Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([OH:14])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.C(O)[CH2:17][CH2:18][CH2:19][CH3:20].[C:22]1(C)[CH:27]=CC(S(O)(=O)=O)=[CH:24][CH:23]=1>>[CH2:10]([O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:12]([OH:14])[CH:13]=[C:4]([C:3]([O:2][CH2:1][CH2:20][CH2:19][CH2:18][CH3:17])=[O:15])[CH:5]=1)[CH2:27][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCO
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCOC(=O)c1cc(O)cc(C(=O)OCCCCC)c1
Temperature: 129 °C
Reaction time: 6.3 h

Procedure:
A 100 mL three-neck flask, equipped with a magnetic stir bar, a Claisen adapter with a thermocouple and a subsurface nitrogen inlet, and a short path condenser, was charged with 5.31 grams of dimethyl-5-hydroxyisophthalate, 44 mL of 1-pentanol, and 0.53 gram of p-toluenesulfonic acid. The reaction was stirred at 129° C. for 6.3 hours with a nitrogen sweep. The reaction mixture was taken up in xylenes, extracted with dilute aqueous sodium bicarbonate, washed twice with water, dried over magnesium sulfate, and filtered. Solvent was removed by rotary evaporation to yield 7.3 grams of a straw-colored liquid.
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:10]=[C:9]([C:11](O)=[O:12])[N:8]([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[N:7]=1>CN(C)C=O.C1(C)C=CC=CC=1>[Br:5][C:6]1[CH:10]=[C:9]([C:11]([Cl:3])=[O:12])[N:8]([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[N:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(Br)nn1-c1ncccc1Cl

Procedure:
1.5 ml of thionyl chloride and 2 drops of dimethylformamide were added to a mixed solution comprising 1.0 g of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid and 10 ml of toluene, followed by reflux with heating for one hour, and thionyl chloride and toluene were distilled off to obtain crude product of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride.
Reaction SMILES: O[N:2]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.O.N.[Cl:25][C:26]1[S:27][CH:28]=[C:29]([C:31]([OH:33])=O)[N:30]=1>O.ClCCl>[Cl:25][C:26]1[S:27][CH:28]=[C:29]([C:31]([NH2:2])=[O:33])[N:30]=1
Reactant: O=C(O)c1csc(Cl)n1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: ClCCl
Product: NC(=O)c1csc(Cl)n1
Temperature: 25 °C
Reaction time: 46 h
Yield: 95.5 %

Procedure:
1-hydroxybenzotriazole (0.56 g, 3.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC) (0.7 g, 3.7 mmol) and ammonia water (28%, 0.5 ml)) were added to a dichloromethane solution (10 ml) of 2-chlorothiazole-4-carboxylic acid (0.5 g, 3.06 mmol) and the mixture was stirred at room temperature for 46 hours. Water was added to the reaction solution, which was then extracted with ethyl acetate. The extraction solution with ethyl acetate was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:5→ethyl acetate). The purified product was concentrated to dryness under reduced pressure to obtain 2-chlorothiazole-4-carboxamide (475 mg) as white powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][OH:25].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:19][C:5]1[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[N:7][C:2]([NH:20][C:21]2[CH:22]=[C:23]([CH2:24][OH:25])[CH:26]=[CH:27][CH:28]=2)=[N:3][CH:4]=1
Reactant: COc1cccc(CCNc2nc(Cl)ncc2Cl)c1
Reactant: Nc1cccc(CO)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(CCNc2nc(Nc3cccc(CO)c3)ncc2Cl)c1
Temperature: 100 °C
Yield: 101.7 %

Procedure:
To a solution of 2,5-dichloro-N-[2-(3-methoxyphenyl)ethyl]pyrimidin-4-amine (0.70 g, 2.3 mmol) and 3-aminobenzyl alcohol (0.39 g, 3.2 mmol) in 1,4-dioxane (20.0 mL) was added p-toluenesulfonic acid monohydrate (0.16 g, 0.85 mmol). The mixture was heated at 100° C. for 16 h and the reaction was complete. To the mixture was added NaHCO3 (saturated aqueous solution) and the organic solvent was removed under vacuum, followed by the addition of water and EtOAc. The aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered, and concentrated (then triturated with cold EtOAc) to give the desired product as an off-white powder (0.90 g, 100%). LCMS for C20H22ClN4O2 (M+H)+: m/z=385.1.
Reaction SMILES: [CH3:1][C:2]1[S:11][C:5]2[N:6]=[CH:7][N:8]=[C:9]([OH:10])[C:4]=2[CH:3]=1.[Br:12]Br>C(O)(=O)C>[Br:12][C:3]1[C:4]2[C:9]([OH:10])=[N:8][CH:7]=[N:6][C:5]=2[S:11][C:2]=1[CH3:1]
Reactant: Cc1cc2c(O)ncnc2s1
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1sc2ncnc(O)c2c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
A solution of 6-methylthieno[2,3-d]pyrimidin-4-ol (95 mg, 0.57 mmol, 1.00 equiv) in acetic acid (2 mL) was added Br2 (181 mg, 1.13 mmol, 2.00 equiv) and the resulting solution was stirred overnight at room temperature under nitrogen. After finished of the reaction, the reaction was then quenched with saturated aqueous NaHSO3 and extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give the resulted 5-bromo-6-methylthieno[2,3-d]pyrimidin-4-ol (111 mg, 79%) as a yellow solid.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[CH2:28][O:29][Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:42](Br)[CH:43]=[CH2:44]>CN(C=O)C>[CH2:44]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=2)[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:8]1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[CH2:28][O:29][Si:30]([CH:31]([CH3:32])[CH3:33])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])[CH:43]=[CH2:42]
Reactant: C=CCBr
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OC)cc3CO[Si](C(C)C)(C(C)C)C(C)C)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c(-c2ccc(OC)cc2CO[Si](C(C)C)(C(C)C)C(C)C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Reaction time: 0.08 h
Yield: 84 %

Procedure:
Methyl 3-cyclohexyl-2-(4-methoxy-2-{[(triisopropylsilyl)oxy]methyl}phenyl)-1H-indole-6-carboxylate (1 eq) was dissolved in DMF (0.34M solution) and the solution was degassed. NaH (60% dispersion in mineral oil; 1.1 eq) was added and the mixture was stirred for 5 min. Allyl bromide (1.2 eq) was added and stirring was continued for 5 h. All volatiles were evaporated in vacuo and the residual material was dissolved in Et2O. The solution was washed with 0.5N HCl, saturated aq. NaHCO3 solution and with brine. After drying the organic phase over Na2SO4 all volatiles were evaporated in vacuo and the residual material was purified by FC (PE:EtOAc, 10:1). After evaporation of the solvents the product was obtained as a colourless sticky solid (84%). The material was used without further characterization in the next reaction.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:14]([N:16](CC)CC)C.N#CBr>C1COCC1>[C:14]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)#[N:16]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: N#CBr
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C#N)CC1
Temperature: 0 °C
Reaction time: 12 h
Yield: 86.4 %

Procedure:
1,1-Dimethylethyl 1-piperazinecarboxylate (25 g, 134.2 mmol) was taken into THF (100 mL) followed by addition of triethylamine (25 mL, 178 mmol). The solution was cooled to 0° C. followed by addition dropwise addition of cyanogen bromide (15.6 g, 147.6 mmol) in THF (100 mL) and the resulting mixture was allowed to warm to room temperature then stirred an additional 12 hours. The reaction mixture was concentrated in vacuo and partitioned with ethyl ether and water. The organic layer was washed once with saturated aqueous NaCl then dried over anhydrous magnesium sulfate followed by concentration to afford 1,1-dimethylethyl 4-cyanopiperazine-1-carboxylate (24.5 g, 86% yield) as a colorless crystalline solid. 1H-NMR (400 MHz, CDCl3): 3.51 (tr, 4H), 3.19 (tr, 4H), 1.46 (s, 9H).
Reaction SMILES: [O:1]1[CH2:5][C@@H:4]([OH:6])[C@H:3]2[O:7][CH2:8][C@@H:9]([OH:10])[C@@H:2]12.N12CCCN=C1CCCCC2.[Cl:22][C:23]1[CH:24]=[C:25]2[N:32]=[C:31](S(C)(=O)=O)[N:30]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:26]2=[N:27][C:28]=1[I:29]>CN(C)C=O>[Cl:22][C:23]1[CH:24]=[C:25]2[N:32]=[C:31]([O:6][C@H:4]3[C@H:3]4[O:7][CH2:8][C@@H:9]([OH:10])[C@H:2]4[O:1][CH2:5]3)[N:30]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:26]2=[N:27][C:28]=1[I:29]
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cc(Cl)c(I)nc21
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2cc(Cl)c(I)nc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(3R,3aR,6R,6aR)-Hexahydrofuro[3,2-b]furan-3,6-diol (1.84 g) is dissolved in N,N-dimethylformamide (10 mL) and treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU; 1.9 mL). A solution of 6-chloro-5-iodo-2-(methylsulfonyl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridine (2.05 g) in N,N-dimethylformamide (20 mL) is added drop wise and the mixture is stirred for 2 hours at room temperature. The mixture is partitioned between water and ethyl acetate and the organic phase is washed with brine and dried (MgSO4). The solvents are evaporated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 80:20→0:100) to give the title compound. LC (method 1): tR=1.17 min; Mass spectrum (ESI+): m/z=554 [M+H]+.
Reaction SMILES: S(Cl)(Cl)=[O:2].[C:5]([CH:8]1[CH2:13][CH:12]([CH3:14])[CH2:11][CH2:10][CH:9]1[NH2:15])(O)=O.[CH3:16][OH:17]>>[C:16]([CH2:5][CH:8]1[CH2:13][CH:12]([CH3:14])[CH2:11][CH2:10][CH:9]1[NH2:15])([OH:2])=[O:17]
Reactant: O=S(Cl)Cl
Reactant: CO
Reactant: CC1CCC(N)C(C(=O)O)C1
Product: CC1CCC(N)C(CC(=O)O)C1
Reaction time: 4 h
Yield: 85 %

Procedure:
7.3 ml (0.1 mol) of thionyl chloride are added to 30 ml of methanol at -5° C. under N2, and 15 g (0.096 mol) of 2-carboxy-4-methylcyclohexan-1-yl-amine in 10 ml of methanol are then added dropwise to this solution at 0° C. After the mixture has been stirred under reflux for 12 hours it is cooled, a further 10 ml of methanol and 3 ml (0.04 mol) of thionyl chloride are added, and stirring under reflux is continued for 4 hours. After cooling and evaporation to dryness, 5 g of the residue is taken up in about 50 ml of diethyl ether and the mixture is washed in about 100 ml of cold 1N Naton lye and water. The organic phase is dried and concentrated. 3.5 g (85% of theory) of 2-carboxymethyl-4-methyl-cyclohexan-1-yl-amine are obtained as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]2[NH:44][C:43](=[O:45])[O:42][N:41]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:33])[N:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH:26]3[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28][CH2:27]3)=[CH:21][CH:20]=2)[C:12]([CH3:18])=[N:13][C:14]=1[CH2:15][CH2:16][CH3:17].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[C:4]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]2[NH:44][C:43](=[O:45])[O:42][N:41]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:33])[N:11]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH:26]3[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]3)=[CH:23][CH:24]=2)[C:12]([CH3:18])=[N:13][C:14]=1[CH2:15][CH2:16][CH3:17]
Reactant: CCCc1nc(C)n(-c2ccc(OC3CCC(O)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(OC3CCC(=O)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1F
Reaction time: 15 h
Yield: 87.8 %

Procedure:
To a solution of 5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-{4-[(4-hydroxycyclohexyl)oxy]phenyl}-2-methyl-6-propylpyrimidin-4(3H)-one (0.40 g) in methylene chloride (4 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.42 g), and the mixture was stirred for 15 hr. Ethyl acetate, water and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred for 30 min and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.35 g, 88%).
Reaction SMILES: C([O:9][C@H:10]1[C@@H:17]2[N:13]([N:14]=[C:15]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([Cl:28])[C:21]=3[CH3:29])[C@H:16]2[O:18][CH3:19])[CH2:12][CH2:11]1)(=O)C1C=CC=CC=1.O[Li].O>C1COCC1.O>[Cl:28][C:22]1[C:21]([CH3:29])=[C:20]([C:15]2[C@@H:16]([O:18][CH3:19])[C@@H:17]3[C@H:10]([OH:9])[CH2:11][CH2:12][N:13]3[N:14]=2)[CH:25]=[CH:24][C:23]=1[C:26]#[N:27]
Reactant: CO[C@@H]1C(c2ccc(C#N)c(Cl)c2C)=NN2CC[C@@H](OC(=O)c3ccccc3)[C@@H]12
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CO[C@@H]1C(c2ccc(C#N)c(Cl)c2C)=NN2CC[C@@H](O)[C@@H]12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3S,3aS,4R)-2-(3-chloro-4-cyano-2-methylphenyl)-3-methoxy-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-4-yl benzoate (80 mg, 0.0.195 mmol) in THF (2 mL) at 0° C. was added a solution of LiOH.H2O (25 mg, 0.586 mmol) in water and the reaction mixture was stirred at room temperature for overnight. Once the starting material had disappeared (monitored by TLC), reaction mixture was extracted with ethyl acetate. Organic layer was washed with saturated NaHCO3 solution, water, and brine and then dried over Na2SO4 and concentrated. Purification of the crude by column chromatography over silica gel using 2% MeOH in DCM provided the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:6][CH2:7][N:8]([CH2:10][CH2:11]O)[CH3:9].S(Cl)([Cl:20])=O>C(Cl)Cl>[Cl:20][CH2:11][CH2:10][N:8]([CH2:7][CH2:6][C:5]1[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:9]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CCN(C)CCO)cc1OC
Solvent: ClCCl
Product: COc1ccc(CCN(C)CCCl)cc1OC
Reaction time: 24 h

Procedure:
The 2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethanol as produced in Example 4-(1) in an amount of 2 g (8.36 mmol) was added to methylene chloride (20 ml) and thionyl chloride (0.91 ml, 12.54 mmol) was slowly added dropwise at room temperature, followed by stirring for 24 h. Thereafter, the reaction mixture was subjected to extraction with methylene chloride and washed with a saturated solution of sodium bicarbonate, followed by drying with anhydrous magnesium sulfate and evaporation of the solvent to yield the end compound 1-chloro-2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane (2.15 g)
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9].BrN1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[Cl:30]C1C=CC=CC=1>>[Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][Cl:30])=[CH:4][C:3]=1[F:9]
Reactant: Cc1cnc(Br)c(F)c1
Reactant: Clc1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Product: Fc1cc(CCl)cnc1Br
Yield: 42 %

Procedure:
10.00 g (52.63 mmol) of 6-bromo-5-fluoro-3-methylpyridin (cf. F. L. Setliff, Organic Preparations and Procedures International 1971, 3, 217-222), 12.18 g (68.42 mmol) of N-bromosuccinimide and 0.86 g (5.26 mmol) of 2,2′-azobis(2-methylpropanenitrile) in 1 of chlorobenzene are boiled under reflux for 6 hours. The reaction mixture is washed with saturated aqueous sodium sulphite solution and sodium bicarbonate solution and then dried over sodium sulphate and concentrated under reduced pressure. Column chromatography of the residue on silica gel (silica gel 60-Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (1:20) gives 6.0 g (42% of theory) of 6-bromo-3-chloromethyl-5-fluoropyridine.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:8]([O:10]C(C)(C)C)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])O.C1C=NC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:56][C:57]1[CH:58]=[C:59]([P:63](=[O:66])([OH:65])[OH:64])[CH:60]=[CH:61][CH:62]=1>CN(C=O)C.C(N(CC)CC)C>[P:63]([C:59]1[CH:58]=[C:57]([NH:56][C:5](=[O:7])[CH2:4][CH2:3][C@@H:2]([C:8]([OH:10])=[O:9])[NH2:1])[CH:62]=[CH:61][CH:60]=1)([OH:66])([OH:65])=[O:64]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Reactant: Nc1cccc(P(=O)(O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N[C@@H](CCC(=O)Nc1cccc(P(=O)(O)O)c1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Boc-Glu-OtBu (236 mg, 0.78 mmol), HOAt (127 mg, 0.936 mmol) and HATU (356 mg, 0.936 mmol) were dissolved in 1 mL of DMF, and triethylamine (0.21 ml) was added thereto. 10 minutes later, the crude product of (3-aminophenyl)phosphonic acid was added thereto and stirred at room temperature overnight. After removing a solvent, purification was conducted in accordance with the purification process A to obtain a title compound.
Reaction SMILES: [NH2:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([NH:12][C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=4)=[O:14])([CH2:5]3)[CH2:3]1)[CH2:9]2.CCN(C(C)C)C(C)C.[CH3:31][N:32]1[CH:36]=[CH:35][C:34]([C:37](Cl)=[O:38])=[N:33]1>C(Cl)Cl>[CH3:31][N:32]1[CH:36]=[CH:35][C:34]([C:37]([NH:1][C:2]23[CH2:11][CH:6]4[CH2:7][CH:8]([CH2:10][C:4]([NH:12][C:13]([C:15]5[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=5)=[O:14])([CH2:5]4)[CH2:3]2)[CH2:9]3)=[O:38])=[N:33]1
Reactant: Cn1ccc(C(=O)Cl)n1
Reactant: Cc1cccc(C(=O)NC23CC4CC(CC(N)(C4)C2)C3)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccc(C(=O)NC23CC4CC(C2)CC(NC(=O)c2ccn(C)n2)(C4)C3)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.3 %

Procedure:
To a solution of 6-methyl-pyridine-2-carboxylic acid (3-amino-adamantan-1-yl)-amide (Intermediate 1, 20 mg, 0.07 mmol) in DCM (5 mL) was added DIEA (30 mg, 0.2 mmol) and 1-methyl-1H-pyrazole-3-carbonyl chloride (20 mg, 0.1 mmol, Maybridge Chemical Co., Cornwall, UK). After stirring at room temperature for 16 h, the reaction mixture was partitioned into dichloromethane and saturated sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified on a RP-HPLC/MS purification system (Gradient: acetonitrile in water, 25-95%, in 3.9 minutes with a cycle time of 5 min. Flow rate: 100 mL/min. Mobile phase additive: 25 mM of ammonium formate. Column: Inertsil® C8, 30×50 mm, 5 μm particle size (GL Sciences, Tokyo, Japan)) to afford 10 mg (30%) of the title compound, 6-methyl-pyridine-2-carboxylic acid {3-[(1-methyl-1H-pyrazole-3-carbonyl)-amino]-adamantan-1-yl}-amide, as a white solid. 1H NMR (400 MHz, CDCl3) δ8.07 (s, br, 1H), 7.95 (d, J=7.7 Hz, 1H), 7.69 (t, J=7.8 Hz, 1H), 7.33 (d, J=2.3 Hz, 1H), 7.26-7.21 (m, 1H), 6.76-6.72 (m, 2H), 3.89 (s, 3H), 2.55 (s, 3H), 2.54-2.52 (m, 2H), 2.35-2.08 (m, 10H), 1.72-1.69 (m, 2H). ESI-MS m/z: 394.1 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH:5]([C:11](=O)[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=O)[CH3:2].C([O-])(=O)C.[NH4+:26]>C(O)(=O)C>[CH3:2][C:1]1[O:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:11]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)[N:26]=1
Reactant: [NH4+]
Reactant: CCOC(=O)C(OC(C)=O)C(=O)CCc1cccc(C)c1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CCOC(=O)c1oc(C)nc1CCc1cccc(C)c1

Procedure:
A mixture of the product from step (ii) (19.6 g) and ammonium acetate (25.8 g) in acetic acid (150 ml) was heated under reflux for 2 hours. The reaction mixture was evaporated to dryness and the residue partitioned between water and ethyl acetate. The organic phase was washed with aqueous sodium bicarbonate and water, dried (MgSO4) and evaporated under reduced pressure. The product was used without purification in the next step.
Reaction SMILES: [Cl-:1].[Li+].C1(C)C=CC(S(O[CH2:13][CH:14]([OH:37])[CH2:15][CH:16]([C:28]2[CH:33]=[C:32]([F:34])[C:31]([F:35])=[C:30]([F:36])[CH:29]=2)[C:17]([NH:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:18])(=O)=O)=CC=1.O.C(OCC)(=O)C>CN(C=O)C>[Cl:1][CH2:13][CH:14]([OH:37])[CH2:15][CH:16]([C:28]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[C:30]([F:36])[CH:29]=1)[C:17]([NH:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:18]
Reactant: [Cl-]
Reactant: Cc1ccc(S(=O)(=O)OCC(O)CC(C(=O)NNC(=O)OC(C)(C)C)c2cc(F)c(F)c(F)c2)cc1
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NNC(=O)C(CC(O)CCl)c1cc(F)c(F)c(F)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
Lithium chloride (818 mg) was added to a solution of 5-(N′-tert-butoxycarbonylhydrazino)-2-hydroxy-5-oxo-4-(3,4,5-trifluorophenyl)pentyl toluene-4-sulfonate (1.03 g) in DMF (8 mL). The reaction solution was stirred at 80° C. for three hours and then left to cool to room temperature. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 734 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([OH:17])[C:8]([C:14](=[O:16])[CH3:15])=[CH:9][C:10]=1[C:11](=[O:13])[CH3:12])(=O)[CH3:2].[H-].[Na+].C(I)C.Cl>CN1CCCC1=O.C(O)C>[C:11]([C:10]1[CH:9]=[C:8]([C:14](=[O:16])[CH3:15])[C:7]([OH:17])=[CH:6][C:5]=1[NH:4][CH2:1][CH3:2])(=[O:13])[CH3:12]
Reactant: CC(=O)Nc1cc(O)c(C(C)=O)cc1C(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN1CCCC1=O
Solvent: CCI
Product: CCNc1cc(O)c(C(C)=O)cc1C(C)=O
Reaction time: 2 h
Yield: 63 %

Procedure:
3-Acetamido-4,6-diacetylphenol (0.01 mole) in N-methylpyrrolidone (NMP) (20 ml) was added to a cooled (<5° C.), stirred suspension of sodium hydride (0.022 mole) in NMP (5 ml). After 15 minutes the mixture was treated with ethyliodide (0.019 mole). After two hours at <5° C., the mixture was acidified with ethanol/conc. HCl (1:1, 20 ml) and heated to reflux for 21/2 hours. The mixture was allowed to cool and the crystalline subtitle compound isolated by filtration. Yield 63%, mp 103°-104° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8]O.P(Br)(Br)[Br:11].C(Cl)Cl>C1COCC1>[BrH:11].[Br:11][CH2:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[I:1]
Reactant: BrP(Br)Br
Reactant: OCc1ccncc1I
Solvent: ClCCl
Solvent: C1CCOC1
Product: Br
Product: BrCc1ccncc1I
Temperature: 25 °C
Yield: 171.5 %

Procedure:
A mixture of 24A (142 mg, 0.604 mmol) and PBr3 (0.61 mL, 1M in CH2Cl2, 0.61 mmol) in THF (5 mL) was heated to reflux for 30 minutes. The reaction mixture was cooled to room temperature, CH2Cl2 was added and the mixture was filtered. The solid was rinsed with CH2Cl2 and dried to give 24B (198.2 mg, 86.6%). HPLC Rt=1.756 min.