Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[S:16]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[S:16]1[CH:20]=[CH:19][C:18]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=2)=[CH:17]1
Reactant: OB(O)c1ccsc1
Reactant: CC(CNS(C)(=O)=O)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(CNS(C)(=O)=O)c1ccc(-c2ccsc2)cc1
Temperature: 100 °C
Yield: 26.5 %

Procedure:
To a degassed solution of 1.5 g (5.1 mmol) of material from Example 1, 1.0 g (7.7 mmol) of thiophene-3-boronic acid and 1.1 g (7.7 mmol) of potassium carbonate in 30 mL of toluene was added 0.3 g (0.3 mmol) of tetrakis(triphenyl-phosphine)palladium(0). The mixture was heated to 100° C. for 4 hours, cooled to ambient temperature and diluted with 20 mL of ethyl acetate. The mixture was then washed once with water, and the organic portion was separated. The aqueous portion was extracted twice with ethyl acetate and the combined organics were dried (MgSO4), filtered and concentrated in vacuo. Chromatography on 50 g silica gel (35% ethyl acetate/hexane) afforded a solid which was recrystallized from bromobutane, filtered and dried in vacuo at 60° C. to afford 0.4 g (27%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH2:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]>[Ni].C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH2:24][CH2:25][CH2:26][N:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCCCN1CCOCC1
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCCCN1CCOCC1

Procedure:
The (3-chloro-4-fluorophenyl)-[7-(3-morpholin-4-yl-propoxy )-6-nitroquinazolin-4-yl]-amine (I) obtained was subsequently hydrogenated inter alia over Raney nickel in THF as solvent to give (3-chloro-4-fluorophenyl)-[7-(3-morpholin-4-yl-propoxy)-6-aminoquinazolin-4-yl]-amine (VII)
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([C:15](O)=[O:16])[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5]>C1COCC1>[CH2:2]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([CH2:15][OH:16])[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:1]
Reactant: CCOC(=O)c1cc2ccc(C(=O)O)cc2s1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2ccc(CO)cc2s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
A solution of benzo[b]thiophene-2,6-dicarboxylic acid 2-ethyl ester (1.6 g, 6.4 mmol) in anhydrous THF (40 mL, 25 vol) was cooled to 0° C. To this BH3 (1M in THF, 30 mL, 30.0 mmol) was added slowly. The reaction was allowed to warm to r.t. and stirred for 3 h. The solution was then cooled to 0° C. and quenched using 1N HCl (7.5 mL). The reaction mixture was concentrated under vacuum to remove all THF and the resulting solid isolated by filtration and dried under vacuum to give 6-hydroxymethyl-benzo[b]thiophene-2-carboxylic acid ethyl ester (1.3 g, 87%). LCMS m/z 237 [M++H]+, 1H NMR (300 MHz, DMSO), δ: 1.34 (3H, t J=6.9 Hz, CH3), 4.35 (2H, q J=7.1 Hz, CH2), 4.65 (2H, s, CH2), 6.53 (1H, br s, OH), 7.42 (1H, d J=9.4 Hz), 7.98 (3H, m, ArH), 8.18 (1H, s, ArH).
Reaction SMILES: [CH2:1]([N:8]([CH3:16])[C:9]1[CH:14]=[N:13][CH:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[CH:21][C:20]=1[OH:34]>>[CH2:1]([N:8]([CH3:16])[C:9]1[N:10]=[C:11]([C:23]2[CH:22]=[CH:21][C:20]([OH:34])=[C:19]([O:18][CH3:17])[CH:24]=2)[CH:12]=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)c1cncc(Cl)n1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Product: COc1cc(-c2cncc(N(C)Cc3ccccc3)n2)ccc1O
Yield: 51 %

Procedure:
In a procedure analogous to Example 22, reaction of N-benzyl-6-chloro-N-methylpyrazin-2-amine and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol furnished the product (51%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.CO.[NH3:15]>>[CH3:12][O:11][C:4]1[N:3]=[C:2]([NH2:15])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: N
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c(N)n1
Yield: 84 %

Procedure:
A solution/suspension of 2-chloro-6-(methyloxy)-3-nitropyridine (65.7 g, 348 mmol) in 2M ammonia in methanol (500 ml, 1000 mmol) and aqueous ammonia (500 ml, 348 mmol) was stirred at 65° C. for 18 h. The reaction was cooled down and the solid filtered off and washed with water (2×100 ml). The solid was dried in the vacuum oven at 40° C. overnight to afford the product as a bright yellow solid (52.14 g, 84% purity by NMR, 74%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[N:10][S:11][C:12]=2[C:13]2[C:14]([NH:19][CH2:20][CH3:21])=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])(=O)C.[Na+].[Br:27]Br>C(O)(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([C:8]2[N:9]=[N:10][S:11][C:12]=2[C:13]2[C:14]([NH:19][CH2:20][CH3:21])=[N:15][CH:16]=[C:17]([Br:27])[CH:18]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: BrBr
Reactant: CCNc1ncccc1-c1snnc1-c1cccnc1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCNc1ncc(Br)cc1-c1snnc1-c1cccnc1Cl
Reaction time: 0.08 h
Yield: 81.3 %

Procedure:
To a solution of 4-(2-chloropyridin-3-yl)-5-(2-ethylaminopyridin-3-yl)-1, 2, 3-thiadiazole (0.324 g) in acetic acid (4 mL) containing sodium acetate (0.098 g) was added dropwise a solution of bromine (0.185 g) in acetic acid (1 mL). After 5 minutes, the mixture was diluted with ethyl acetate, washed with aqueous potassium carbonate, dried, filtered and evaporated. Chromatography of the residue over silica gel (ethyl acetate/hexane/chloroform 1/3/0.5) gave 4-(2-chloropyridin-3-yl)-5-(2-ethylamino-5-bromo-pyridin-3-yl)-1, 2, 3-thiadiazole (0.329 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CCOCC.CC1C=CC=CC=1C>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOCC
Solvent: Cc1ccccc1C
Product: CC(=O)c1ccc(-c2ccccc2)cc1
Temperature: 130 °C
Yield: 101.9 %

Procedure:
Compound 5 (30 mg, 2 μmol Pd), 1-(4-bromophenyl)ethan-1-one (0.20 g, 1 mmol), phenylboronic acid (0.15 g, 1.2 mmol), potassium carbonate (0.21 g, 1.5 mmol), and o-xylene (3 mL) were sequentially added to a 15 mL septum-sealed test tube under protection of nitrogen. The mixture was then heated at 130° C. for 5 h. After it was cooled to the room temperature, 8 mL of anhydrous ether was added to precipitate compound 5. The mixture was centrifuged and f the upper liquid layer was transferred via a syringe into a 20 mL round-bottom flask. Repeated the above precipitation procedure once. The combined liquid layer was concentrated under reduced pressure to give an oily residue. A saturated ammonium chloride solution (5 mL) was then added. The resulting mixture was extracted by ethyl acetate (10 mL×3), dried over anhydrous magnesium sulfate, filtrated, and concentrated to give a crude product. The crude product was further purified by column chromatography (silica gel, hexane/ethyl acetate=4/1) to give 0.20 g (99% yield) of 4-acetylbiphenyl. 1H NMR (300 MHz, DMSO-d6) δ 2.61 (s, 3H), 7.42–7.44 (m, 1H), 7.48–7.51 (m, 2H), 7.73 (d, J=8.5 Hz, 2H), 7.81 (d, J=8.5 Hz, 2H), 7.69 (d, J=8.5 Hz, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]([F:25])([F:24])[F:23])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=3)[C:6]=2[CH:21]=1.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>ClCCl.N1C=CC=CC=1>[C:27](=[O:28])([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[O:20][CH2:19][CH2:18][C:15]1[CH:14]=[CH:13][C:12]([N:7]2[C:6]3[CH:21]=[C:2]([Cl:1])[C:3]([C:22]([F:23])([F:25])[F:24])=[CH:4][C:5]=3[N:9]=[C:8]2[CH2:10][CH3:11])=[CH:17][CH:16]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCO)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
To a stirred solution of 2-[4-(6-Chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl)phenyl]ethanol (step 4 of Example 104, 3.90 g, 10.6 mmol) in dichloromethane (20 mL) and pyridine (2 ml) was added dropwise phenyl chloroformate (1.6 mL, 12.7 mmol), and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with dichloromethane (50 mL), washed with water (50 ml). The organic layer was dried over Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography eluting with hexane/ethyl acetate (3:1) afforded 4.2 g (82%) of the title compound as a colorless syrup.
Reaction SMILES: Br[C:2]1[C:3]2[CH:18]=[CH:17][CH:16]=[N:15][C:4]=2[C:5]2[NH:6][C:7](=[O:14])[C:8](=[O:13])[N:9]([OH:12])[C:10]=2[CH:11]=1>CN(C)C=O.[Pd]>[OH:12][N:9]1[C:10]2[CH:11]=[CH:2][C:3]3[CH:18]=[CH:17][CH:16]=[N:15][C:4]=3[C:5]=2[NH:6][C:7](=[O:14])[C:8]1=[O:13]
Reactant: O=c1[nH]c2c3ncccc3c(Br)cc2n(O)c1=O
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=c1[nH]c2c3ncccc3ccc2n(O)c1=O
Yield: 87.3 %

Procedure:
0.3 g (1.0 mmol) 6-Bromo-4-hydroxypyrido[2,3-f]quinoxaline-2,3(1H,4H)-dione in 20 ml dimethylformamide was hydrogenated at atm. pressure by using 300 mg Pd/c (5%) as a catalyst. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was stirred with ethanol and the precipitate was filtered off to give 0.2 g (90%) of 4-hydroxypyrido[2,3-f]quinoxaline-2,3(1H,4H)-dione. M.p. decomp. MS m/z: 229 (M+, 25%), 212 (100%), 185 (45%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][OH:14])=[C:11]([CH3:15])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][N:20]=1.O>C1COCC1>[CH3:26][O:25][C:23](=[O:24])[C:22]1[CH:27]=[CH:28][C:19]([O:14][CH2:13][C:12]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=[N:10][C:11]=2[CH3:15])=[N:20][CH:21]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(OCc2c(C)nnn2-c2ccc(F)cc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
A solution of [3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-yl]-methanol (425 mg, 2.05 mmol) in THF (3 mL) was added dropwise at 0° C. to a suspension of NaH (55% in oil, 100 mg, 2.05 mmol) in THF (6 mL) and the reaction mixture was then stirred at room temperature for 30 min. Then a solution of methyl 6-chloronicotinate (390 mg, 8.0 mmol) in THF (3 mL) was added dropwise at 0° C. and the reaction mixture stirred at room temperature for 20 h. The mixture was then poured into water extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 10 to 50% ethyl acetate in heptane) afforded the title compound (621 mg, 88%) as a white solid. MS: m/e=343.3 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.O1CCOCC1.[OH-].[Na+].[C:18](Cl)([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>O.C(OCC)(=O)C>[C:18]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1)([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]
Reactant: O=C(O)C1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
In a 1-L round-bottom flask with a stir bar and equipped with an additional funnel was charged isonipecotic acid (13 g, 0.1 mol) followed by 1,4-dioxane (50 mL). The resulting stirred white suspension was added 5N NaOH aqueous solution (30 mL, 0.15 mol) at room temperature and the overall almost homogeneous solution was cooled in an ice-water bath. CbzCl (19 mL, 0.13 mol) was dropped from an additional funnel slowly in 15 min and the overall heterogeneous mixture was stirred at room temperature for 3.5 h. The resulting mixture was diluted with water (20 mL) and ethyl acetate (100 mL) and the separated aqueous layer was extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with brine, dried over MgSO4, and concentrated to give the N-Cbz isonipecotic acid 3 as a colorless oil which was carried through to the next step without further purification. MS (ES+): 264 (M+H)+.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([F:21])[C:19]=1[F:20])[C:14]([OH:16])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:44]=[C:45]([N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1)[CH2:46][NH:47][C:48]([C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:52][CH:51]=1)=[O:49]>CN(C=O)C.O>[O:44]=[C:45]([N:62]1[CH2:67][CH2:66][N:65]([C:14](=[O:16])[C:13]2[CH:17]=[C:18]([F:21])[C:19]([F:20])=[C:11]([F:10])[CH:12]=2)[CH2:64][CH2:63]1)[CH2:46][NH:47][C:48]([C:50]1[CH:51]=[CH:52][C:53]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:54][CH:55]=1)=[O:49]
Reactant: O=C(O)c1cc(F)c(F)c(F)c1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)c(F)c(F)c2)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.6 %

Procedure:
DIPEA (149.8 mg, 1.15 mmol) was added to a stirred solution of 3,4,5-trifluoro-benzoic acid (45.3 mg, 0.26 mmol) in DMF (3 mL), HOBt (38.2 mg, 0.28 mmol) and EDCI.HCl (123.4 mg, 0.64 mmol) at room temperature. After 2 minutes biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.31 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, and the resulting precipitate was filtered. The residue was purified by column chromatography (using 60-120 mesh silica gel and 60% EtOAc in hexane as eluent) to afford 32 mg (25.8% yield) of biphenyl-4-carboxylicacid {2-oxo-2-[4-(3,4,5-trifluoro-benzoyl)-piperazin-1-yl]-ethyl}-amide, LC-MS purity: 98.04%, 1H NMR: (DMSO) δ 8.76-8.6 (bs, 1H), 8.08-7.92 (m, 2H), 7.88-7.72 (m, 4H), 7.6-7.4 (m, 4H), 4.2 (s, 2H), 3.6 (s, 5H), 3.2 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[C@@H:14]([NH:15]C(=O)OC(C)(C)C)[CH2:13][C@@H:12]([N:23]2[CH2:30][C:29]3[C:25](=[N:26][N:27]([S:31]([CH:34]4[CH2:36][CH2:35]4)(=[O:33])=[O:32])[CH:28]=3)[CH2:24]2)[CH2:11][O:10]1.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[C@@H:14]([NH2:15])[CH2:13][C@@H:12]([N:23]2[CH2:30][C:29]3[C:25](=[N:26][N:27]([S:31]([CH:34]4[CH2:36][CH2:35]4)(=[O:32])=[O:33])[CH:28]=3)[CH2:24]2)[CH2:11][O:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2Cc3cn(S(=O)(=O)C4CC4)nc3C2)CO[C@@H]1c1cc(F)ccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1C[C@@H](N2Cc3cn(S(=O)(=O)C4CC4)nc3C2)CO[C@@H]1c1cc(F)ccc1F
Reaction time: 1.5 h

Procedure:
A solution of the intermediate from Step A above (93 mg, 0.16 mmol) in dichloromethane (6 mL) was treated with trifluoroacetic acid (3 ml) at room temperature. After 1.5 h, the reaction mixture was concentrated to give the title compound. 1H NMR (500 MHz, CD3OD): δ 1.17-1.23 (m, 2H); 1.34-1.40 (m, 2H); 2.08 (q, 1H, J=12 Hz); 2.80 (d, 1H, J=12 Hz); 2.91-2.97 (m, 1H); 3.58-3.66 (m, 1H); 3.76 (t, 1H, J=12 Hz), 3.82-3.90 (m, 1H); 4.47-4.62 (m, 5H); 4.70 (d, 1H, J=10 Hz); 7.18-7.26 (m, 2H); 7.28-7.32 (m, 1H); 8.05 (s, 1H). LC-MS: 425.01 (M+1).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1[N:15]([CH:16]([C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=2[C:23]#N)[C:17]([OH:20])([CH3:19])[CH3:18])[CH:14]=[N:13][CH:12]=1)(C(C)(C)C)(C)C.S(=O)(=O)(O)[OH:30].O.[OH-].[Na+]>C1COCC1>[OH:8][CH2:9][CH2:10][C:11]1[N:15]([CH:16]2[C:21]3[C:22](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23](=[O:30])[O:20][C:17]2([CH3:19])[CH3:18])[CH:14]=[N:13][CH:12]=1
Reactant: CC(C)(O)C(c1ccccc1C#N)n1cncc1CCO[Si](C)(C)C(C)(C)C
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OC(=O)c2ccccc2C1n1cncc1CCO

Procedure:
2-(1-{5-[2-(tert-Butyldimethylsilanyloxy)-ethyl]-imidazol-1-yl}-2-hydroxy-2-methyl-propyl)-benzonitrile (1.5 g, 3.75 mmol) is dissolved in THF (15 mL). Concentrated sulfuric acid (0.80 mL, 15.03 mmol) and water (0.80 mL) are added and the mixture is stirred at reflux for 24 h. After cooling down, the mixture is basified to pH 10 using 10% aqueous sodium hydroxide and is then extracted with ethyl acetate twice. The combined organic phase is dried over Na2SO4 and concentration in vacuo. The residue obtained is purified by silica gel chromatography (dichloromethane-methanol, 9:1) to give 4-[5-(2-hydroxy-ethyl)-imidazol-1-yl]-3,3-dimethyl-isochroman-1-one; HRMS (ESI) m/z 287.1403; [(M+H)+ Calcd for C16H19N2O3: 287.1396]; 1H NMR (400 MHz, MeOD) δ ppm 1.26 (s, 3 H), 1.56 (s, 3 H), 3.06 (br. s, 2 H), 3.75-4.18 (m, 2 H), 5.74 (br. s, 1 H), 6.92 (br. s, 1 H), 7.15 (d, J=1.3 Hz, 1 H), 7.57 (d, J=7.3 Hz, 1 H), 7.67 (t, J=7.3 Hz, 1 H), 7.78 (t, J=7.3 Hz, 1 H), 8.24 (d, J=7.3 Hz, 1 H)
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>C(#N)C.O>[CH2:1]([O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: O=Cc1cccc(OCc2ccccc2)c1
Yield: 103.9 %

Procedure:
In acetonitrile (50 mL) solvent, benzyl bromide (4.6 mL, 38.68 mmol) was added to a solution including 3-hydroxybenzaldehyde (5.0 g, 40.94 mmol) and potassium carbonate (8.49 g, 61.43 mmol), and the reaction mixture was refluxed for 3 hours. After cooling, the reaction mixture was distributed between methylene chloride and water. An organic layer was dried by using MgSO4 and filtered. The filtrate was evaporated, and water was added to the resultant solid. The solid was filtered and washed with water to obtain Compound 123a (8.53 g, 98%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].CN(C=O)C.[N-:18]=[N+:19]=[N-:20].[Na+]>CCOC(C)=O>[N:18]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=[O:4])=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: CSc1ccc(C(=O)CBr)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1ccc(C(=O)CN=[N+]=[N-])cc1
Temperature: 15 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
A solution consisting of 2-bromo-1-(4-methylsulfanyl-phenyl)-ethanone (2.00 g, 8.16 mmol) and DMF (7 mL) was cooled to 15° C. and treated portion-wise with sodium azide (583 mg, 8.98 mmol). Once addition was complete, the reaction mixture was stirred for 3 h with gradual warming to rt. The reaction mixture was then diluted with EtOAc (20 mL) and washed with water (25 mL×2), NaHCO3 (satd., 25 mL×2), and brine. The combined organic phases were dried (Na2SO4) and concentrated to dryness to yield the title compound (1.69 g, 100%).
Reaction SMILES: [C:1]([NH:4][C:5](=[O:32])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:21]=[N:22][C:23]([O:26]C(C)(C)C)=[CH:24][CH:25]=3)[CH2:16][CH2:15]2)[C:9]=1[F:31])(=[NH:3])[NH2:2].C(O)(C(F)(F)F)=O.CCO.[C:43]([OH:52])(=[O:51])[C@@H:44]([C@H:46]([C:48]([OH:50])=[O:49])[OH:47])[OH:45]>ClCCl>[C:48]([C@@H:46]([C@H:44]([C:43]([OH:52])=[O:51])[OH:45])[OH:47])([OH:50])=[O:49].[C:1]([NH:4][C:5](=[O:32])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23](=[O:26])[NH:22][CH:21]=3)[CH2:16][CH2:15]2)[C:9]=1[F:31])(=[NH:2])[NH2:3]
Reactant: CC(C)(C)Oc1ccc(N2CCN(c3cccc(COC(=O)NC(=N)N)c3F)CC2)cn1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: N=C(N)NC(=O)OCc1cccc(N2CCN(c3ccc(=O)[nH]c3)CC2)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
3-[4-(6 tert-Butoxypyridin-3-yl)piperazin-1-yl]-2-fluorobenzyl carbamimidoylcarbamate (132 mg) was dissolved in dichloromethane (3.4 ml), and TFA (508 mg) was added thereto, followed by stirring at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, the residue was mixed with CHCl3/MeOH, and basic silica gel was added thereto, followed by concentrating under reduced pressure. The residue was purified by basic silica gel column chromatography (CHCl3/MeOH). The purified product thus obtained was mixed with EtOH (5 ml), and L-tartaric acid (41.0 mg) were added thereto, followed by stirring at 80° C. for 1 hour, and then stirring at room temperature for 1 hour. The solid was collected by filtration, washed with EtOH, and then dried at 50° C. under reduced pressure to obtain 2-fluoro-3-[4-(6-oxo-1,6-dihydropyridin-3-yl)piperazin-1-yl]benzyl carbamimidoylcarbamate L-tartrate (125 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH:9](C(OCC)=O)[C:10]([O:12][CH2:13]C)=[O:11])=[CH:3][CH:2]=1>C(O)C.[OH-].[Na+]>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(CCc1ccncc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)CCCc1ccncc1
Yield: 89 %

Procedure:
A solution of diethyl β-(4-pyridyl)-ethylmalonate (25 g, 94 mmol) in ethanol (100 mL) and NaOH (1M, 200 mL) was refluxed for 2 hours. The ethanol was removed by distillation, and the solution was acidified with concentrated H2SO4. The resulting solution was refluxed for 30 minutes, and the pH was adjusted to 4. The solvent was removed and the residue was dried under vacuum. The residue was taken up in methanol (300 mL), trimethyl orthoformate (10 mL) and H2SO4 (5 mL), and the resulting solution was refluxed for 3 hours. The solvent was removed, and the residue was taken up in CHCl3 and extracted with NaOH (1M) and saturated brine, dried (Na2SO4) and evaporated to yield methyl 4-(4-pyridyl)butanoate (48) (15 g).