Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N([O-])=O.[K+].C1OCCOCCOCCOCCOCCOC1.[CH2:23]([O:25][C:26]([C@:28]1([N:48]=[N+:49]=[N-:50])[C@H:33]([O:34]S(C(F)(F)F)(=O)=O)[CH2:32][C@@H:31]2[C@H:29]1[C@@:30]2([F:47])[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:27])[CH3:24].O>CN(C)C=O>[CH2:23]([O:25][C:26]([C@:28]1([N:48]=[N+:49]=[N-:50])[C@@H:33]([OH:34])[CH2:32][C@@H:31]2[C@H:29]1[C@@:30]2([F:47])[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:27])[CH3:24]
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](OS(=O)(=O)C(F)(F)F)[C@@](N=[N+]=[N-])(C(=O)OCC)[C@@H]21
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=N[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@@]1(F)[C@@H]2C[C@H](O)[C@@](N=[N+]=[N-])(C(=O)OCC)[C@@H]21
Temperature: 25 °C
Reaction time: 36 h
Yield: 79.6 %

Procedure:
688 mg of potassium nitrite and 428 mg of 18-crown 6-ether was added to 701 mg of (1R,2R,3R,5R,6R)-2-azido-6-fluoro-3-trifluoromethanesulfonyloxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester dissolved in 6.9 mL of N,N-dimethylformamide, and the mixture was stirred for 1.5 days at room temperature and further stirred for 3.5 days at 45° C., under a nitrogen atmosphere. Water was added thereto, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: Wako gel C200, eluent: hexane-ethyl acetate=5:1), thereby yielding 388 mg of (1R,2R,3S,5R,6R)-2-azido-6-fluoro-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2,6-diethyl ester.
Reaction SMILES: Cl.C(OC[N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[C:11]1[S:12][CH:13]=[CH:14][N:15]=1)C.[OH-].[Na+].C([O-])(O)=O.[Na+]>C(O)C.O>[NH:6]1[CH:10]=[CH:9][N:8]=[C:7]1[C:11]1[S:12][CH:13]=[CH:14][N:15]=1
Reactant: CCOCn1ccnc1-c1nccs1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: c1c[nH]c(-c2nccs2)n1
Temperature: 0 °C

Procedure:
Concentrated HCl (10 ml) is added to a solution of 2-(1-ethoxymethyl-1H-imidazol-2-yl)-thiazole (940 mg, 4.49 mmol) in 24 mL of 1:1 EtOH—H2O at room temperature. The solution is stirred at reflux for 3 hours. The reaction mixture is then cooled to 0° C. and made basic by the addition of about 12 mL of 10 N aqueous NaOH. The mixture is back titrated to approximately pH 4 using concentrated HCl. Solid NaHCO3 is added to the point of saturation and approximately pH 8. The mixture is then extracted twice using a mixture of THF and EtOAc. The combined extracts are dried over Na2SO4 and concentrated to an oily solid, which is triturated with a small amount of CH2Cl2. The solid is collected by filtration. The filtrate is concentrated, and the oily solid triturated once more with CH2Cl2. The second resultant solid is collected by filtration and combined with the solid first obtained. The product, 2-(1H-imidazol-2-yl)-thiazole, is obtained as a slightly off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.04 (br, 1H), 7.87 (d, J=3.2 Hz, 1H), 7.70 (d, J=3.2 Hz, 1H), 7.14 (br, 2H) ppm.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1)#[N:2].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[NH2:30][C:31]1[CH:32]=[C:33]([F:51])[C:34]([F:50])=[C:35]([C@:37]2([CH2:48][F:49])[CH2:42][C@@H:41]([C:43]([F:46])([F:45])[F:44])[O:40][C:39]([NH2:47])=[N:38]2)[CH:36]=1>CO>[NH2:47][C:39]1[O:40][C@H:41]([C:43]([F:44])([F:46])[F:45])[CH2:42][C@:37]([C:35]2[CH:36]=[C:31]([NH:30][C:9](=[O:11])[C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=3)[CH:32]=[C:33]([F:51])[C:34]=2[F:50])([CH2:48][F:49])[N:38]=1
Reactant: NC1=N[C@](CF)(c2cc(N)cc(F)c2F)C[C@@H](C(F)(F)F)O1
Reactant: N#Cc1ccc(C(=O)O)nc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: N#Cc1ccc(C(=O)Nc2cc(F)c(F)c([C@]3(CF)C[C@@H](C(F)(F)F)OC(N)=N3)c2)nc1
Reaction time: 0.5 h
Yield: 36.9 %

Procedure:
To a cooled (ice bath) solution of 5-cyanopicolinic acid (0.043 g, 0.293 mmol) in MeOH (10.0 mL) was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (0.094 g, 0.318 mmol). After stirred for 30 min, (4S,6S)-4-(5-amino-2,3-difluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (0.080 g, 0.244 mmol) in MeOH (10.0 mL) was added dropwise. The reaction was then stirred at room temperature for 17 h. LCMS showed about 30% remaining starting material. The reaction was quenched with saturated sodium bicarbonate solution. MeOH was removed by rotary evaporation. The aqueous residue was extracted with EtOAc (2×). The organic extracts were combined, concentrated and purified by Shimadzu HPLC to afford N-(3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4,5-difluorophenyl)-5-cyanopicolinamide (0.041 g, 0.090 mmol, 36.7% yield) as white solid. MS m/z=458.1 [M+H]+. Calculated for C19H13F6N5O2: 457.3
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:13]([C:14]([OH:16])=O)=[C:12]([CH3:17])[O:11][N:10]=1.[Cl:18][C:19]1[CH:25]=[C:24]([Cl:26])[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:22][C:20]=1[NH2:21].C(O)(C(F)(F)F)=O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[NH2:21][C:20]1[C:19]([Cl:18])=[CH:25][C:24]([Cl:26])=[C:23]([N:27]2[CH2:28][CH2:29][N:30]([C:14]([C:13]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[N:10][O:11][C:12]=3[CH3:17])=[O:16])[CH2:31][CH2:32]2)[CH:22]=1
Reactant: Nc1cc(N2CCNCC2)c(Cl)cc1Cl
Reactant: COc1ccccc1-c1noc(C)c1C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: COc1ccccc1-c1noc(C)c1C(=O)N1CCN(c2cc(N)c(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
The reaction mixture of 3-(2-methoxyphenyl)-5-methylisoxazole-4-carboxylic acid (0.131 g, 0.561 mmol), 2,4-dichloro-5-(piperazin-1-yl)aniline, 2 TFA (0.253 g, 0.534 mmol), EDC (0.123 g, 0.641 mmol) and DMAP (0.130 g, 1.07 mmol) in DCM (4 mL) was stirred at RT overnight. The crude product was purified by flash chromatography (MeOH/DCM, gradient 2%-4%, Rf 0.31 with 3% MeOH) to give 0.221 g of the title compound (90% yield). 1H-NMR (CD3OD, 400 MHz): δ 7.57-7.50 (2H, m), 7.19 (1H, s), 7.18-7.07 (2H, m), 6.43 (1H, s), 3.81 (3H, s), 3.74 (2H, s), 3.24 (2H, s), 2.88 (2H, s), 2.53 (3H, s), 2.35 (2H, s).
Reaction SMILES: C([O:3][C:4](=[O:37])[CH:5]([O:35][CH3:36])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH2:18][CH2:19][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:9][CH:8]=1)C.[OH-].[Na+]>C1COCC1.CCO>[CH3:36][O:35][CH:5]([CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH2:18][CH2:19][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:9][CH:8]=1)[C:4]([OH:37])=[O:3]
Reactant: CCOC(=O)C(Cc1ccc(OCCCc2nc(-c3ccc(OC)cc3)oc2C)c2ccccc12)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(-c2nc(CCCOc3ccc(CC(OC)C(=O)O)c4ccccc34)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
0.143 g of the above prepared [rac]-2-methoxy-3-(4-{3-[2-(4-methoxy-phenyl)-5-methyl-oxazol-4-yl]-propoxy}-naphthalen-1-yl)-propionic acid ethyl ester (0.28 mmol) was dissolved in 1.5 ml of THF/EtOH=1/1 and treated with 0.47 ml of 3N NaOH (5 eq.). The reaction mixture was stirred at ambient temperature for 2 h and was then poured onto crashed ice/HCl dil. and extracted twice with AcOEt. The organic layer was washed with water, dried over sodium sulfate, and evaporated to dryness. Crystallization from AcOEt/hexane afforded finally 0.120 g of the title product as white crystals of mp. 67-70°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([OH:18])[C:10]=1[CH2:19][CH2:20][CH3:21])[CH3:2].[S:23]([O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35]OS(=O)(=O)C)(=[O:26])(=[O:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([O:18][CH2:35][CH2:34][O:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][S:23]([CH3:24])(=[O:25])=[O:26])[C:10]=1[CH2:19][CH2:20][CH3:21])[CH3:2]
Reactant: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1O
Reactant: CS(=O)(=O)OCCOCCOCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1OCCOCCOCCOS(C)(=O)=O
Yield: 44.6 %

Procedure:
A mixture of 4.0 g of 4-(4-acetyl-3-hydroxy-2-propylphenoxy)butanoic acid ethyl ester, 19.9 g of triethylene glycol dimesylate and 3.6 g of anhydrous potassium carbonate in 80 ml of anhydrous acetone and 40 ml of anhydrous dimethylformamide was stirred at reflux for 23 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to an oil which was purified by high pressure liquid chromatography using 30% ethyl acetate-toluene to give 3.0 g (45% yield) of 4-[4-acetyl-3-[2-[2-[2-[(methylsulfonyl)oxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoic acid ethyl ester as an oil.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[F:2].[CH2:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C>[F:2][CH2:1][CH:3]([OH:5])[CH2:4][N:13]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:4][CH:3]([OH:5])[CH2:1][F:2]
Reactant: NCc1ccccc1
Reactant: FCC1CO1
Solvent: CCO
Product: OC(CF)CN(Cc1ccccc1)CC(O)CF
Yield: 100.1 %

Procedure:
A solution of 27.28 g (0.359 mole) of epifluorohydrin and 19.20 g (0.1795 mole) of benzylamine dissolved in 200 ml of ethanol was heated under reflux for 4 hours. The reaction mixture was then concentrated by evaporation under reduced pressure, to give 46.6 g of N,N-bis(3-fluoro-2-hydroxypropyl)benzylamine as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:19])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[N+:4]([O-:19])[C:3]=1[C:9]#[N:10]
Reactant: Cc1ccc(C)c(C#N)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C)[n+]([O-])c1C#N
Temperature: 25 °C
Reaction time: 7 h
Yield: 57.4 %

Procedure:
To a solution of 3,6-dimethyl-2-pyridinecarbonitrile (8.20 g, may be prepared as described in Russell et al., J. Med. Chem., 48(5), 1367, (2005)) in chloroform (60 ml) was added dropwise a solution of m-chloroperbenzoic acid (20 g) in chloroform (210 ml) and the solution stirred at ambient temperature for 7 hours. Sodium sulphite (2.4 g) was added and the mixture stirred for 1.5 hours, filtered and the solid washed with dichloromethane. The filtrate was washed with saturated sodium bicarbonate (120 ml) and water (120 ml), dried (MgSO4) and concentrated in vacuo. The residue was recrystallised from ether to afford the title compound (5.28 g, 58%) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([NH:16][NH2:17])=O)=[N:4][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][N:7]=1.Cl.[C:19](N)(=[NH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])C.[Na+]>CN(C=O)C>[C:20]1([C:19]2[NH:26][C:14]([C:3]3[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([C:8]4[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=4)[N:4]=3)=[N:16][N:17]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N=C(N)c1ccccc1
Reactant: NNC(=O)c1nc(-c2cccnc2)cnc1N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncc(-c2cccnc2)nc1-c1nnc(-c2ccccc2)[nH]1
Temperature: 200 °C
Yield: 22.9 %

Procedure:
A mixture of 3-amino-6-(3-pyridyl)pyrazine-2-carbohydrazide (40 mg, 0.173 mmol), benzamidine hydrochloride (27.2 mg, 0.173 mmol) and sodium ethanolate (11.82 mg, 0.173 mmol) were added to a 5 mL microwave vial in DMF (1 mL). The reaction mixture was heated in the microwave at 200° C. for 20 min. The mixture was concentrated in vacuo and the residue purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100 A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were freeze-dried to give the title compound as a solid (12.5 mg, 20% Yield). 1H NMR (500 MHz, DMSO) d 7.5 (m, 3H), 7.66 (m, 1H), 7.94 (br s, 2H), 8.16 (m, 2H), 8.66 (s, 1H), 8.79 (br s, 1H), 8.96 (s, 1H), 9.52 (s, 1H) and 14.94 (s, 1H) ppm; MS (ES+) 316
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[CH:9][C:10]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Br:20]Br>C(Cl)Cl.[Fe]>[Br:20][C:8]1[C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:19][C:11]2[C:12]([CH3:18])([CH3:17])[CH2:13][CH2:14][CH2:15][CH2:16][C:10]=2[CH:9]=1
Reactant: CCCCCCc1ccc2c(c1)C(C)(C)CCCC2
Reactant: BrBr
Agent: [Fe]
Solvent: ClCCl
Product: CCCCCCc1cc2c(cc1Br)CCCCC2(C)C
Reaction time: 0.5 h

Procedure:
This 3.08 g of 2-hexyl-9,9-dimethyl-6,7,8,9-tetrahydro-5H-benzocycloheptene were dissolved in 35 ml of CH2Cl2, treated at 0° with a spatula tip of Fe powder and then reacted with a solution of 0.67 ml of Br2 (1.1 eq.) in 5 ml of CH2Cl2. After 30 min., the mixture was poured on to ice, extracted with diethyl ether, washed with bisulphite solution and NaCl soln., dried over Na2SO4 and evaporated to dryness. Flash chromatography on SiO2 (hexane) gave 3.21 g of 2-bromo-3-hexyl-5,5-dimethyl-6,7,8,9-tetrahydro-5H-benzocycloheptene as a colorless oil (GC purity: 82%, moreover 2% ed., 2.6% regioisomer, 8.3% dibromo compound and further prod.).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N+:3]=1[O-]>C(OC(=O)C)(=O)C>[C:6]([O:8][CH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1)(=[O:7])[CH3:5]
Reactant: COC(=O)c1ccc(C)[n+]([O-])c1
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1ccc(COC(C)=O)nc1
Yield: 121.2 %

Procedure:
To a solution of methyl 6-methylnicotinate (6.05 g) in methylene chloride (100 mL) was added m-chloroperbenzoic acid (77%, 13.5 g). The reaction mixture was stirred at room temperature for 2 h and then diluted with chloroform (100 mL). The mixture was washed successively with aqueous sodium sulfite, saturated sodium bicarbonate, and brine. The organic later was then dried (sodium sulfate), filtered, and concentrated under reduced pressure to provide 6.21 g of methyl 6-methylnicotinate 1-oxide. A solution of methyl 6-methylnicotinate 1-oxide (4.35 g) in acetic anhydride (50 mL) was heated at 120° C. for 2 h and then concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 1:2 to 3:5 ethyl acetate/hexanes) provided 3.3 g of the title compound: 3H NMR (300 MHz, CDCl3) δ 9.18, 8.31, 7.44, 5.29, 3.96, 2.19.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:13])(=[O:3])[CH3:2].[CH2:14]([O:16][C:17](=O)[CH3:18])[CH3:15]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:14]([O:16][CH2:17][CH3:18])[C:15]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:5]1=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C(=O)Cc2ccccc21
Reactant: CCOC(C)=O
Product: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1

Procedure:
Yield: about 67% of theory, the product contains about 25 to 34% of 1-acetyl-2-indolinone. Melting point: 123-129° C. (with an amount of 34% of 1-acetyl-2-indolinone). An insoluble fraction is isolated from the above mixture by combining with ethylacetate, extracting with dilute aqueous sodium carbonate solution and with water and by filtering, this fraction being the pure product. Melting point: 187-189° C.; C19H17NO3 ; Calc.: C, 74.25; H, 5.57; N, 4.56; Found: 73.95; 5.57; 4.53.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](=O)[CH2:8][C:9]([O:11]C)=[O:10].[N:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])=[N+:15]=[N-:16].CO.C[O-].[Na+].[OH-].[Na+]>CO>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:14]1[C:7]([CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[C:8]([C:9]([OH:11])=[O:10])[N:16]=[N:15]1
Reactant: COCCCCC(=O)CC(=O)OC
Reactant: [N-]=[N+]=Nc1ccccc1F
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCCCCc1c(C(=O)O)nnn1-c1ccccc1F
Temperature: 60 °C
Reaction time: 3 h
Yield: 78.4 %

Procedure:
A solution of methyl 7-methoxy-3-oxoheptanoate (2.0 g) in methanol (70 ml) was cooled to 0° C.-5° C., 1-azido-2-fluorobenzene (960 mg) and 28% sodium methoxide methanol solution (2 g) were added and the mixture was stirred at 60° C. for 3 hr. Then, 1N sodium hydroxide (14 ml) was added, and the mixture was stirred at 60° C. for 1 hr. The solvent was evaporated under reduced pressure and water (20 ml) was added to the residue. 1N Hydrochloric acid was added for neutralization and the mixture was extracted with ethyl acetate (50 ml×2). The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (1.61 g) as an oil.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[Cl:13][C:14]1[CH:22]=[C:21]([O:23][C:24]2[CH:25]=[N:26][C:27]([CH:31]3[CH2:33][CH2:32]3)=[C:28]([Cl:30])[CH:29]=2)[C:20]([Cl:34])=[CH:19][C:15]=1[C:16](O)=[O:17].[CH3:35][S:36]([NH2:39])(=[O:38])=[O:37]>CN(C)C1C=CN=CC=1.ClCCl>[Cl:13][C:14]1[CH:22]=[C:21]([O:23][C:24]2[CH:25]=[N:26][C:27]([CH:31]3[CH2:33][CH2:32]3)=[C:28]([Cl:30])[CH:29]=2)[C:20]([Cl:34])=[CH:19][C:15]=1[C:16]([NH:39][S:36]([CH3:35])(=[O:38])=[O:37])=[O:17]
Reactant: O=C(O)c1cc(Cl)c(Oc2cnc(C3CC3)c(Cl)c2)cc1Cl
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(Oc2cnc(C3CC3)c(Cl)c2)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 12.4 %

Procedure:
4-Dimethylaminopyridine (51 mg, 0.42 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (80 mg, 0.42 mmol) were added to a suspension of 2,5-dichloro-4-(5-chloro-6-cyclopropylpyridin-3-yloxy)benzoic acid (Preparation 220, 100 mg, 0.28 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at room temperature for 20 minutes. Methylsulfonamide (40 mg, 0.42 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours before concentrating in vacuo. The crude compound was purified by reverse phase column chromatography eluting with acetonitrile:water (from 5:95 to 95:5) followed by preparative HPLC to afford the title compound (15.1 mg, 12%).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([S:6][CH2:7][CH2:8][S:9][CH2:10][CH2:11][S:12][C:13](=[O:17])[CH2:14][CH2:15]Cl)=[O:5].C(N(CC)CC)C.CCCCCC.O>CC(C)=O>[C:4]([S:6][CH2:7][CH2:8][S:9][CH2:10][CH2:11][S:12][C:13](=[O:17])[CH:14]=[CH2:15])(=[O:5])[CH:3]=[CH2:2]
Reactant: O=C(CCCl)SCCSCCSC(=O)CCCl
Solvent: CC(C)=O
Solvent: O
Solvent: CCCCCC
Product: C=CC(=O)SCCSCCSC(=O)C=C
Reaction time: 2 h

Procedure:
476.54 g of the thus-obtained bis[2-(3-chloropropionylthio) ethyl]sulfide (1.35 mol for a target product with the converted purity) was dissolved in 2000 g of acetone to obtain a solution. Thereinto were dropped 323.80 g of triethyl amine (3.20 mol) at 5° C. over an hour. When the triethyl amine was all dropped, the reaction mixture was further reacted while being stirred for another 2 hours, and then no raw material existing in the HPLC was confirmed and returned to room temperature (25° C.). Thereto were added 7000 g of hexane and 7000 g of pure water to stir at 25° C. and extract. 10% hydrochloric acid was added to the hexane solution in the organic layer at room temperature, washing and separation were repeated until no chlorine ion was detected, and then solution separation was performed to take out the organic layer. 450 mg of 4-methoxyphenol, i.e., a polymerization inhibitor was added thereto, hexane was removed at 35° C. under reduced pressure and concentrated to obtain 348.04 g of a colorless and transparent liquid, i.e., bis(2-acryloylthio ethyl) sulfide (MESDA). The yield was 84% [yield from bis(2-mercaptoethy) sulfide, purity conversion value] and the purity was 95% (HPLC analysis by the internal standard method).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH:18]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=3)(=[O:24])=[O:23])[C:19]#[N:20])=[CH:13][CH:12]=2)[S:6]1(=[O:36])=[O:35])([CH3:4])([CH3:3])[CH3:2].[OH2:37]>>[C:1]([N:5]1[C:9](=[O:10])[CH2:8][CH:7]([C:11]2[CH:12]=[CH:13][C:14]([CH2:17][CH:18]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=3)(=[O:24])=[O:23])[C:19]([NH2:20])=[O:37])=[CH:15][CH:16]=2)[S:6]1(=[O:35])=[O:36])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N1C(=O)CC(c2ccc(CC(C#N)NS(=O)(=O)c3cccc(C(F)(F)F)c3)cc2)S1(=O)=O
Reactant: O
Product: CC(C)(C)N1C(=O)CC(c2ccc(CC(NS(=O)(=O)c3cccc(C(F)(F)F)c3)C(N)=O)cc2)S1(=O)=O

Procedure:
This compound was prepared according to the procedure of Example 1.37, Step 4, using 4.22-B of Step 2 as the starting material. LCMS found for C25H33F3N3O7S2 (M+(H2O)+H)+: m/z=608.
Reaction SMILES: [OH:1][C:2]1[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[C:11]([O:13][CH3:14])=[O:12])=[O:5].[H][H]>CO.[Pd]>[NH2:19][C:18]1[C:2]([OH:1])=[C:3]([CH:15]=[CH:16][CH:17]=1)[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[C:11]([O:13][CH3:14])=[O:12])=[O:5]
Reactant: COC(=O)[C@H]1CCCN1C(=O)c1cccc([N+](=O)[O-])c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H]1CCCN1C(=O)c1cccc(N)c1O
Yield: 73.6 %

Procedure:
A solution of 4.03 g (13.63 mmol; 1.0 eq) of methyl (R)-1-(2-hydroxy-3-nitrobenzoyl)pyrrolidine-2-carboxylate in 50 ml of methanol was stirred at hydrogen atmospheric pressure in the presence of 390 mg (10% by weight) of palladium on carbon at 10% for 3 days. The reaction medium was filtered through celite, rinsed with methanol and evaporated. The residue was chromatographed on silica gel (200 g prepacked column) eluted with heptane/ethyl acetate (gradient). 2.65 g of methyl (R)-1-(3-amino-2-hydroxybenzoyl)pyrrolidine-2-carboxylate were obtained in the form of a yellow oil. Yield=74%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([CH2:15][C@@H:16]([OH:20])[C:17]([OH:19])=O)(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.Cl.Cl.[CH3:24][N:25]1[C:29]([CH2:30][N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:28][S:27]/[C:26]/1=[N:37]\[CH3:38].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([CH2:15][C@@H:16]([OH:20])[C:17]([N:34]1[CH2:35][CH2:36][N:31]([CH2:30][C:29]3[N:25]([CH3:24])/[C:26](=[N:37]/[CH3:38])/[S:27][CH:28]=3)[CH2:32][CH2:33]1)=[O:19])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(O)[C@H](O)CS(=O)(=O)c1ccc2cc(Cl)ccc2c1
Reactant: C/N=c1\scc(CN2CCNCC2)n1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C/N=c1\scc(CN2CCN(C(=O)[C@H](O)CS(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)n1C
Yield: 22.6 %

Procedure:
To a suspension of (2S)-3-((6-chloronaphthalen-2-yl)sulfonyl)-2-hydroxypropanoic acid (0.32 g), N-((2Z)-3-methyl-4-(-1-piperazinylmethyl)-1,3-thiazol-2(3H)-ylidene)methanamine trihydrochloride (0.51 g), HOBt (0.20 g) and triethylamine (0.63 mL) in DMF (5 mL), WSC (0.21 g) was added, and the mixture was mixed at room temperature for 22 hours. The reaction solution was concentrated under reduced pressure. The residue was basified with an aqueous potassium carbonate solution, and then the mixture was extracted with ethyl acetate/THF. The extract was dried over anhydrous magnesium sulfate, the solvent was then distilled off, and the residue was purified with a basic silica gel column to give the title compound (0.12 g, 23%) as a colorless powder.