Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][CH2:11][CH2:12][NH2:13])=[CH:5][CH:4]=1.[Cl:14][C:15]1[N:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=1.S([O-])([O-])(=O)=O.[Mg+2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[Cl:14][C:15]1[N:20]=[CH:19][C:18]([CH2:21][NH:13][CH2:12][CH2:11][S:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(Cl)nc1
Reactant: COc1ccc(CSCCN)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCCl
Product: COc1ccc(CSCCNCc2ccc(Cl)nc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 70.9 %

Procedure:
Under a dry nitrogen atmosphere, a mixture of 8.0 grams (0.041 mole) of 2-[(4methoxyphenyl)-methylthio]ethylamine (known compound), 5.7 grams (0.041 mole) of 6-chloropyridine-3-carbaldehyde and 9.7 grams (0.081 mole) of magnesium sulfate in 160 mL of 1,2-dichloroethane was stirred at ambient temperature for about five hours. Sodium triacetoxyborohydride (12.9 grams, 0.061 mole) was added and the reaction mixture stirred at ambient temperature for about 18 hours. After this time 200 mL of an aqueous 5% sodium carbonate solution was added and the mixture stirred for two hours. The mixture was filtered and the filter cake rinsed with methylene chloride. The filtrate and rinse were combined and extracted with three portions of methylene chloride. The combined extracts were dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a yellow oil. The oil was subjected to several column chromatography purifications on silica gel, combining the appropriate fractions and concentrating prior to the next purification, eluting with mixtures of methylene chloride and methanol. The third chromatography purification provided 9.39 grams of [(6-chloro(3-pyridyl))methyl]{2-[(4-methoxyphenyl)methylthio]ethyl}amine as an oil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.CCN(C(C)C)C(C)C.Cl.[CH2:22]([C:24]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25]1)[CH3:23].O>CS(C)=O>[CH2:22]([C:24]1([NH:29][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1)[CH3:23]
Reactant: CSc1ncc(C#N)c(Cl)n1
Reactant: CCC1(N)CCCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: CCC1(Nc2nc(SC)ncc2C#N)CCCC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 60.4 %

Procedure:
To a stirring solution of 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (984 mg, 5.3 mmol) in DMSO (10 mL) was added DIEA (2.1 g, 15.9 mmol) and 1-ethylcyclopentanamine hydrochloride (900 mg crude). The resulting mixture was stirred at 60° C. for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to afford the crude product. The crude product was purified by silica gel column chromatography (5% ethyl acetate in petroleum ether) to get the desired product as a yellow oil (830 mg, 3.2 mmol, 53.5% yield). MS (ESI) m/z=263.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][N:12]=[C:11]([CH2:14]O)[CH:10]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:20])=O>C(Cl)(Cl)Cl>[Cl:20][CH2:14][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=2)[NH:13][N:12]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(-c2ccc(C(F)(F)F)cc2)[nH]n1
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1ccc(-c2cc(CCl)n[nH]2)cc1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 97.1 %

Procedure:
To a solution of [5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-yl]-methanol (40 mg, 0.17 mmol) in chloroform (4 ml) was added thionyl chloride (0.34 ml, 4.7 mmol) at 0° C. under an argon atmosphere. The solution was stirred at 40° C. for 2 h and at 60° C. for 10 min. The mixture was poured onto ice water/aqueous NaHCO3 1/1, extracted two times with dichloromethane and the combinded extracts were dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave 43 mg (0.165 mmol, 97%) of the title compound as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH3:14][S:15][C:16]1[C:20]([C:21]#[N:22])=[C:19](SC)[S:18][N:17]=1.[Cl-].[NH4+]>C1COCC1.O>[CH3:14][S:15][C:16]1[C:20]([C:21]#[N:22])=[C:19]([NH:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[S:18][N:17]=1
Reactant: CSc1nsc(SC)c1C#N
Reactant: Nc1ccncc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CSc1nsc(Nc2ccncc2)c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
4-aminopyridine (930 mg, 9.9 mmol) is dissolved in anhydrous THF (30 mL) and potassium tertbutoxide (1.11 g, 9.9 mmol) is added. The resulting solution is stirred for 1 hour at room temperature. 3,5-Bis-methylsulfanyl-isothiazole-4-carbonitrile (6) (1.0 g, 4.94 mmol) is added and the reaction is stirred for 3 days. Ammonium chloride (173 mg, 9.9 mmol) is added and the resulting suspension is stirred at room temperature for 30 min. A small amount of water is added and the solution is filtered. The mother liquor is concentrated in vacuo. Chromatography (5% MeOH/methylene chloride) provides 7 (1.0g, 81%). 1H NMR (d6 DMSO): δ 8.29 (2H, broad s), 7.04 (2H, broad s), 2.60 (3H, s).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCCCCC.C(OCC)(=O)C.O>[Cl:8][C:6]1[CH:5]=[C:4]([O:18][C:15]2[CH:16]=[CH:17][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=2)[N:3]=[CH:2][N:7]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2cc(Cl)ncn2)cc1
Yield: 77.5 %

Procedure:
2,4-Dichloropyrimidine (2.98 g, 20.0 mmol), 4-nitrophenol (2.78 g, 20.0 mmol) and potassium carbonate (4.15 g, 30.0 mmol) were stirred together in dimethylformamide (20 ml) at room temperature for 15 hours. The reaction solution was distributed between ethyl acetate and water, the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent—ethyl acetate:hexane=1:4), and the fraction containing the target substance was concentrated to obtain the title compound (3.89 g, 15.5 mmol, 77%) as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:10]=1[CH2:11][N:12]([C:15]1[N:20]=[N:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=1)[CH2:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.[C:41]([O:47][CH2:48][CH3:49])(=[O:46])[CH2:42]C([O-])=O.[K+].[Cl-].[Mg+2].[Cl-]>C(#N)C.C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:10]=1[CH2:11][N:12]([C:15]1[N:20]=[N:19][C:18]([C:21]([CH2:42][C:41]([O:47][CH2:48][CH3:49])=[O:46])=[O:23])=[CH:17][CH:16]=1)[CH2:13][CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: CCN(Cc1cc(Br)ccc1OCc1ccccc1)c1ccc(C(=O)O)nn1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)c1ccc(N(CC)Cc2cc(Br)ccc2OCc2ccccc2)nn1
Temperature: 5 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
A mixture of 6-[N-(2-benzyloxy-5-bromobenzyl)-N-ethylamino]pyridazine-3-carboxylic acid (12.5 g) and carbonyl di-imidazole (6.0 g) was heated at 5° C. for 1 hour. Separately, a mixture of potassium ethyl malonate (7.0 g), triethylamine (8.0 ml) and anhydrous magnesium chloride (5.0 g) in acetonitrile (200 ml) was stirred at ambient temperature for 2 hours. The two mixtures were combined and stirred for 18 hours at ambient temperature, then at reflux for 1 hour. The solvents were evaporated, and the residue partitioned between dichloromethane and 2N HCl. The organic solution was dried (MgSO4) and evaporated. The resulting residue was purified by flash chromatography, eluting with diethyl ether, to give ethyl [6-[N-(2-benzyloxy-5-bromobenzyl)-N-ethylamino]pyridazin-3-ylcarbonyl]acetate (12.5 g) as a yellow gum.
Reaction SMILES: II.Br[C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1.CO[CH:16]=[C:17]=[CH2:18].[Cl-].[NH4+]>C1COCC1.[Cu]Br.CCOC(C)=O.CCCCCC>[CH2:18]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)[C:17]#[CH:16]
Reactant: Brc1ccc2ccccc2c1
Reactant: C=C=COC
Agent: [Cu]Br
Agent: II
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C#CCc1ccc2ccccc2c1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 18 %

Procedure:
To a suspension of Mg powder (5.3 mmol) and one piece of iodine in THF (4 ml) is added 2-bromonaphthalene (4.6 mmol) in THF (2 ml) at room temperature and the mixture is stirred at 85° C. for 0.5 h. Copper(I) bromide (0.32 mmol) is added at room temperature then methoxyallene (4.6 mmol) in THF (3 ml) is added at 0° C. and the mixture is stirred at room temperature for 2 h. The mixture is poured into saturated ammonium chloride, extracted with AcOEt. The organic layer is washed with brine, dried over sodium sulfate and concentrated. Chromatography on silica gel (n-hexane:AcOEt=20:1) gives the product in 18% yield. Rf=0.5 (n-hexane:AcOEt=10:1)
Reaction SMILES: [CH2:1]([N:5]1[C:13]([N:14]2[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:20])[CH2:15]2)=[N:12][C:11]2[C:6]1=[N:7][C:8]([C:27]1[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=1)=[N:9][C:10]=2[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[CH:2]([CH3:4])[CH3:3].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[OH:59][C@H:60]([CH3:65])[CH2:61][C:62](O)=[O:63]>CN(C)C=O>[NH2:33][C:30]1[N:31]=[CH:32][C:27]([C:8]2[N:7]=[C:6]3[C:11]([N:12]=[C:13]([N:14]4[CH2:19][CH2:18][N:17]([C:62](=[O:63])[CH2:61][C@H:60]([OH:59])[CH3:65])[C@@H:16]([CH3:20])[CH2:15]4)[N:5]3[CH2:1][CH:2]([CH3:4])[CH3:3])=[C:10]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:9]=2)=[CH:28][N:29]=1
Reactant: C[C@@H](O)CC(=O)O
Reactant: CC(C)Cn1c(N2CCN[C@@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)Cn1c(N2CCN(C(=O)C[C@@H](C)O)[C@@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Temperature: 40 °C
Reaction time: 16 h
Yield: 28.1 %

Procedure:
5-{9-Isobutyl-8-[(3S)-3-methylpiperazin-1-yl]-6-morpholin-4-yl-9H-purin-2-yl}pyrimidin-2-amine (150 mg, 0.33 mmol), dicyclohexylcarbodiimide (103 mg, 0.5 mmol), 1-hydroxybenzotriazole (45 mg, 0.33 mmol), and (R)-3-hydroxybutyric acid (70 mg, 0.67 mmol) were dissolved in dimethylformamide (5 ml) and the resulting mixture was stirred at 40° C. for 16 hours. The solvent was evaporated under reduced pressure and then the residue was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (50 mg, 28%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][CH:16]=[CH:17][C:18]=2[C:19](OC)=[O:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][CH:16]=[CH:17][C:18]=2[CH2:19][OH:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccoc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2occc2CO)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 177.7 %

Procedure:
A solution of 4-(3-methoxycarbonylfuran-2-yl)piperidine-1-carboxylic acid t-butyl ester (550 mg, 1.6 mmol, 1.0 eq.) in THF (15 mL) was added to a solution of LiAlH4 (120 mg, 3.2 mmol, 2.0 eq.) in THF (25 mL) at −30° C. The resulting solution was stirred for 1 hour and allowed to warm to 0° C., then stirred for 1 hour at 0° C. Water (120 mg) was added dropwise to quench the reaction. The mixture was allowed to warn to room temperature, and 15% NaOH (360 mg) and water (120 mg) was added. The mixture was stirred for 1 hour at room temperature. The solids were filtered and the filter cake was washed with EtOAc (20 mL). The residue was applied onto a silica gel column and purified by chromatography with PE/EtOAc (10:1˜5:1). The product was combined with another lot of material, then crystallized (PE/EtOAc=3:1, 1.2 mL), to yield 4-(3-hydroxymethylfuran-2-yl)piperidine-1-carboxylic acid t-butyl ester (0.8 g) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+].[Cl:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][C:43]=1[Cl:44])[CH:39]=O>C(Cl)(Cl)Cl>[Cl:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][C:43]=1[Cl:44])[CH2:39][NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCCNCc1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 69.8 %

Procedure:
tert-Butyl N-(2-aminoethyl)carbamate (1.51 g) was dissolved in chloroform (20 ml) and 3,4-dichlorobenzaldehyde (1.65 g), acetic acid (0.54 ml) and sodium triacetoxyborohydride (2.6 g) were added at room temperature. The mixture was stirred overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the obtained reaction mixture and the mixture was stirred and extracted three times with chloroform. The combined organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to give tert-butyl [2-(3,4-dichlorobenzylamino)ethyl]carbamate (2.1 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH2:13][CH2:12]3)[CH:6]=[N:7][CH:8]=1.CC(O)=O.[Si:25]([O:32][CH2:33][CH:34]=O)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].[BH3-]C#N.[Na+].C([O-])(O)=O.[Na+]>CO.C1COCC1.CCOC(C)=O>[C:28]([Si:25]([CH3:27])([CH3:26])[O:32][CH2:33][CH2:34][NH:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH2:13][CH2:12]3)[CH:6]=[N:7][CH:8]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: CN1C(=O)CCc2cc(-c3cncc(N)c3)ccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1C(=O)CCc2cc(-c3cncc(NCCO[Si](C)(C)C(C)(C)C)c3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
To a solution of 6-(5-amino-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-quinolin-2-one hydrochloride (intermediate A-2, 0.062 g, 0.214 mmol) in MeOH (1.5 mL) was added AcOH (0.154 g, 2.57 mmol), followed by 2-(tert-butyldimethylsilyloxy)acetaldehyde (0.039 g, 0.225 mmol) and the reaction mixture was stirred at room temperature for 1 h. Then, NaBH3CN (0.027 g, 0.428 mmol) in THF (0.6 mL) was added to the reaction mixture and stirring at room temperature was continued for 2 h. The mixture was diluted with EtOAc, poured into aq. NaHCO3 (10 mL) and the aqueous layer was extracted with EtOAc (2×25 mL). Combined organics were washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 5% MeOH-DCM gradient to give the title compound (0.06 g, 68%) as a yellow solid. MS: 412.3 (M+H+).
Reaction SMILES: [C:1](Cl)(=[O:9])[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([CH:35]=[CH:36][CH:37]=1)[C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](=[O:34])(=[O:33])[NH2:32])=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C1C=CN=CC=1.O1CCCC1>[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([CH:35]=[CH:36][CH:37]=1)[C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:32][C:1]([O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:9])(=[O:34])=[O:33])=[O:23])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccccc2)c1
Reactant: O=C(Cl)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: O=C(NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccccc2)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
In a stream of nitrogen and at 0° C., 0.36 ml (2.87 mmol) of phenyl chlorocarbonate was added to an anhydrous tetrahydrofuran (10 ml) solution containing 1 g (2.60 mmol) of 3-benzyloxy-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 1 and 702 mg (5.75 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was recrystallized from acetonitrile to obtain 1.00 g (yield: 77.0%) of the title compound.
Reaction SMILES: [NH2:1][C:2](=[O:15])[CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.F[B-](F)(F)F.[CH3:21][O+](C)C.Cl>C(Cl)Cl>[CH2:7]([O:6][C:5]([NH:4][CH2:3][C:2](=[NH:1])[O:15][CH3:21])=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NC(=O)CNC(=O)OCc1ccccc1
Reactant: C[O+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC(=N)CNC(=O)OCc1ccccc1
Reaction time: 24 h

Procedure:
To a solution of benzyl (2-amino-2-oxoethyl)carbamate (8.5 g, 40.8 mmol) in CH2Cl2 (204 mL) was added trimethyloxonium tetrafluoroborate (6.0 g, 40.8 mmol) in one portion. The resulting mixture was stirred for 24 h, then acidified to pH˜3 with 1N ethereal HCl. The resulting mixture was concentrated under reduced pressure to yield methyl 2-(((benzyloxy)carbonyl)amino)acetimidate. A solution of methyl 2-(((benzyloxy)carbonyl)amino)acetimidate (9.3 g, 36 mmol), 4-(benzyloxy)benzothiohydrazide (8.0 g, 24 mmol) and diisopropylethylamine (4.2 mL, 24 mmol) in methanol (480 mL) was refluxed for 12 h. The resulting mixture was cooled to room temperature, at which point benzyl ((5-(4-(benzyloxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)carbamate precipitated and was collected (MS m/z=432 MH+).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.[CH3:24][S:25]([O:28][C@@H:29]([C@H:31]1[C@H:35]([CH2:36][O:37][Si](C(C)C)(C(C)C)C(C)C)[O:34][C:33]([CH3:49])([CH3:48])[O:32]1)[CH3:30])(=[O:27])=[O:26].[Cl-].[NH4+].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:24][S:25]([O:28][C@@H:29]([C@@H:31]1[C@H:35]([CH2:36][OH:37])[O:34][C:33]([CH3:48])([CH3:49])[O:32]1)[CH3:30])(=[O:26])=[O:27]
Reactant: CC(C)[Si](OC[C@@H]1OC(C)(C)O[C@H]1[C@@H](C)OS(C)(=O)=O)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H](OS(C)(=O)=O)[C@H]1OC(C)(C)O[C@H]1CO
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 146.8 %

Procedure:
5.8 mL of a 1 mol/L tetrabutyl ammonium fluoride/tetrahydrofuran solution was added to a solution of 1.98 g of (1R)-1-((4R,5S)-2,2-dimethyl-5-(((tris(propan-2-yl)silyl)oxy)methy)-1,3-dioxolane-4-yl)ethyl methanesulfonate in 24 mL of tetrahydrofuran at a temperature of 5° C. to 10° C., and the obtained mixture was then stirred at room temperature for 20 minutes. Thereafter, a saturated ammonium chloride aqueous solution, a saturated sodium hydrogen carbonate aqueous solution and ethyl acetate were added to the reaction mixture. The organic layer was fractionated, and it was washed with a saturated sodium chloride aqueous solution and was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, so as to obtain 1.8 g of (1R)-1-((4S,5S)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolane-4-yl)ethyl methanesulfonate in the form of a colorless oily product.
Reaction SMILES: [ClH:1].Cl.Cl.[NH2:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]2[N:13]=[C:14]([N:17]=[C:18]([NH2:20])[NH2:19])[S:15][CH:16]=2)[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[NH2:28][C:29]1[C:32](=[O:33])[C:31](=[O:34])[C:30]=1OCC>CO>[ClH:1].[NH2:28][C:29]1[C:32](=[O:33])[C:31](=[O:34])[C:30]=1[NH:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]2[N:13]=[C:14]([N:17]=[C:18]([NH2:20])[NH2:19])[S:15][CH:16]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: CCOc1c(N)c(=O)c1=O
Reactant: NCc1cccc(-c2csc(N=C(N)N)n2)n1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: NC(N)=Nc1nc(-c2cccc(CNc3c(N)c(=O)c3=O)n2)cs1
Yield: 73.5 %

Procedure:
A mixture of 4-(6-aminomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole trihydrochloride (1.5 g), triethylamine (1.8 ml) and 1-amino-2-ethoxy-1-cyclobutene-3,4-dione (0.65 g) in methanol (30 ml) was heated under reflux for 7 hours. The solvent was removed by concentration in vacuo. To the residue was added a mixture of water and ethyl acetate, and the mixture was adjusted to pH 1.0 with 6N-hydrochloric acid. The isolated precipitate was collected by filtration and dried. The precipitate was recrystallized from an aqueous N,N-dimethylformamide to give 4-[6-(1-amino-3,4-dioxo-1-cyclobuten-2-yl)aminomethylpyridin-2-yl]-2-(diaminomethyleneamino)thiazole hydrochloride (1.17 g).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][C:17]([S:20][C:21]2[CH:34]=[C:33]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:24]([O:25][CH2:26][CH2:27][CH2:28][C:29]([O:31]C)=[O:30])=[C:23]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:22]=2)([CH3:19])[CH3:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].CO.O.O.[OH-].[Li+].Cl>[Cl-].[Na+].O>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([S:16][C:17]([S:20][C:21]2[CH:22]=[C:23]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:24]([O:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[C:33]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH:34]=2)([CH3:18])[CH3:19])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: COC(=O)CCCOc1c(C(C)(C)C)cc(SC(C)(C)Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1C(C)(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CO
Product: CC(C)(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)Sc1cc(C(C)(C)C)c(OCCCC(=O)O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.6 %

Procedure:
Methyl 4-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]butyrate (0.95 g, obtained above) was dissolved in THI/MeOH/H2O (4:1;1, 15.4 mL) and lithium hydroxide hydrate (0.19 g) was added. The mixture was stirred at room temperature for four hours and then acidified with 0.3 N HCl. The mixture was poured into brine and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated to give 0.60 g of 4-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]butyric acid (Compound A) as a solid.