Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([C:6](=S)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[C:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH2:5].C(O)(=O)C>C(Cl)Cl>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]2[NH:7][C:6]3=[N:1][CH2:2][CH2:3][N:4]3[N:5]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[CH:10]=1
Reactant: NCCN(N)C(=S)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: Clc1ccc2c(c1)C(c1ccccc1)=NN1CCN=C1N2

Procedure:
A mixture containing 10.0 grams of the intermediate 1-(2-aminoethyl)-N-(2-benzoyl-4-chlorophenyl)-hydrazinecarbothioamide (Example 14) and 200 ml of glacial acetic acid was refluxed for 30 minutes with stirring. The acetic acid was removed in vacuo to leave a yellow oil. The residue was dissolved in methylenechloride, washed with separate rinses of 10% sodium hydroxide and water, and dried with magnesium sulfate. The solvent was evaporated to leave the 8-chloro-2,3-dihydro-6-phenyl-11H-imidazo(2,1-b)(1,3,4)benzotriazepine. The product was recrystallized from isopropanol to yield yellow crystals having a melting point of 191.5° to 193.5° C. Infrared analysis was used to confirm the structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:16]([O-])=O)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13]>CO.[H][H].[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13]
Reactant: [H][H]
Reactant: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1Cl
Agent: [Ni]
Solvent: CO
Product: CCN(CC)CCOc1ccc(N)cc1Cl

Procedure:
41.0 g (150 mmol) of 3-chloro-4-(2-diethylaminoethoxy)nitrobenzene (IV.1.a) is dissolved in 250 mL of methanol and hydrogenated for 5 hours at ambient temperature at a pressure of 50 psi with hydrogen and 4.0 g of Raney nickel as catalyst. Then the catalyst is filtered off and the solvent is eliminated. The residue is recrystallized from petroleum ether and dried in vacuo. Yield: 33.0 g (91% of theory); Rf value: 0.40 (silica gel, methylene chloride/methanol/ammonia=9:1:0.01); C12H19ClN2O; EII mass spectrum: m/z=243/245 [M+H]+.
Reaction SMILES: C1(/[C:7](/[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])C=CC=CC=1.[O-:21][C:22]#[N:23].[Na+].FC(F)(F)C(O)=O>C(Cl)Cl>[C:22]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]/[CH:8]=[CH:7]/[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)(=[O:21])[NH2:23]
Reactant: OCCCCC/C=C(\c1ccccc1)c1cccnc1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)OCCCCC/C=C/c1cccnc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 105 %

Procedure:
(E)-7-Phenyl-7-(3-pyridyl)-6-hepten-1-ol (2.0 g, 7.4 mmoles) was dissolved in methylene chloride (20 ml), and sodium cyanate (0.50 g, 7.7 mmoles) and trifluoroacetic acid (5 ml) were added. The mixture was stirred at room temperature for 20 hours and concentrated under reduced pressure. The residue was shaken with potassium carbonate (1 g), water (20 ml) and methylene chloride (50 ml), and the organic layer was separated, washed with water, dried and concentrated. Recrystallization of the residue from isopropyl ether gave 1-carbamoyloxy-(E)-7-(3-pyridyl)-6-heptene (1.82 g, 79%) (Compound Id-23).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][C@@H:13]([C:15]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=4[CH3:30])[CH2:19][CH2:18]3)=[O:16])[NH:12][C:11]2=[O:31])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+].C([O-])([O-])=O.[Na+].[Na+]>CC(C)=O.C(OCC)(=O)C>[C:1]1([S:7]([N:10]2[CH2:14][C@@H:13]([C:15]([N:17]3[CH2:18][CH2:19][N:20]([C:23]4[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=4[CH3:30])[CH2:21][CH2:22]3)=[O:16])[N:12]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:11]2=[O:31])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)[C@@H]3CN(S(=O)(=O)c4ccccc4)C(=O)N3)CC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: Cc1ccc(C)c(N2CCN(C(=O)[C@@H]3CN(S(=O)(=O)c4ccccc4)C(=O)N3Cc3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-1-benzenesulfonyl-4-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-imidazolidin-2-one (40 mg) in acetone (5 mL) was treated with benzyl bromide (0.02 mL) and potassium carbonate (25 mg). The reaction mixture was stirred at ambient temperature overnight, additional benzyl bromide (0.03 mL) and potassium carbonate (37 mg) were added, and the mixture was heated to 70° C. for 5 h. After cooling to room temperature, ethyl acetate and a diluted aqueous solution of Na2CO3 were added. The phases were separated and the inorganic one was extracted with ethyl acetate. The combined organic phases were washed with brine, dried (Na2SO4) and evaporated. Purification by column chromatography (SiO2, n-heptane/ethyl acetate 3:1 to 1:1) yielded (S)-1-benzenesulfonyl-3-benzyl-4-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-imidazolidin-2-one (41 mg) as a white solid. MS: 533.3 ([M+H]+)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[F:14].Cl.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][NH2:26]>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH2:5][CH:6]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=2[F:14])[N:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[Cl:18])[N:26]=1)=[O:16]
Reactant: COC(=O)C(=O)C=Cc1ccc(Br)cc1F
Reactant: NNc1ccccc1Cl
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)C1=NN(c2ccccc2Cl)C(c2ccc(Br)cc2F)C1
Temperature: 80 °C
Reaction time: 2 h
Yield: 104.1 %

Procedure:
4-(4-Bromo-2-fluoro-phenyl)-2-oxo-3-butenoic acid methyl ester (2.0 g, 7.0 mmol) prepared in Step 2 and 2-chlorophenylhydrazine hydrochloride (1.4 g, 7.7 mmol) were added to acetic acid (25.0 mL). The reaction mixture was stirred at 80° C. for 2 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The mixture was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 3.0 g of the titled compound as a black liquid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([CH2:19][N:20]([CH3:28])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[N:22]=2)=[CH:17][CH:16]=1.[B:31](OC(C)C)([O:36]C(C)C)[O:32]C(C)C.[Cl-].[NH4+]>C1COCC1>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]([CH3:28])[C:21]2[N:22]=[C:23]([F:27])[C:24]([B:31]([OH:36])[OH:32])=[CH:25][CH:26]=2)=[CH:29][CH:30]=1
Reactant: COc1ccc(CN(C)c2cccc(F)n2)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc(CN(C)c2ccc(B(O)O)c(F)n2)cc1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 36.2 %

Procedure:
In a microwave tube was placed 2,6-difluoropyridine (0.183 mL, 2.00 mmol) and (4-methoxyphenyl)-N-methylmethanamine (0.604 g, 4.00 mmol) in 2 mL of water. The mixture was heated at 150° C. for 20 min. Water was added and the mixture was extracted with ethyl acetate (3×). The combined organic layer were dried over anhydrous sodium sulfate, filtered and concentrated to give 470 mg of a crude yellow oil, which was purified by column chromatography (3/1 hexanes/ethyl acetate) to give 400 mg of N-(4-methoxybenzyl)-6-fluoro-N-methylpyridin-2-amine as a clear, colorless oil. To a solution of diisopropylamine (1.92 mL, 13.6 mmol) in 25 mL of THF at 0° C. was added butyllithium (1.6 M in hexanes, 8.93 mL, 14.3 mmol). The mixture stirred for 30 minutes and was then cooled to −60° C. and N-(4-methoxybenzyl)-6-fluoro-N-methylpyridin-2-amine (1.760 g, 7.15 mmol) was added dropwise in 10 mL of THF. The reaction stirred for 1 h at −60° C. and then triisopropyl borate (2.88 mL, 12.5 mmol) was added and the reaction allowed to warm up to RT and stirred for 1 h. Ammonium chloride (sat.) was added and the reaction was extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 2.13 g of a crude yellow foam, which was purified by column chromatography (3/1 hexanes/ethyl acetate to 1/1 ethyl acetate/hexanes) to give 750 mg of a off-white solid. ES+=291.2 (M+H)
Reaction SMILES: C(=O)([O-])[O-:2].[K+].[K+].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][N:14]=[C:13]([O:16][CH2:17][CH:18]3[O:20][CH2:19]3)[C:12]=2[CH:21]=1.O>C(#N)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][N:14]=[C:13]([O:16][CH2:17][CH:18]([OH:20])[CH2:19][OH:2])[C:12]=2[CH:21]=1
Reactant: O=C([O-])[O-]
Reactant: Clc1ccc2onc(OCC3CO3)c2c1
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: OCC(O)COc1noc2ccc(Cl)cc12
Yield: 74.2 %

Procedure:
256 ml of a 10% w/v aqueous solution of potassium carbonate were added to a suspension of 21.0 g (92.7 mmoles) of 5-chloro-3-(2,3-epoxypropoxy)-1,2-benzisoxazole (prepared according to the method described in Japanese Patent Provisional Publication No. Sho. 52-31070) in 100 ml of acetonitrile, and the mixture was then heated under reflux for 3 hours. At the end of this time, the reaction mixture was cooled by allowing it to stand, and then 500 ml of water were added. The reaction mixture was then extracted with 1 liter of ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was removed by distillation to give a solid residue. This was then recrystallized from a mixture of ethyl acetate and diethyl ether, to give 16.7 g (yield 74.2%) of the title compound as a colorless amorphous powder, melting at 61°-62° C.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].[CH2:22]([O:24][C:25]([C@@H:27]1[CH2:31][CH2:30][CH2:29][C@@H:28]1[NH:32][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[O:26])[CH3:23].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl>CN(C)C=O>[CH2:22]([O:24][C:25]([C@@H:27]1[CH2:31][CH2:30][CH2:29][C@@H:28]1[N:32]([C:17](=[O:19])[CH2:16][C:11]1[NH:10][C:9]2[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[S:13](=[O:14])(=[O:15])[N:12]=1)[CH2:33][CH2:34][CH:35]([CH3:36])[CH3:37])=[O:26])[CH3:23]
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1NCCC(C)C
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CCC[C@@H]1N(CCC(C)C)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 7 h
Yield: 100 %

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.1 g, 0.3 mmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL). (1R,2S)-2-(3-Methyl-butylamino)-cyclopentanecarboxylic acid ethyl ester (0.068 g, 0.3 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.06 g, 0.315 mmol). Then N-methylmorpholine (0.064 g, 0.63 mmol) was added into the above reaction mixture. The mixture was stirred at 25° C. for 7 h. The solution was poured into a 1.0 M aqueous hydrochloric acid solution (50 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to afford the crude product, (1R,2S)-2-[[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-(3-methyl-butyl)-amino]-cyclopentanecarboxylic acid ethyl ester (0.3 mmol), as a light yellow oil, which was used directly for next step. LC-MS (ESI) calcd for C23H34N4O7S2 542.19, found 543.3 [M+H+].
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([C:7]([OH:9])=O)[S:5][CH:6]=1.Cl.[NH2:12][C:13]1[CH:14]=[C:15]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:16]([NH:18][CH:19]1[CH2:21][CH2:20]1)=[O:17]>>[Br:1][C:2]1[C:3]([CH3:10])=[C:4]([C:7]([NH:12][C:13]2[CH:14]=[C:15]([C:16](=[O:17])[NH:18][CH:19]3[CH2:21][CH2:20]3)[CH:22]=[CH:23][C:24]=2[CH3:25])=[O:9])[S:5][CH:6]=1
Reactant: Cc1c(Br)csc1C(=O)O
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N
Agent: Cl
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1scc(Br)c1C

Procedure:
The compound a was prepared by coupling commercially available 4-bromo-3-methylthiophene-2-carboxylic acid with 3-amino-N-cyclopropyl-4-methylbenzamide hydrochloride (prepared as described in WO 04/071440) using the method described in Example 128. HPLC Ret time=3.12 min. LCMS [M+H]+ 393.13.
Reaction SMILES: [C:1](Cl)([CH3:3])=[O:2].[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)([O-:7])=[O:6]>C(Cl)Cl.N1C=CC=CC=1>[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:1](=[O:2])[CH3:3])=[CH:10][CH:9]=1)([O-:7])=[O:6]
Reactant: CC(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of Pyridine (3 mL) and AcCl (1.017 g, 13.043) in DCM (15 mL) was added the solution of 4-nitrobenzenamine (1.5 g, 10.870 mmol) in pyridine (3 mL) at 0° C. The mixture was stirred at room temperature for 1 h. The volatiles were removed under reduced pressure and the residue was washed with water (10 mL×3), dried under reduced pressure to afford N-(4-nitrophenyl)acetamide as yellow powder (1.9 g, yield: 97%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[OH:16])[C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[C:19](OC(=O)C)(=[O:21])[CH3:20].Cl>O>[C:1]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[O:16][C:19](=[O:21])[CH3:20])[C:10]([OH:12])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(O)c(-c2ccccc2)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Oc1ccc(C(=O)O)cc1-c1ccccc1

Procedure:
A solution of 3-phenyl-4-hydroxybenzoic acid (131.1 g, 0.061 mole) and a 50 weight percent aqueous solution of NaOH (10.5 g, 0.131 mole) in 350 ml of deionized water was added to a 500 ml, three-necked, round-bottom flask equipped with a thermometer and a polytetrafluoroethylene-coated magnetic stir bar. The solution was stirred to homogeneity and then immersed in an ice water bath. With the solution temperature at 10° C., acetic anhydride (12.7 g, 0.124 mole) was added rapidly with stirring. Immediately, a white precipitate began to form. The reaction mixture was stirred for one hour at 10° C., then neutralized with concentrated HCl. The precipitate was filtered, washed in 500 ml of deionized water for one hour, filtered, and dried in an 80° C. vacuum oven for three hours yielding an off-white solid. The solid was recrystallized from a toluene and hexane mixture to give a fluffy white solid, 3-phenyl-4-acetoxybenzoic acid with a m.p. of 185° C. to 187° C.
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH2:11][C:12]([O:14]CC)=[O:13])=[C:4]([C:17]#[C:18][Si](C)(C)C)[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:29]1COC[CH2:30]1.CO>CCOCC>[CH2:29]([CH:11]([C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([F:1])=[CH:3][C:4]=1[C:17]#[CH:18])[C:12]([OH:14])=[O:13])[CH3:30]
Reactant: CCOC(=O)Cc1cc([N+](=O)[O-])c(F)cc1C#C[Si](C)(C)C
Reactant: C1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CO
Product: C#Cc1cc(F)c([N+](=O)[O-])cc1C(CC)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 2-(4-fluoro-5-nitro-2-(2-(trimethylsilyl)ethynyl)phenyl)acetate (0.85 g, 2.6 mmol) and K2CO3 (3.6 g) were dissolved in THF/MeOH (5:1, 30 mL) and the mixture was stirred overnight at RT. The reaction mixture was diluted with Et2O and washed with sat'd NH4Cl solution. The organic layer was dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain ethyl 2-(2-ethynyl-4-fluoro-5-nitrophenyl)acetic acid.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([CH:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[C:16]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[K+].[K+]>COCCOC>[C:16]([C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:15]3[C:10]([CH:9]=[C:8]4[C:3]=2[CH:4]=[CH:5][CH:6]=[CH:7]4)=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: Brc1c2ccccc2cc2ccccc12
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CC(C)(C)c1ccc(-c2c3ccccc3cc3ccccc23)cc1
Temperature: 25 °C

Procedure:
5.1 g (20 mmol) of 9-bromoanthracene, 3.6 g (20 mmol) of 4-tert-butylphenylboronic acid, and 244 mg (0.80 mmol) of tri(o-tolyl)phosphine were put into a 100-mL three-neck flask, and nitrogen substitution in the system was carried out. 20 mL of ethylene glycol dimethyl ether (DME) was added to this mixture, and the mixture was stirred under reduced pressure and degassed. After that, 45 mg (0.20 mmol) of palladium acetate(II) and 10 mL (2.0 mol/L) of a potassium carbonate solution were added. This reaction mixture was stirred at 80° C. for 3 hours under nitrogen gas stream. Then, the reaction mixture was cooled to the room temperature, and a solid that was precipitated was collected by suction filtration. The collected solid was dissolved in toluene, and the solution was subjected to suction filtration through Florisil, celite, and then alumina. The filtrate was condensed to obtain a solid, and the solid was recrystallized with ethanol, whereby 5.0 g of a white powdery solid, which was a target matter, was obtained with the yield of 81%.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([CH3:39])([CH3:38])[CH2:36][OH:37])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].[H-].[Na+].[CH3:42]I>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:3]1[N:4]([C:28]2[CH:29]=[CH:30][C:31]([O:34][C:35]([CH3:39])([CH3:38])[CH2:36][O:37][CH3:42])=[CH:32][CH:33]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:17][CH:18]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2]
Reactant: CCCc1nc(CC)n(-c2ccc(OC(C)(C)CO)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1nc(CC)n(-c2ccc(OC(C)(C)COC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 0.25 h
Yield: 48 %

Procedure:
To a solution of 4′-({2-ethyl-1-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.48 g) in N,N-dimethylformamide (10 mL) was added sodium hydride (0.07 g, 60%), and the mixture was stirred for 15 min. Then methyl iodide (0.11 mL) was added, and the mixture was further stirred for 2 hr. Small pieces of ice were added to the reaction mixture, and the mixture was stirred for 15 min, diluted with ethyl acetate, washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.24 g, 48%).
Reaction SMILES: [NH2:1][C@@H:2]([C@H:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:6])[CH2:3][OH:4].[Cl:12][C:13]1[N:18]=[C:17](Cl)[CH:16]=[C:15]([CH3:20])[N:14]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[C:8]([O:7][C@H:5]([CH3:6])[C@H:2]([NH:1][C:17]1[CH:16]=[C:15]([CH3:20])[N:14]=[C:13]([Cl:12])[N:18]=1)[CH2:3][OH:4])([CH3:10])([CH3:9])[CH3:11]
Reactant: C[C@@H](OC(C)(C)C)[C@H](N)CO
Reactant: Cc1cc(Cl)nc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1cc(N[C@H](CO)[C@@H](C)OC(C)(C)C)nc(Cl)n1
Temperature: 25 °C
Yield: 24.3 %

Procedure:
A solution of (2R,3R)-2-amino-3-(tert-butoxy)butan-1-ol (267 mg, 1.35 mmol, 1.1 equiv), 2,4-dichloro-6-methylpyrimidine (200 mg, 1.23 mmol, 1.0 equiv), and N-ethyl-N-isopropylpropan-2-amine (0.54 mL, 3.1 mmol, 2.5 equiv) in 1,4-dioxane (6 mL) was heated at 75° C. for 4 h. The reaction was cooled to room temperature and concentrated in vacuo. Silica gel column chromatography (EtOAc/Heptane) provided (2R,3R)-3-(tert-butoxy)-2-((2-chloro-6-methylpyrimidin-4-yl)amino)butan-1-ol (86 mg, white solid) in 24% yield. 1H NMR (400 MHz, CDCl3) δ 6.17 (s, 1H), 4.02 (m, 2H), 3.79-3.64 (m, 2H), 2.30 (s, 3H), 1.22 (s, 9H), 1.18 (d, J=6.2 Hz, 3H); MS m/z 288.1 (M+H)+; Rt-0.59 min.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][C:13]4=[O:20])=[CH:8][N:7]3[C:21]=2[CH3:22])[CH2:3][CH2:2]1.[F:23][C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([CH2:18][O:19][C:27]5[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=5)=[CH:14][C:13]4=[O:20])=[CH:8][N:7]3[C:21]=2[CH3:22])[CH2:2][CH2:3]1
Reactant: Oc1ccc(F)cc1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(CO)cc3=O)cn12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(COc4ccc(F)cc4)cc3=O)cn12
Temperature: 60 °C
Reaction time: 5 h
Yield: 12.1 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-(hydroxymethyl)pyridin-2(1H)-one (150 mg), 4-fluorophenol (85 mg) and tributylphosphine (307 mg) in THF (20 ml) was added 1,1′-(azodicarbonyl)dipiperidine (386 mg), and the mixture was stirred at 60° C. for 5 h. The reaction mixture was cooled to room temperature, concentrated in vacuo, and diluted with DCM. The mixture was washed with water and brine successively, dried over Na2SO4, concentrated in vacuo and purified by column chromatography (MeOH/DCM) followed by preparative HPLC to afford the title compound (24 mg) as a white solid.
Reaction SMILES: [CH2:1]([C@H:8]([NH:32][C:33](=[O:43])[O:34][C@@H:35]1[C@H:42]2[C@H:38]([O:39][CH2:40][CH2:41]2)[O:37][CH2:36]1)[C@H:9]([OH:31])[CH2:10][N:11]([O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C>[Pd].C(OCC)(=O)C>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([N:11]([O:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)[CH2:10][C@@H:9]([OH:31])[C@@H:8]([NH:32][C:33](=[O:43])[O:34][C@@H:35]2[C@H:42]3[C@H:38]([O:39][CH2:40][CH2:41]3)[O:37][CH2:36]2)[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)(=[O:14])=[O:13])=[CH:16][CH:17]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CN(OC1CCCCC1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1)O[C@H]1CO[C@H]2OCC[C@H]21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)OC2CCCCC2)cc1
Reaction time: 16 h
Yield: 81.1 %

Procedure:
To a solution of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-{(cyclohexyloxy)[(4-nitrophenyl)sulfonyl]amino}-2-hydroxypropylcarbamate (115 mg, 0.186 mmol) in a 1:1 mixture of ethanol:ethyl acetate (6 mL) was added Palladium on charcoal (10 wt %, 30 mg). The starting material was reduced under an atmosphere of Hydrogen gas over 16 hrs. The reaction mixture was filtered and evaporated in vacuo. The residue was purified on a preparative TLC plate (20×20 cm, 500 uM) eluting with 3:1 ethyl acetate:hexane. The product band was removed, eluted with 3:1 methylene chloride:methanol, filtered, and evaporated in vacuo. The residue was triturated with water, filtered and dried under high vacuum to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[[(4-aminophenyl)sulfonyl](cyclohexyloxy)amino]-1-benzyl-2-hydroxypropylcarbamate (89 mg, 81%). H1-NMR (chloroform-D3): 1.26 (m, 6H), 1.58 (m, 5H), 2.05 (m, 2H), 2.90 (m, 4H), 3.09 (b, 2H), 3.68 (m, 2H), 3.88 (m, 4H), 4.16 (m, 1H), 4.24 (b, 1H), 4.81 (d, 1H), 5.00 (m, 1H), 5.63 (d, 1H), 6.66 (d, 2H), 7.23 (m, 5H), 7.56 (d, 2H). MS(ESI): 612(M+Na).