Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([CH2:8]Cl)[CH:7]=1.[C-:14]#[N:15].[Na+]>CS(C)=O.O>[C:10]([C:4]1[CH:5]=[C:6]([CH2:8][C:14]#[N:15])[CH:7]=[C:2]([Br:1])[C:3]=1[OH:13])(=[O:12])[CH3:11]
Reactant: [C-]#N
Reactant: CC(=O)c1cc(CCl)cc(Br)c1O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)c1cc(CC#N)cc(Br)c1O
Reaction time: 15 h
Yield: 58 %

Procedure:
A solution of 1-(3-Bromo-5-chloromethyl-2-hydroxy-phenyl)-ethanone 212 (7.6 mmol) in 6 mL DMSO is added dropwise to a suspension of 8.2 mmol of NaCN in 4 mL DMSO. The mixture is stirred for 12-18 h and diluted with 80 mL water to yield a solid. The solid is isolated and recrystallized from ethanol to yield (3-acetyl-5-bromo-4-hydroxy-phenyl)-acetonitrile 213 in a 58% yield.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][C:5]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][N:3]=1.[CH:13]([CH:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1)[OH:16])=[CH2:14].C(N(CC)C(C)C)(C)C.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.IC1C=CC=CN=1>C([O-])(=O)C.C([O-])(=O)C.[Pd+2].CN(C)C=O>[Cl:1][C:2]1[C:7]([CH2:14][CH2:13][C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)=[O:16])=[CH:6][C:5]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][N:3]=1
Reactant: C=CC(O)c1ccc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)c1cnc(Cl)c(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1cnc(Cl)c(CCC(=O)c2ccc(Cl)c(Cl)c2)c1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
A mixture of 0.95 g of 2-chloro-3-iodo-5-(methylsulfonyl)pyridine, 0.91 g of α-ethenyl-3,4-dichlorobenzenemethanol, 0.77 g of N,N-diisopropylethylamine, 0.04 g of tri-o-tolyphosphine, 0.02 g of palladium diacetate and 3 ml of dimethylformamide was heated to 100° C. under nitrogen. The mixture was heated at this temperature for 20 minutes and then at 116° C. for an additional 20 minutes at which point thin layer chromatography showed no iodopyridine starting material. The mixture was then cooled and partitioned between 1N hydrochloric acid and methyl acetate. The ethyl acetate layer was washed twice with aqueous saturated sodium chloride solution, dried over magnesium sulfate and filtered and the filtrate was concentrated to a dark solid residue. Column chromatography of this residue (silica gel, 1:1 ethyl acetate/hexane) gave a pale yellow solid. This was recrystallized from ethanol/ethyl acetate to give 3-[2-chloro-5-(methylsulfonyl)-3-pyridinyl]-1-(3,4-dichlorophenyl)propan-1-one melting at about 128.5°-130.5° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](Cl)=[O:32]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:31]([C:30]4[CH:34]=[CH:35][CH:36]=[C:28]([O:27][CH3:26])[CH:29]=4)=[O:32])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: COc1cccc(C(=O)Cl)c1
Agent: Cl
Product: COc1cccc(C(=O)N2CCC(N3N=C(c4ccc(OC)c(OC)c4)C(C)(C)C3=O)CC2)c1

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 3-methoxybenzoyl chloride as starting compounds. The crude product is purified by crystallization from EA to yield the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[CH3:18][O:19][C:20](=O)[O:21]C.[H-].[Na+]>C1COCC1>[C:20]([CH:15]1[CH2:16][CH:11]([C:8]2[CH:9]=[CH:10][C:5]([C:1]([O:3][CH3:4])=[O:2])=[CH:6][CH:7]=2)[CH2:12][CH2:13][C:14]1=[O:17])([O:19][CH3:18])=[O:21]
Reactant: COC(=O)OC
Reactant: COC(=O)c1ccc(C2CCC(=O)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C2CCC(=O)C(C(=O)OC)C2)cc1
Yield: 63 %

Procedure:
Compound 14 was acylated with dimethylcarbonate/NaH/-KH in THF to give 15 (63%).
Reaction SMILES: [CH3:1]I.[CH2:3]([N:10]1[CH2:15][CH2:14][C:13]([N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[NH:19][C:18]2=[O:26])([CH3:16])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H-].[Na+]>O>[CH2:3]([N:10]1[CH2:15][CH2:14][C:13]([N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]([CH3:1])[C:18]2=[O:26])([CH3:16])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CI
Reactant: CC1(n2c(=O)[nH]c3ccccc32)CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cn1c(=O)n(C2(C)CCN(Cc3ccccc3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.4 %

Procedure:
170 mg methyliodide was added to 320 mg 1-(1-benzyl-4-methyl-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one and 50 mg sodium hydride (60% oil dispersion). The reaction was stirred 1 h at RT. The reaction was diluted with water and extracted with ethylacetate. The organic layer was evaporated and the residue was purified by column chromatographie on silica gel (heptane/ethylacetate/triethylamine:1/1/0.01) to give 155 mg of the desired product.
Reaction SMILES: CS(O[CH2:6][C@H:7]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=O)=O.[NH:22]1[CH2:27][CH2:26][CH:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]1.C(N(C(C)C)CC)(C)C>C1COCC1>[C:18]([O:17][C:15]([NH:14][C@H:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][N:22]1[CH2:27][CH2:26][CH:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](COS(C)(=O)=O)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)CC1
Temperature: 70 °C
Reaction time: 14 h

Procedure:
To a solution of 1 g of (2R)-2-[(tert-butoxycarbonyl)amino]-2-phenylethyl methanesulfonate in 5 mL of THF were added 0.4 mL of ethyl piperidine-4-carboxylate and 1 mL of diisopropylethylamine, followed by stirring at 70° C. for 14 hours, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 160 mg of ethyl 1-{(2R)-2-[(tert-butoxycarbonyl)amino]-2-phenylethyl}piperidine-4-carboxylate.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2].C[Mg:14][Br:15]>C(OCC)C>[C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[O:12][Mg:14][Br:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Mg]Br
Reactant: Cc1ccc(O)c(C(C)(C)C)c1
Solvent: CCOCC
Product: Cc1ccc(O[Mg]Br)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In an atmosphere of nitrogen, 3.29 g (20 mmol) of 2-tert-butyl-4-methylphenol was dissolved in 10 ml of diethyl ether and 6.7 ml of methylmagnesium bromide (20 mmol of diethyl ether solution) was added dropwise to this at 0° C. for 5 minutes. After completion of the dropwise addition, the reaction mixture was stirred at 25° C. for 10 minutes, subsequently, the diethyl ether was evaporated under vacuum, and 30 ml of toluene was added to-obtain a toluene solution of 2-tert-butyl-4-methylphenoxymagnesium bromide. To the solution, 1.07 g (10 mmol) of picolinaldehyde was added dropwise at 25° C. and it was reacted for 5 hours while refluxing. After cooling, the reaction was stopped by adding aqueous 5% hydrochloric acid solution and successively, after neutralizing it with aqueous sodium hydrogencarbonate solution, the organic layer obtained was washed with a saturated aqueous sodium chloride solution. After drying it over anhydrous magnesium sulfate, the solvent was distilled off. The residue was purified by silica gel column chromatography (a developing solvent: hexane/ethyl acetate=20/1-1/1) to obtain 2-bis(2-hydroxy-3-tert-butyl-5-methylphenyl)methylpyridine.
Reaction SMILES: C([O-])(=O)C.[P:5]([O:9]P(O)(O)=O)([OH:8])([OH:7])=[O:6].[C@@H:14]1([N:23]2[C:32]3[N:31]=[CH:30][N:29]=[C:27]([OH:28])[C:26]=3[N:25]=[CH:24]2)[O:22][C@H:19]([CH2:20]O)[C@@H:17]([OH:18])[C@H:15]1[OH:16]>>[C@@H:14]1([N:23]2[C:32]3[N:31]=[CH:30][N:29]=[C:27]([OH:28])[C:26]=3[N:25]=[CH:24]2)[O:22][C@H:19]([CH2:20][O:9][P:5]([OH:7])([OH:8])=[O:6])[C@@H:17]([OH:18])[C@H:15]1[OH:16]
Reactant: O=P(O)(O)OP(=O)(O)O
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Agent: CC(=O)[O-]
Product: O=P(O)(O)OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 24 h

Procedure:
Cells of Escherichia coli JM109 introduced with each of the aforementioned mutant EB-AP genes were added at a density of 100 mg/dl in terms of dry cell weight to a solution in an acetate buffer (pH 4.0) containing 12 g/dl of pyrophosphoric acid and 6 g/dl of inosine, and reaction was performed at 30° C. for 24 hours while pH was maintained at 4.0. The results of measurement of the produced amount of 5′-inosinic acid are shown in Table 4. The produced inosinic acid consisted only of 5′-inosinic acid, and 2′-inosinic acid and 3′-inosinic acid byproducts were not observed at all.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[C:19](Cl)(=[O:23])/[CH:20]=[CH:21]/[CH3:22]>C1COCC1.CCOCC>[C:19]([N:9]1[C@@H:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][O:11][C:10]1=[O:13])(=[O:23])/[CH:20]=[CH:21]/[CH3:22]
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: C/C=C/C(=O)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: C/C=C/C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 109.2 %

Procedure:
A solution of (4S)-4-benzyl-2-oxazolidinone (1.0 g, 5.6 mmol) in anhydrous THF (20 ml) was cooled to −78° C. n-BuLi (1.6 M solution in hexanes, 3.5 ml, 5.6 mmol) was added dropwise to the cooled solution. After 30 minutes, crotonyl chloride (0.59 ml, 6.2 mmol) was added to the mixture. The reaction was stirred for 30 minutes at −78° C., then warmed slowly to room temperature. The reaction mixture was quenched by addition of 4 ml saturated aqueous ammonium chloride. The resultant reaction mixture was diluted with ether, and washed with water and brine. The organic layer was dried using anhydrous Na2SO4 and evaporated under reduced pressure. Flash chromatography on a silica gel column using ethyl acetate/hexane (1/3) as eluent provided compound 1, i.e., (4S)-3-((E)-2-butenoyl)-4-benzyl-2-oxazolidinone, (1.50 g, 87%) as a white solid. m.p.: 83° C. IR (KBr): 3027, 2922, 2539, 1772, 1682, 1351, 1209 cm−1. 1H NMR (400 MHz, CDCl3): 7.36-7.15 (m, 7H, aromatic H's, CH═CH); 4.75-4.70 (m, 1H, CHN); 4.23-4.15 (m, 2H, CH2O); 3.33 (dd, 1H, J=3.3, 13.4 Hz, CHHPh); 2.79 (dd, 1H, J=9.5, 13.4 Hz, CHHPh); 1.98 (dd, 3H, J=1.0, 6.2 Hz, CH3). 13C NMR (100 MHz, CDCl3): δ 164.69, 153.51, 146.95, 135.28, 129.37, 128.86, 127.23, 121.74, 66.01, 55.20, 37.79, 18.50.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.[Cl:32][C:33]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[C:35]([O:48][CH3:49])[C:34]=1[OH:50]>>[C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:30])[CH3:29])[CH2:20][CH2:19]1)=[CH:3][C:2]([C:37]1[CH:36]=[C:35]([O:48][CH3:49])[C:34]([OH:50])=[C:33]([Cl:32])[CH:38]=1)=[CH:11][CH:10]=2)(=[O:16])[CH2:13][CH2:14][CH3:15]
Reactant: CCCC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Product: CCCC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(OC)c3)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1

Procedure:
Following general procedure D, tert-butyl (trans-4-((6-bromo-3-butyrylquinolin-4-yl)amino)cyclohexyl)carbamate (49 mg, 0.10 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (43 mg, 0.15 mmol) to afford the desired product (36 mg, 63%) as a yellow solid. ESI MS m/z 568 [C31H38ClN3O5+H]+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.O.[NH2:13][NH2:14]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH:13][NH2:14]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Yield: 92.2 %

Procedure:
690 μL 3,4-difluoronitrobenzene was added to 15 mL anhydrous ethanol, and then the blend was heated to reflux. Hydrazine hydrate (611.5 μL) was slowly dropped into the blend and the resultant mixture was refluxed for another 2 hours to complete reaction, after which the reaction mixture was cooled down to room temperature. The yellow solid precipitated upon cooling was filtered. The filter cake was washed with petroleum ether, and then was dried to get 884.5 mg of a yellow solid, with a yield of 92.2%.
Reaction SMILES: C[C:2]1[N:6]2[C:7]([NH2:15])=[C:8]([Cl:14])[CH:9]=[C:10]([C:11]([OH:13])=O)[C:5]2=[N:4][C:3]=1[CH3:16].[NH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1>>[NH2:15][C:7]1[N:6]2[CH:2]=[C:3]([CH3:16])[N:4]=[C:5]2[C:10]([C:11]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[O:13])=[CH:9][C:8]=1[Cl:14]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: Cc1nc2c(C(=O)O)cc(Cl)c(N)n2c1C
Product: Cc1cn2c(N)c(Cl)cc(C(=O)NCC3CCN(C(=O)OC(C)(C)C)CC3)c2n1

Procedure:
The title compound was prepared, according to the procedure described in the step 6 of EXAMPLE 1, from 5-amino-6-chloro-2-methylimidazo[1,2-a]pyridine-8-carboxylic acid (EXAMPLE 1, Step 5) and tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (J. Prugh, L. A. Birchenough and M. S. Egbertson, Synth. Commun., 1992, 22, 2357–60).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([N+:12]([O-])=O)=[CH:6][C:5]=1[F:15].OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>[Pd].C(O)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([NH2:12])=[CH:6][C:5]=1[F:15]
Reactant: COC(=O)c1cc(OC)c([N+](=O)[O-])cc1F
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CCO
Product: COC(=O)c1cc(OC)c(N)cc1F
Yield: 97.7 %

Procedure:
To a solution of 0.92 g (4.01 mmole) of 2-fluoro-5-methoxy-4-nitro-benzoic acid methyl ester and 30 mL of ethanol was added 0.10 g of 10% Pd/C. The mixture was hydrogenated in a Parr hydrogenator at 50 Psi for 1 day. The catalyst was removed by filtration and the solution was concentrated under reduced pressure to give 0.78 g of 4-amino-2-fluoro-5-methoxy-benzoic acid methyl ester.
Reaction SMILES: [CH3:1][N:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[C:8]2[CH:7]=[C:6]([S:17](Cl)(=[O:19])=[O:18])[CH:5]=[CH:4][C:3]1=2.[NH:21]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:22]([C:25]([OH:27])=[O:26])[CH2:23][NH2:24].C(N(CC)CC)C>ClCCl>[NH:21]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:22]([C:25]([OH:27])=[O:26])[CH2:23][NH2:24].[C:31]([O:30][C:28]([NH:21][CH:22]([CH2:23][NH:24][S:17]([C:6]1[CH:5]=[CH:4][C:3]2[N:2]([CH3:1])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[C:8]=2[CH:7]=1)(=[O:19])=[O:18])[C:25]([OH:27])=[O:26])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: Cn1c2ccccc2c(=O)c2cc(S(=O)(=O)Cl)ccc21
Agent: CC(C)(C)OC(=O)N[C@@H](CN)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c2ccccc2c(=O)c2cc(S(=O)(=O)NCC(NC(=O)OC(C)(C)C)C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
110 mg of the material (2) shown in Table 2 was dissolved in 12 ml of dichloromethane (DCM) (Wako Pure Chemical). 80 mg of Boc-Dap-OH (Bachem) was added to the solution, and then 6 ml of triethylamine (TEA) (Wako Pure Chemical) was added little by little, followed by stirring at room temperature overnight. After the reaction was over, the reaction solution was subjected to evaporation by an evaporator to remove the solvent, supplied with 5% NaHCO3(aq), and further supplied with 0.3 N HCl until the solution got acidic to form a precipitate, which was then filtered by suction and dried in a desiccator. Boc-Dap-OH and the compound (3) thus obtained, 2-tert-butoxycarbonylamino-3-(10-methyl-9-oxo-9,10-dihydro-acridine-2-sulfonylamino)-propionic acid were analyzed to get their respective 1H-NMR data. The results are shown in FIG. 6 and FIG. 7. The product was further purified by silica gel column chromatography to give a substance, which was then analyzed to give the 1H-NMR data. The result was shown in FIG. 8.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.[Na+].[Na+].[Na+].P(C1C=C(S([O-])(=O)=O)C=CC=1)(C1C=C(S([O-])(=O)=O)C=CC=1)C1C=C(S([O-])(=O)=O)C=CC=1.C(NC(C)C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O.CN(C)C=O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[C:11]([OH:12])=[C:10]([N+:13]([O-:15])=[O:14])[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1cc(Br)c(O)c([N+](=O)[O-])c1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2ccc(F)cc2)c(O)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 40.8 %

Procedure:
To a solution of methyl 3-bromo-4-hydroxy-5-nitrobenzoate (1.0 g, 3.62 mmol), (4-fluorophenyl)-boronic acid (0.76 g, 5.43 mmol), 3,3′,3″-phosphinidynetris (benzensulfonic acid) trisodium salt (0.17 mg, 0.27 mmol), palladium(II) acetate (20.0 mg, 0.09 mmol) and diisopropylamine (0.52 mL, 3.62 mmol) were added N,N-dimethylformamide (13.6 mL) and water (4.5 mL). The mixture was heated to 80° C. After 18 h, the mixture was cooled to ambient temperature and ethyl acetate was added. The organic layer was washed with water (3×), brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→25% hexanes/ethyl acetate). Another purification using reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (0.43 g). LC-MS [M+1]=291.9.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:32]=[CH:33][CH:34]=1)[CH2:10][N:11]1[CH2:31][CH2:30][C:14]2([O:19][CH2:18][CH2:17][N:16]([C:20]([C:22]3[N:23]=[C:24]([CH:27]([CH3:29])[CH3:28])[S:25][CH:26]=3)=[O:21])[CH2:15]2)[CH2:13][CH2:12]1)C.O>C(O)(=O)C>[CH:27]([C:24]1[S:25][CH:26]=[C:22]([C:20]([N:16]2[CH2:15][C:14]3([CH2:13][CH2:12][N:11]([CH2:10][C:9]4[CH:8]=[C:7]([CH:34]=[CH:33][CH:32]=4)[O:6][CH2:5][CH:4]=[O:3])[CH2:31][CH2:30]3)[O:19][CH2:18][CH2:17]2)=[O:21])[N:23]=1)([CH3:29])[CH3:28]
Reactant: CCOC(COc1cccc(CN2CCC3(CC2)CN(C(=O)c2csc(C(C)C)n2)CCO3)c1)OCC
Solvent: CC(=O)O
Solvent: O
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(OCC=O)c4)CC3)C2)cs1
Temperature: 65 °C

Procedure:
A solution of (9-(3-(2,2-diethoxyethoxy)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone (example 64, step a) (0.36 g) in acetic acid (20 mL) was treated with water (20 mL) and the reaction mixture then heated at 65° C. for 18 hours under nitrogen. The solvents were evaporated under reduced pressure and the residue was azeotroped with toluene to afford the subtitled compound. Yield 0.31 g. Used directly.
Reaction SMILES: C(Cl)Cl.[Cl:4][C:5]1[C:6]([CH:12]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[CH:7][C:8]([NH2:11])=[N:9][CH:10]=1.N1C=CC=CC=1.OS(C(F)(F)F)(=O)=O.[N:45]1[CH:50]=[CH:49][C:48]([CH2:51][S:52](Cl)(=[O:54])=[O:53])=[CH:47][CH:46]=1>C(OCC)(=O)C.CO>[Cl:4][C:5]1[C:6]([CH:12]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[CH:7][C:8]([NH:11][S:52]([CH2:51][C:48]2[CH:49]=[CH:50][N:45]=[CH:46][CH:47]=2)(=[O:54])=[O:53])=[N:9][CH:10]=1
Reactant: Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Reactant: O=S(=O)(Cl)Cc1ccncc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Cc1ccncc1)Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Temperature: 25 °C
Reaction time: 17 h
Yield: 46.7 %

Procedure:
To a methylene chloride (2 ml) solution of the [5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]amine (104 mg, 0.242 mmol) obtained in Example 196 and pyridine (74 μl, 0.533 mmol) was added (4-pyridylmethyl)sulfonyl chloride triflate (91 mg, 0.266 mmol). The resulting mixture was stirred at room temperature for 17 hours. To the reaction mixture were added pyridine (74 μl, 0.533 mmol) and (4-pyridylmethyl)sulfonyl chloride triflate (91 mg, 0.266 mmol). The resulting mixture was stirred at room temperature for 19 hours. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography. The fraction obtained from the methanol:methylene chloride (=1:40) eluate was concentrated under reduced pressure to give the title compound (66 mg, 0.113 mmol, 47%) as a white solid.
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([Br:12])[C:5]=2[N:6]=1.[Br:13](O)(=O)=O.BrBr.N([O-])=O.[Na+].[OH-].[Na+]>>[Br:13][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([Br:12])[C:5]=2[N:6]=1
Reactant: [O-][Br+2]([O-])O
Reactant: Cc1cc(Br)c2nc(N)sc2c1
Agent: BrBr
Agent: O=N[O-]
Agent: [Na+]
Product: Cc1cc(Br)c2nc(Br)sc2c1
Reaction time: 2 h

Procedure:
4.7 g of 2-amino-4-bromo-6-methylbenzothiazole, 14 ml of 48% bromic acid solution and 10 g of bromine were introduced into a reaction vessel while keeping the temperature at 10° C. To this mixture was slowly added dropwise 10 ml of aqueous solution containing 3.5 g of sodium nitrite at 0° C. and the whole mixture was stirred for 2 hours. Then, 15 ml of 40% sodium hydroxide solution was slowly added dropwise while keeping the temperature below 20° C. and the reaction mixture was stirred for one hour and extracted with diethyl ether. The extract was dried with anhydrous sodium sulfate and evaporated to obtain the title compound in the form of transparent liquid (Yield: 91%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=3)[CH2:11][N:10](P(=O)(OCC)OCC)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=3)[CH2:9][NH:10][CH2:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOP(=O)(OCC)N1CC(c2cccc(Br)c2)(c2cccc(Br)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Brc1cccc(C2(c3cccc(Br)c3)CNC2)c1
Temperature: 20 °C
Reaction time: 3 h
Yield: 84.2 %

Procedure:
To a solution of diethyl 3,3-bis(3-bromophenyl)azetidin-1-ylphosphonate (960 mg, 1.9 mmol) in anhydrous dichloromethane (5 mL) under N2 was added TFA (5 mL). The mixture was stirred at 20° C. for 3 h, then concentrated by rotary evaporation. The residue was dissolved in dichloromethane (20 mL) and washed with aq. NaHCO3 (30 mL). The organic layer was dried and concentrated to afford 595 mg of the title compound (1.6 mmol, 85%) as a yellow oil which was used directly to next step without purification. LC/MS: [M+1]=368.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](Br)[CH:5]=[CH:4][C:3]1=2.[BH:16]([OH:18])[OH:17]>>[CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([B:16]([OH:18])[OH:17])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(Br)ccc21
Reactant: OBO
Product: CC1(C)CCC(C)(C)c2cc(B(O)O)ccc21

Procedure:
In a similar manner to Example 3(a), starting with 5 g (18.7 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-bromonaphthalene, 4.3 g (100%) of the expected boronic acid are obtained.