Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1.CS[C:21]1[S:22][CH2:23][CH2:24][N:25]=1.Cl>>[S:22]1[CH2:23][CH2:24][N:25]=[C:21]1[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CSC1=NCCS1
Reactant: CC(=O)Nc1nc(CCc2ccc(N)cc2)cs1
Agent: Cl
Product: CC(=O)Nc1nc(CCc2ccc(NC3=NCCS3)cc2)cs1
Temperature: 120 °C
Reaction time: 10 h
Yield: 20.3 %

Procedure:
N-(4-(2-(4-Aminophenyl)ethyl)-1,3-thiazol-2-yl)acetamide (1.8 g) prepared in a similar manner according to Step 6 of Production Example 1, 2-(methylsulfanyl)-4,5-dihydro-1,3-thiazole (918 mg), hydrochloric acid concentrate (0.57 ml) and 2-methoxyethanol (28 ml) were combined under nitrogen atmosphere, and stirred at 120° C. for 10 hours. After cooled to room temperature, the reaction mixture was concentrated in vacuo. The residue was dissolved in tetrahydrofuran/water, and made basic with aqueous potassium carbonate. The mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash column chromatography over silica gel with chloroform/methanol (30:1→20:1) as an eluent, and triturated with ethyl acetate to give N-(4-(2-(4-(4,5-dihydro-1,3-thiazol-2-ylamino)phenyl)ethyl)-1,3-thiazol-2-yl)acetamide (484.7 mg) as an off-white solid.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:8][C:7]1=[O:20].S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.O>[O:20]=[C:7]1[CH2:8][C:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])([C:10]([O:12][CH2:13][CH3:14])=[O:11])[NH:6]1
Reactant: CCOC(=O)C1(C(=O)OCC)CC(=O)N1Cc1ccc(OC)cc1OC
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C1(C(=O)OCC)CC(=O)N1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
1(b) 17.4 g of diethyl 1-(2,4-dimethoxybenzyl)-2-oxoazetidine-4,4-dicarboxylate (prepared as described above) were dissolved in a mixture of 350 ml of acetonitrile and 350 ml of water. 11.2 g of potassium persulfate and 37.4 g of dibasic potassium phosphate were then added to the resulting solution, and the mixture was stirred at 65° C. for 1 hour. At the end of this time, insoluble materials were filtered off and the filtrate was freed from the solvent by evaporation under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, with an aqueous solution of sodium bicarbonate and with a saturated aqueous solution of sodium chloride, in that order. The solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, eluted with a 1:2 by volume mixture of ethyl acetate and benzene, to give 5.72 g of diethyl 2-oxoazetidine-4,4-dicarboxylate.
Reaction SMILES: C(OP([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[CH3:16][O:17][CH:18]([O:21][CH3:22])[CH:19]=O.O>CCCCCCC>[CH3:16][O:17][CH:18]([O:21][CH3:22])/[CH:19]=[C:9](\[CH3:15])/[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: COC(C=O)OC
Solvent: CCCCCCC
Solvent: O
Product: CCOC(=O)/C(C)=C/C(OC)OC
Temperature: 60 °C
Reaction time: 15 h
Yield: 121.4 %

Procedure:
To a stirred solution of ethyl 2-(diethoxyphosphoryl)propanoate (450 μL, 2.1 mmol) in heptane (5 mL) was added 2,2-dimethoxy acetaldehyde (60% in water, 1.0 mL, 4.2 mmol). The solution was stirred for 15 h at 60° C. After the reaction was cooled, water was added and the mixture was extracted with CH2Cl2 and filtered through a phase separator and a silica plug. Concentration under reduced pressure afforded (E)-ethyl 4,4-dimethoxy-2-methylbut-2-enoate (480 mg, >100%). The procedure was adapted from Tetrahedron 2002, 2533.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]([CH3:9])[C:7]([C:10]2[C:18]3[C:13](=[C:14]([CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])[CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)=[C:6]([O:24]CC2C=CC(OC)=CC=2)[C:5](=[O:34])[CH:4]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>ClCCl.O>[OH:24][C:6]1[C:5](=[O:34])[CH:4]=[C:3]([CH2:2][OH:1])[N:8]([CH3:9])[C:7]=1[C:10]1[C:18]2[C:13](=[C:14]([CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1
Reactant: COc1ccc(COc2c(-c3c[nH]c4c(CC=C(C)C)cccc34)n(C)c(CO)cc2=O)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Product: CC(C)=CCc1cccc2c(-c3c(O)c(=O)cc(CO)n3C)c[nH]c12
Reaction time: 2 h

Procedure:
To a stirring solution of 213 (75 mg, 0.16 mmol) in dichloromethane (1.5 mL) and water (88 μL) was added DDQ (38 mg, 0.17 mmol) at 0° C. After the cold bath was removed, the mixture was stirred for 2 h. The DDQH2 was removed by filtration and washed with EtOAc. The solution was washed with water and brine. The organic layer was dried over Na2SO4 and the solvent removed under vacuum. After flash column chromatography, the desired product was obtained as a yellow solid (45 mg, 81%). Mp: 215° C. (dec). 1H NMR (CDCl3): δ 1.65 (3H, s), 1.74 (3H, s), 2.49 (3H, s), 3.71 (2H, d, J=6.6 Hz), 4.67 (2H, s), 5.29 (1H, m), 5.67 (1H, s), 7.3-7.4 (2H, m), 7.81 (1H, m), 8.31 (1H, m). 13C NMR (CDCl3): δ 28.4, 30.9, 33.3, 34.7, 61.7, 109.7, 119.2, 123.5, 123.7, 125.0, 126.4, 127.6, 129.2, 129.9, 130.6, 133.8, 134.5, 137.7, 149.6, 160.5, 176.2. IR (KBr): 3360, 3197, 2971, 2856, 1604, 1552, 1298, 984 cm−1. HRMS (EI): m/z Calcd. C20H22N2O3 for [M+] 338.1630, found 338.1632.
Reaction SMILES: S(Cl)([Cl:3])=O.C(N(CC)C1C=CC=CC=1)C.[CH3:16][S:17]([C:20]1[CH:21]=[C:22]([CH:26](O)[CH3:27])[CH:23]=[CH:24][CH:25]=1)(=[O:19])=[O:18].CCOC(C)=O>C1(C)C=CC=CC=1>[Cl:3][CH:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([S:17]([CH3:16])(=[O:19])=[O:18])[CH:21]=1)[CH3:27]
Reactant: CC(O)c1cccc(S(C)(=O)=O)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)c1ccccc1
Solvent: CCOC(C)=O
Product: CC(Cl)c1cccc(S(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30.1 %

Procedure:
Thionyl chloride (0.11 g, 0.91 mmol) was added to a solution of N,N-diethylaniline (0.19 g, 1.3 mmol) and 1-[3-(methylsulfonyl)phenyl]ethanol (0.26 g, 1.3 mmol) in toluene (4 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes followed by addition of EtOAc. The organic phase was washed subsequently with 2M HCl (aq), water, saturated sodium bicarbonate, and brine, and then dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on silica (ethyl acetate:hexane gradient elution 20:80 to 25:75) to give the title compound (60 mg) that was used in the next step without any further purification (approximate purity 75%).
Reaction SMILES: [CH:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]C1.[OH2:11].[OH-].[Li+].Cl>C1COCC1.CO.O>[CH:6]1([C:1]([S:7]([NH2:10])(=[O:8])=[O:9])=[O:11])[CH2:3][CH2:4][CH2:5]1
Reactant: NS(=O)(=O)C1CCCCC1
Reactant: O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: NS(=O)(=O)C(=O)C1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of intermediate 5 from Example 344 (700 mg, 2.7 mmol) in THF (90 mL), methanol (50 mL) and water (12 mL) mixture, lithium hydroxide monohydrate (1700 mg, 2.0 mmol) was added. The reaction mixture was stirred at rt. for overnight. Then it was acidified with 1N HCl solution to pH=3 to 5. Extracted with ethyl acetate (2×20 mL) and the organic layers were combined and dried (MgSO4). Evaporation of solvent gave thick colorless oil as product (intermediate 7) (0.58, 88% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[NH:12][C:8]=2[CH:7]=1)([CH3:5])[CH3:4].C(N(CC)CC)C.ClCCl.[S:31](Cl)([CH3:34])(=[O:33])=[O:32]>O>[CH3:34][S:31]([NH:1][CH2:2][C:3]([C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[NH:12][C:8]=2[CH:7]=1)([CH3:4])[CH3:5])(=[O:33])=[O:32]
Reactant: CC(C)(CN)c1ccc2nc(-c3ccncc3)[nH]c2c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(CNS(C)(=O)=O)c1ccc2nc(-c3ccncc3)[nH]c2c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To 2.0 g. of the 5-(2-aminomethylprop-2-yl)-2-(4-pyridinyl)-benzimidazole (prepared in Example 1) and 830 mg. triethylamine in 50 ml. dry dichloromethane are added dropwise, while cooling with ice water, 953 mg. mesyl chloride. The reaction mixture is stirred for 10 minutes and then 20 ml. water are added thereto. After filtering off with suction, washing with water and dichloromethane and recrystallising from water/ethanol (2:1 v/v), there are obtained 2.0 g. (85% of theory) of the title compound as a hydrate in the form of yellowish crystals which sinter above 130° C., again crystalline above 150° C. and then melt at 215°-216° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])[NH2:7].C([O-])([O-])=O.[Na+].[Na+].[C:20]1([CH:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O.C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])[NH:7][C:27](=[O:28])[CH:26]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1cccc(C[C@H](N)C(=O)O)c1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(C[C@H](NC(=O)C(c2ccccc2)c2ccccc2)C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-methyl-L-phenylalanine (1.8 g, 10.06 mmol) and Na2CO3 (3.2 g, 3.0.18 mmol) in water (150 mL) is added a solution of diphenylacetyl chloride (2.32 g, 10.06 mmol) in THF (150 mL), and the resulting solution is stirred vigorously at room temperature overnight. The THF is then evaporated and the aqueous layer is diluted with 6% aqueous Na2CO3 (100 mL), and washed with Et2O (3×150 mL). The aqueous layer is then acidified to pH 1 with conc. HCl, and the resulting slurry is extracted with EtOAc (3×100 mL). The organic phase is then washed with water (2×100 mL) and brine (1×100 mL), dried over MgSO4 and evaporated to yield 3-methyl-N-(2,2-diphenylacetyl)-L-phenylalanine, as a white solid.
Reaction SMILES: C[O-].[Na+].[CH3:4][N:5]([S:31]([CH3:34])(=[O:33])=[O:32])[C:6]1[N:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[C:13]([O:20]S(C2C=CC(C)=CC=2)(=O)=O)=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2.C(O)(=O)C>CO.CN(C=O)C>[OH:20][C:13]1[C:14]([C:16]([O:18][CH3:19])=[O:17])=[N:15][C:6]([N:5]([CH3:4])[S:31]([CH3:34])(=[O:33])=[O:32])=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2
Reactant: COC(=O)c1nc(N(C)S(C)(=O)=O)c2cccnc2c1OS(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)c1nc(N(C)S(C)(=O)=O)c2cccnc2c1O
Temperature: 50 °C

Procedure:
A solution of sodium methoxide (122 mg, 2.26 mmol) in dry methanol (5 mL) was added to methyl 5-[methyl(methylsulfonyl)amino]-8-{[(4-methylphenyl)sulfonyl]oxy}-1,6-naphthyridine-7-carboxylate (420 mg, 0.90 mmol) dissolved in a minimum amount of DMF and the resulting solution was heated to 50° C. for one hour. The reaction was cooled, glacial acetic acid (104 μL, 1.80 mmol) was added and the reaction was concentrated to dryness in vacuo. The resulting residue was triturated with ethanol and the solids were collected by vacuum filtration to give the desired product as a yellow solid.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])C(C)(C)C.Br[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>C(#N)C>[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[CH2:11][NH:1][CH2:2][C:7]([O:9][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:8]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)[C@H](N)C(=O)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)CNCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.2 %

Procedure:
To a solution of t-butylglycine (1.40 g, 10.67 mmol) in acetonitrile (20 mL) cooled to 0° C. was added ethyldisopropylamine (1.86 mL, 10.67 mmol) and t-butyl bromoacetate (1.57 mL, 10.67 mmol). The resulting solution was stirred for 24 h at room temperature. The mixture was concentrated to dryness in vacuo, water was added and the solution was extracted with dichloromethane (3×70 mL). The combined organic phases were washed with brine (70 mL), dried over Na2SO4 and concentrated to dryness in vacuo. The crude material was purified by silica gel chromatography (20-80% EtOAc in hexanes) to give the compound 14 (0.88 g, 33.6%). 1H NMR (400 MHz, CDCl3) δ 1.43 (s, 18H), 3.30 (s, 4H).
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10](B2OC(C)(C)C(C)(C)O2)=[C:9]([O:22][CH3:23])[CH:8]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[Br:24][C:25]1[CH:26]=[CH:27][C:28]([F:32])=[C:29](I)[CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([F:32])=[C:27]([C:10]2[CH:11]=[CH:12][C:7]([S:4]([CH:1]([CH3:2])[CH3:3])(=[O:5])=[O:6])=[CH:8][C:9]=2[O:22][CH3:23])[CH:26]=1
Reactant: COc1cc(S(=O)(=O)C(C)C)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: Fc1ccc(Br)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(S(=O)(=O)C(C)C)ccc1-c1cc(Br)ccc1F
Temperature: 100 °C
Reaction time: 12 h
Yield: 69 %

Procedure:
To a solution of 2-(4-(isopropylsulfonyl)-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation 36, 374 mg, 1.10 mmol) and 5-bromo-2-fluoroiodobenzene (300 mg, 1.00 mmol) in dioxane (6 mL) and water (2.5 mL) was added sodium carbonate (317 mg, 3.00 mmol). The mixture was degassed with nitrogen for 20 minutes, tetrakis(triphenylphosphine)palladium(0) (58.0 mg, 0.05 mmol) was added and the reaction mixture was stirred at 100° C. under a nitrogen atmosphere for 12 hours. The cooled reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were dried over MgSO4, filtered and evaporated in vacuo. The crude material was purified by silica gel column chromatography eluting with EtOAc/cyclohexane 25/75 to afford the title compound as a yellow oil in 69% yield, 0.27 g.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:19](O)=[O:20])[CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:11]=1)=[O:5])[CH3:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[NH2:45][C@@H:46]([CH3:49])[CH2:47][OH:48].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[OH:48][CH2:47][C@@H:46]([NH:45][C:19]([C:8]1[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[CH:9]=1)=[O:20])[CH3:49]
Reactant: C[C@H](N)CO
Reactant: CCOC(=O)c1cc(C(=O)O)cc(-c2ccc(C)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(C(=O)N[C@@H](C)CO)cc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(ethoxycarbonyl)-4′-methylbiphenyl-3-carboxylic acid (35 mg, 0.12 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (47 mg, 0.25 mmol), 1-hydroxybenzotriazole hydrate (19 mg, 0.12 mmol), and CH2Cl2 (3 mL) were added (S)-2-aminopropan-1-ol (10 mg, 0.14 mmol) and N,N-diisopropylethylamine (0.032 mL, 0.18 mmol). The mixture was stirred at room temperature overnight, and then concentrated. The residue was purified by preparative HPLC (100×21.2 mm C18 column, 30-70% MeCN/water[10 mM Et2NH]) to afford a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN([C:20]([O:24][N:25]1N=NC2C=CC=N[C:26]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.O>C(Cl)Cl>[CH3:20][O:24][N:25]([CH3:26])[C:14]([CH:10]1[O:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:16]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
To a solution of 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (10 g, 43 mmol) in DCM (60 mL) was added HATU (19 g, 50 mmol) in portions, The mixture was stirred at room temperature for 0.5 h. Then DIPEA (12.9 g, 100 mmol) and N, O-dimethylhydroxylamine hydrochloride (5.0 g, 51.5 mmol) were added in the mixture. The mixture was stirred at room temperature overnight. Water (40 mL) was added and the mixture was extracted by DCM (100 mL*3). The organic layer was washed with brine (5 mL) and dried over sodium sulfate. Concentration and purification by column chromatography on silica gel (eluted: petroleum ether/ethyl acetate=20/1-10/1) to give tert-butyl 2-(methoxy(methyl)carbamoyl)morpholine-4-carboxylate (10 g, 84%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=O.P(Cl)(Cl)(Cl)=O.C([N:20](CC)CC)C.[CH2:25](N)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(C(C)=O)C(C)C.C1(C)C=CC=CC=1>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH2:20])[N:6]=[C:5]2[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCN(CC)CC
Reactant: O=c1[nH]cnc2ccc(I)cc12
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CC(=O)CC(C)C
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1nc(Cc2ccccc2)c2cc(I)ccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
In a 20 ml-volume glass vessel equipped with a stirrer, a thermometer and a reflux condenser were placed 2.0 g (7.4 mmol) of 6-iodoquinazolin-4-one) 1.35 g (8.8 mmol) of phosphorus oxychloride, and 10 mL of toluene in a nitrogen atmosphere. While the mixture was stirred at room temperature, 0.66 g (6.6 mmol) of triethylamine was slowly added. The resulting mixture was heated to 75° C., and then reaction was carried out for 2 hours. Subsequently, the mixture was cooled to room temperature, and 3 mL of methyl isobutyl ketone and 3.15 g (29.4 mmol) of benzylamine were added. The resulting mixture was again heated to 75° C., and then reaction was carried out under stirring for one hour. After the reaction was complete, the reaction mixture was cooled to room temperature. Thus precipitated crystalline product was collected by filtration. Subsequently, the crystalline product was placed in 30 mL of aqueous sodium hydroxide (1 mol/L), and the aqueous mixture was stirred for 30 minutes at room temperature. The crystalline product was collected by filtration, washed with 30 mL of water, and dried under reduced pressure, to give 2.26 g (isolated yield: 84%, purity 99% in terms of area percentage determined by high performance liquid chromatography) of 6-iodo-4-benzyl-aminoquinazoline as a yellowish crystalline product.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)([OH:3])=[O:2].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[CH2:19]([O:18][C:16]([CH2:15][O:2][C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)=[O:3])=[O:17])[CH3:20]
Reactant: CCOC(=O)CBr
Reactant: O=C(O)c1cc2cccc(O)c2o1
Product: CCOC(=O)COC(=O)c1cc2cccc(OCC(=O)OCC)c2o1
Yield: 78 %

Procedure:
2-Carboxy-7-hydroxybenzofuran and ethyl bromoacetate were reacted to give 2-(ethoxycarbonylmethoxycarbonyl)-7-(ethoxycarbonylmethoxy)benzofuran (yield: 78%, MS (m/z): 350 (M+), 305, 277, 249 and 219), which was then reacted with chlorosulfonic acid as in Example 1, yielding 2-(ethoxycarbonylmethoxycarbonyl)-4-chlorosulfonyl-7-ethoxycarbonylmethoxybenzofuran (yield: 68%, MS (m/z): 448 (M+), 413, 382 and 350). The obtained chlorosulfonyl compound was reacted with glycine ethyl ester hydrochloride as in Example 1 to give an ester compound (yield: 98%, MS (m/z): 515 (M+), 470, 442, 414 and 350), which was then hydrolyzed to give 2-carboxy-4-(N-carboxy-methylsulfamoyl)-7-(carboxymethoxy)benzofuran (colorless needles, yield: 83%). The physical constants are shown in Table 4.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](SC)[N:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([O:26]O)=[O:25])[CH:19]=1.[NH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1.C1CCN2C(=NCCC2)CC1>ClCCl>[NH2:1][C:2]1[N:3]=[C:4]([NH:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:26][C:24](=[O:25])[C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[CH:19]=3)=[CH:33][CH:32]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: NCCc1ccc(O)cc1
Reactant: CSc1nc(N)nc(-c2ccco2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: N#Cc1c(NCCc2ccc(OC(=O)c3cccc(Cl)c3)cc2)nc(N)nc1-c1ccco1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 10.2 %

Procedure:
To a cooled (0° C.) stirred suspension of 1.6 g (6.9 mmol) 2-amino-4-(2-furyl)-6-(methylthio)-5-pyrimidinecarbonitrile in 100 ml dichloromethane was added 3.6 g (20.7 mmol) m-chloroperbenzoic acid (70% purity) and stirring continued for 15 minutes at 0° C. The reaction mixture was then concentrated in vacuo and residue resuspended in 100 ml DME. To this stirred suspension were added 0.47 g (3.4 mmol) tyramine and 1.4 ml (10.3 mmol) DBU and the mixture heated at 100° C. for 1 hour. The reaction mixture was then concentrated in vacuo. Chromatography (ethyl acetate) followed by trituration in ether afforded 160 mg (5%) 3-chloro-benzoic acid 4-[2-(2-amino-5-cyano-6-furan-2-yl-pyrimidin-4-ylamino)-ethyl]-phenyl ester as a white crystalline solid. ES-MS m/e (%): 484 (M{37Cl}+Na+, 10), 482 (M{35Cl}+Na+, 25), 462 (M{37Cl}+H+, 35), 460 (M{35Cl}+H+, 100).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[O:25][CH2:26][CH2:27][S:28][CH3:29])(=[O:5])[CH2:2][CH2:3][CH3:4].[OH2:30].Cl[O-].[Na+].[CH2:34](Cl)Cl>>[CH:26]([O:25][CH:10]([CH3:9])[CH3:11])([CH3:27])[CH3:34].[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[C:18]([CH3:24])=[CH:19][CH:20]=[CH:21][C:22]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:25][CH2:26][CH2:27][S:28]([CH3:29])=[O:30])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O
Reactant: ClCCl
Reactant: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1c(C)cccc1C
Agent: [Na+]
Agent: [O-]Cl
Product: CC(C)OC(C)C
Product: CCCC(=O)c1cnc2c(OCCS(C)=O)cccc2c1Nc1c(C)cccc1C
Reaction time: 3 h
Yield: 58 %

Procedure:
3-butyryl-4-(2,6-dimethylphenylamino)-8-(2-methylthioethoxy)quinoline (0.33 g, 0.81 mmol) was dissolved in methylene chloride (4 ml). Water (2 ml) and sodium hypochlorite (5% in water) (1.7 ml) were added and the mixture was stirred for 3 h. The organic layer was dried over sodium sulfate and evaporated. Trituration with isopropyl ether gave 0.20 g (58%) of the title compound.