 5-chloro-3-nitropyridin-2-yl)(3-fluorophenyl)methanol (560 mg, 40%) which was used directly for the next step: 1H NMR (400 MHz, CDCl3) δ 8.85 (d, 1H), 8.37 (d, 1H), 7.23 (m, 1H), 7.06 (dd, 1H), 6.95 (dd, 1H), 6.43 (d, 2H), 4.99 (d, 1H); MS (ES) (M+-OH) expect 265.0, found 265.1.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:28][C:29]([NH2:31])=[O:30].CC#N>CCOC(C)=O>[C:17]([C:9]1[C:10]([C:13]([F:16])([F:15])[F:14])=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([CH2:28][C:29]([NH2:31])=[O:30])[C:4]([CH2:3][C:2]([F:1])([F:19])[F:20])=[CH:12]2)#[N:18]
Reactant: N#Cc1ccc2[nH]c(CC(F)(F)F)cc2c1C(F)(F)F
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c(cc(CC(F)(F)F)n2CC(N)=O)c1C(F)(F)F
Temperature: 70 °C
Reaction time: 2 h
Yield: 28.6 %

Procedure:
A mixture of 2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 374A) (0.050 g, 0.17 mmol), Cs2CO3 (0.112 g, 0.34 mmol), 2-bromoacetamide (0.047 g, 0.34 mmol) and CH3CN (4 mL) was stirred at 70° C. for 2 h. The mixture was diluted with EtOAc (25 mL), washed with water (15 mL), brine (1 5 mL), dried over (MgSO4) and concentrated. The residue was stirred in EtOAc (5 mL) for 30 min. The resulting solid was filtered, rinsed with hexanes and dried to afford the title compound (0.017 g, 28%) as a tan solid: 1H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J=8.6 Hz, 1H), 7.79 (d, J=8.6 Hz, 1H), 7.72 (s, 1H), 7.38 (s, 1H), 6.78 (s, 1H), 5.01 (s, 2H), 4.07 (q, 2H); MS m/z 348 (M−H).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:9][CH2:10][CH2:11][OH:12].[N+:13]([C:16]1[CH:21]=[CH:20][C:19](O)=[CH:18][CH:17]=1)([O-])=O>>[N:1]1([CH2:9][CH2:10][CH2:11][O:12][C:19]2[CH:20]=[CH:21][C:16]([NH2:13])=[CH:17][CH:18]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: C1CCCNCC1
Reactant: OCCCBr
Product: Nc1ccc(OCCCN2CCCCCC2)cc1

Procedure:
The target compound was obtained by the method according to Example 138, using azepane, 3-bromopropanol and 4-nitrophenol as starting materials.
Reaction SMILES: C(OP([CH:9]([CH2:15][CH2:16][CH2:17][F:18])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[C:21]([O:25][C:26]([NH:28][C@@H:29]([CH2:37][CH:38]=O)[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:27])([CH3:24])([CH3:23])[CH3:22]>C1COCC1>[C:21]([O:25][C:26]([NH:28][C@H:29]([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[CH2:37]/[CH:38]=[C:9](\[CH2:15][CH2:16][CH2:17][F:18])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:27])([CH3:24])([CH3:22])[CH3:23].[C:21]([O:25][C:26]([NH:28][C@H:29]([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[CH2:37]/[CH:38]=[C:9](/[CH2:15][CH2:16][CH2:17][F:18])\[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOC(=O)C(CCCF)P(=O)(OCC)OCC
Reactant: CC(C)(C)OC(=O)N[C@@H](CC=O)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C(=C/C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CCCF
Product: CCOC(=O)/C(=C\C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CCCF
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of ethyl 2-(diethoxyphosphoryl)-5-fluoropentanoate (1.30 g, 4.12 mmol) in dry THF (15 mL) was added dropwise at 0° C. to a solution of sodium hydride (0.20 g, 60% on mineral oil, 4.94 mmol) in dry THF (35 mL). After stirring for 15 min tert-Butyl (S)-2-[(tert-butoxycarbonyl)amino]-4-oxobutanoate (1.13 g, 4.12 mmol) was added as a solution in dry THF (15 mL) dropwise to the reaction mixture. After stirring for 90 min at 0° C. the reaction was quenched by addition of saturated sodium bicarbonate solution (50 mL). After phase separation the aqueous layer was extracted with ethyl acetate (3×50 mL) and the combined organic layers were dried over sodium sulphate, concentrated under reduced pressure and the residue was purified by column chromatography (silica, hexanes/ethyl acetate gradient) to give 6-tert-Butyl 1-ethyl (E)-(S)-5-[(tert-butoxycarbonyl)amino]-2-(3-fluoropropyl)hex-2-ene-dioate and 6-tert-Butyl 1-ethyl (Z)—(S)-5-[(tert-butoxycarbonyl)amino]-2-(3-fluoropropyl)hex-2-enedioate as a mixture of diastereomers which were separated by HPLC (Chiralpak IC 5 μm 250×30 mm, hexane/2-propanol 90:10, 50 mL/min) to give 6-tert-Butyl 1-ethyl (E)-(S)-5-[(tert-butoxycarbonyl)amino]-2-(3-fluoropropyl)hex-2-enedioate (1e) (0.75 g, 1.86 mmol, 45%) and 6-tert-Butyl 1-ethyl (Z)—(S)-5-[(tert-butoxycarbonyl)amino]-2-(3-fluoropropyl)hex-2-enedioate (1d) (0.23 g, 0.56 mmol, 14%).
Reaction SMILES: Cl[Si](C)(C)C.Br[C:7]([F:14])([F:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:15]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[O:35][CH2:34][CH2:33][N:32]([CH2:36]N3C4C=CC=CC=4N=N3)[CH2:31]2)=[CH:26][CH:25]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C1COCC1.[Zn]>[CH2:11]([O:10][C:8](=[O:9])[C:7]([F:14])([F:13])[CH2:36][N:32]1[CH2:33][CH2:34][O:35][CH:30]([C:27]2[CH:28]=[CH:29][C:24]([O:23][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:25][CH:26]=2)[CH2:31]1)[CH3:12]
Reactant: CCCCCCCCOc1ccc(C2CN(Cn3nnc4ccccc43)CCO2)cc1
Reactant: CCOC(=O)C(F)(F)Br
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(C2CN(CC(F)(F)C(=O)OCC)CCO2)cc1
Temperature: 25 °C

Procedure:
To a suspension of zinc dust (0.34 g; 5.2 mmol) in dry THF (10 mL) was added chlorotrimethylsilane (0.33 mL; 2.6 mmol) and ethyl bromodifluoroacetate (0.50 ml; 3.9 mmol), this mixture was heated under reflux for 10 min. and then cooled to RT. To the resulting mixture was added drop-wise a solution of 1-[2-(4-octyloxy-phenyl)-morpholin-4-ylmethyl]-1H-benzotriazole in THF (5 mL). After the addition is complete the resulting mixture is heated under efflux for 2 hours. After cooling to RT the reaction mixture was filtered over Kieselguhr and the filter-cake was washed with ethanol. The solvents were removed in vacuo and the residue was purified by column chromatography (SiO2, Et2O:hexanes 1:1) to afford 2,2-difluoro-3-(2-(4-octyloxy-phenyl)-morpholin-4-yl)-propionic acid ethyl ester (0.58 g).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH2:26][NH2:27])=[C:24]([CH2:28][CH3:29])[N:23]=[C:22]3[O:30][CH2:31][CH3:32])=[C:16]([F:33])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:34]([S:37][C@@H:38]([CH2:42][CH:43]([CH3:45])[CH3:44])[C:39](O)=[O:40])(=[O:36])[CH3:35].CN1CCOCC1.ON1C2N=CC=CC=2N=N1.CN(C=O)C.C(Cl)CCl>>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH2:26][NH:27][C:39](=[O:40])[C@@H:38]([S:37][C:34](=[O:36])[CH3:35])[CH2:42][CH:43]([CH3:45])[CH3:44])=[C:24]([CH2:28][CH3:29])[N:23]=[C:22]3[O:30][CH2:31][CH3:32])=[C:16]([F:33])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOc1nc(CC)c(CN)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Reactant: CC(=O)S[C@@H](CC(C)C)C(=O)O
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCOc1nc(CC)c(CNC(=O)[C@H](CC(C)C)SC(C)=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4′-(5-Aminomethyl-2-ethoxy-4-ethylimidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylic acid t-butyl ester (5.0 g, 11.0 mmol), (S)-2-acetylsulfanyl-4-methylpentanoic acid (dicyclohexylamine salt; 2.1 g, 11.0 mmol), 4-methylmorpholine (1.2 mL, 11.0 mmol), and 1-hydroxy-7-azabenzotriazole (1.5 g, 11.0 mmol) were combined and dissolved in DMF (120 mL, 1.6 mol) and then cooled at 0° C. for 10 minutes. EDC (2 mL, 11.0 mmol) was added and the mixture was stirred at 0° C. for 1 hour and then at room temperature for 2 hours. The reaction was quenched with water (100 mL), the product extracted with EtOAc (100 mL), and then concentrated. The mixture was purified by column chromatography (0-50% EtOAc:hexanes) to obtain the acetylsulfanyl ester intermediate, 4′-{5-[((S)-2-acetylsulfanyl-4-methylpentanoylamino)methyl]-2-ethoxy-4-ethylimidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylic acid t-butyl ester.
Reaction SMILES: [N:1]([C:4]1[C:13]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[C:5]=1[F:32])=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:1][C:4]1[C:13]([S:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[C:5]=1[F:32]
Reactant: [H][H]
Reactant: COC(=O)c1cc(SCc2ccc(OC)cc2)c(N=[N+]=[N-])c(F)c1Nc1ccccc1Cl
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(SCc2ccc(OC)cc2)c(N)c(F)c1Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
To a solution of methyl 4-azido-5-(4-methoxybenzylthio)-3-fluoro-2-((2-chlorophenyl)amino)-benzoate (21.63 g, 45.74 mmol) in MeOH (500 mL) was added and 10% palladium on carbon (3.40 g) under nitrogen atmosphere. Then the nitrogen atmosphere was completely changed to hydrogen atmosphere. The mixture was stirred for 2 h at ambient temperature. After the insoluble matter was filtered off, the solvent was evaporated in vacuo to give the desired product (19.93 g, 97.5% yield). 1H NMR (400 MHz, CDCl3): δ 8.99 (s, 1H), 7.82 (s, 1H), 7.21 (m, 1H), 7.17 (m, 3H), 6.87 (m, 3H), 6.69 (m, 1H), 4.63 (s, 2H), 3.85 (s, 5H), 3.81 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[O:9])[C:5]([OH:11])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[CH2:15]([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][C:24]=1[N+:31]([O-:33])=[O:32])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+].Cl>O.C(O)C>[CH2:15]([O:22][C:23]1[CH:30]=[CH:29][C:26](/[CH:27]=[CH:10]/[C:8]([C:6]2[CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]=2[OH:11])=[O:9])=[CH:25][C:24]=1[N+:31]([O-:33])=[O:32])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(=O)c1cc(C)cc([N+](=O)[O-])c1O
Reactant: O=Cc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(C(=O)/C=C/c2ccc(OCc3ccccc3)c([N+](=O)[O-])c2)c(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
2-hydroxy-5-methyl-3-nitroacetophenone (200 mg, 1.02 mmol), 4-benzyloxy-3-nitrobenzaldehyde (300 mg, 1.16 mmol) and 3 equivalents of sodium hydroxide (120 mg) were introduced into 80% aqueous ethanol solution and the resulting mixture was stirred for 3 hours at room temperature. The reaction solution was acidified by 2N hydrochloric acid solution and diluted with water. The resulting solid was filtered, washed with large amount of water and methanol, and then dried to give 430 mg (Yield 97%) of the title compound as a yellow solid.
Reaction SMILES: [N+](C1C=CC(C(=O)CBr)=CC=1)([O-])=O.[C:14]([C:16]1[CH:25]=[CH:24][C:19]([C:20](=[O:23])[CH2:21][Cl:22])=[CH:18][CH:17]=1)#[N:15].[Cl:26][C:27]1[CH:28]=[N:29][CH:30]=[N:31][CH:32]=1>N1C=CC=CC=1>[Cl-:22].[C:14]([C:16]1[CH:25]=[CH:24][C:19]([C:20](=[O:23])[CH2:21][N+:29]2[CH:28]=[C:27]([Cl:26])[CH:32]=[N:31][CH:30]=2)=[CH:18][CH:17]=1)#[N:15]
Reactant: N#Cc1ccc(C(=O)CCl)cc1
Reactant: Clc1cncnc1
Agent: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Product: N#Cc1ccc(C(=O)C[n+]2cncc(Cl)c2)cc1
Product: [Cl-]

Procedure:
Employing the procedure of Example III but replacing 4-nitrophenacyl bromide with a substantially equimolecular amount of 4-cyanophenacyl chloride and replacing pyridine with a substantially equimolecular amount of 5-chloropyrimidine there is obtained N-(4-cyanophenacyl) 5-chloropyrimidinium chloride, a solid soluble in water.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:16][CH2:15][C@@H:14]([OH:17])[CH2:13]2)=[O:11])=[CH:6][CH:5]=1.CI.[C:20](=O)([O-])O.[Na+]>CS(C)=O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:16][CH2:15][C@@H:14]([O:17][CH3:20])[CH2:13]2)=[O:11])=[CH:6][CH:5]=1
Reactant: O=C(c1ccc(Br)cc1)N1CC[C@@H](O)C1
Reactant: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: CS(C)=O
Product: CO[C@@H]1CCN(C(=O)c2ccc(Br)cc2)C1
Temperature: 100 °C
Reaction time: 20 h
Yield: 90 %

Procedure:
Sodium hydroxide (10.6 mg, 0.264 mmol) was added to a solution of 54 mg (0.176 mmol) of (R)-(4-bromophenyl)(3-hydroxypyrrolidin-1-yl)methanone in dimethyl sulfoxide (1 ml) synthesized in the same manner as in step (i) of Reference Example 8, 0.11 ml (1.76 mmol) of methyl iodide was then added thereto, and the mixture was stirred at 100° C. for 20 hr. A saturated aqueous sodium hydrogencarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, was dried over anhydrous sodium sulfate, and was then filtered. The filtrate was concentrated under the reduced pressure, and the residue was purified by preparative thin layer chromatography (chloroform:methanol:28% aqueous ammonia=9:2:0.2) to give 45 mg (yield 90%) of the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1([CH3:13])[C:8](=[O:9])[N:7]([CH3:10])[C:6](=[O:11])[NH:5][C:4]1=[O:12].[F:14][C:15]1[C:16]([F:28])=[C:17]([F:27])[C:18]([F:26])=[C:19]2C(=O)O[C:21](=[O:22])[C:20]=12.CCN(CC)CC.CS(C)=O>O>[CH3:10][N:7]1[C:8](=[O:9])[C:3]([NH:2][C:21](=[O:22])[C:20]2[CH:19]=[C:18]([F:26])[C:17]([F:27])=[C:16]([F:28])[C:15]=2[F:14])([CH3:13])[C:4](=[O:12])[NH:5][C:6]1=[O:11]
Reactant: CN1C(=O)NC(=O)C(C)(N)C1=O
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN1C(=O)NC(=O)C(C)(NC(=O)c2cc(F)c(F)c(F)c2F)C1=O
Temperature: 153 °C

Procedure:
A mixture of 5-amino-1,5-dimethylbarbituric acid hydrochloride (0.42 g, 2 mmol), tetrafluorophthalic anhydride (0.44 g, 2 mmol), Et3N (0.28 mL, 0.20 g, 2 mmol) and DMSO (3 mL) was stirred and heated at 153° C. for 5 hours. The reaction mixture was then allowed to cool down to room temperature and poured into water (10 mL). The oil that immediately formed was carefully removed from the solution, from which a solid precipitated after 4 days standing at room temperature. The precipitate was collected by filtration, washed with water and dried under reduced pressure to give 20a as yellow crystals.