Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([C:19](O)=[O:20])[O:16][C:15]2=[O:22])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.Cl.[CH3:24][O:25][NH2:26].Cl.CN(C)CCCN=C=NCC>O1CCCC1.O.O>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([C:19]([NH:26][O:25][CH3:24])=[O:20])[O:16][C:15]2=[O:22])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1
Reactant: CON
Reactant: O=C(O)[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CONC(=O)[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of (5R)-(−)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxylic acid (EXAMPLE 1, Step 1, 150 mg, 0.483 mmol) and O-methylhydroxylamine hydrochloride (61 mg, 0.724 mmol) in tetrahydrofuran/water (1/1, 4.8 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (278 mg, 1.45 mmol), and the resulting mixture was stirred at ambient temperature for 30 minutes and was then diluted with water (10 mL) and extracted with ethyl acetate (2×20 mL). The combined organic phase was washed with water (10 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the crude product was chromatographed on a Flash 40S silica gel (40 g, 32-63 μm) cartridge, eluting with methanol/methylene chloride (2.5/97.5). Pooling and concentration of those fractions with an Rf=0.53 by TLC (methanol/chloroform, 10/90) gives the title compound, mp 206-208° C. (decomp.); MS (ESI+) for C15H18FN3O5 m/z 340 (M+H)+; [α]25D=−56° (c 0.92, DMSO).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].Cl[C:11]([O:13][CH2:14][CH2:15][CH3:16])=[O:12]>C(#N)C>[CH2:14]([O:13][C:11](=[O:12])[NH:4][C:3]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1])[CH2:15][CH3:16]
Reactant: CCCOC(=O)Cl
Reactant: Cc1cccc(C)c1N
Solvent: CC#N
Product: CCCOC(=O)Nc1c(C)cccc1C
Temperature: 150 °C
Yield: 95 %

Procedure:
2,6-Dimethyl-aniline (3.0 mL) and propyl chloroformate (4.1 mL) were dissolved in acetonitrile (15 mL) and heated to 150° C. for 10 minutes in a sealed microwave process vial. The reaction mixture was concentrated in vacuo to furnish 4.79 g (95% yield) of the title compound as a brown solid. The crude product was used without further purification.
Reaction SMILES: O[C:2]1([C:22]([F:25])([F:24])[F:23])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[C:4]([C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)=[N:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:16][S:13]([C:10]1[CH:9]=[CH:8][C:7]([N:5]2[CH:6]=[C:2]([C:22]([F:24])([F:25])[F:23])[N:3]=[C:4]2[C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)=[CH:12][CH:11]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccsc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2ccsc2)cc1
Yield: 63.6 %

Procedure:
A mixture of the 4,5-dihydro-imidazole of step 2 (1.5 g, 3.8 mmol) and p-toluenesulfonic acid monohydrate (0.30 g, 1.5 mmol) in toluene (250 ml) was heated to reflux for 40 hours. An additional p-toluenesulfonic acid monohydrate (0.15.g, 0.78 mmol) was added. The reaction mixture was heated to reflux for 18 hours. The reaction mixture was cooled and the solvent removed under reduced pressure. The crude mixture (3.5 g) was purified by chromatography on silica gel using ethyl acetate/toluene (55/45) to give pure 3-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]thiophene (0.90 g, 64%) as a white solid: mp 194–197° C. Anal. Calc'd. for C15H11N2S2O2F3: C, 48.38, H, 2.98, N, 7.52, S, 17.22. Found: C, 48.74, H, 2.98, N, 7.56, S. 17.45
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH:14]1[CH2:13][CH2:12][CH:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([NH2:1])[CH:10]=3)[CH:6]=[N:7]2)[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3ccc(N)cc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc2cnn(C3CCNCC3)c2c1
Yield: 73.1 %

Procedure:
tert-Butyl 4-(6-amino-1H-indazol-1-yl)piperidine-1-carboxylate (6.64 mmol, 2.1 g) was stirred at room temperature in dichloromethane (10 mL)/trifluoroacetic acid (10 mL) for 1 hour. The reaction mixture was concentrated under vacuum. The resulting residue was purified by SCX column to afford the title compound (1.05 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[CH:16]=[C:15]([CH2:17][OH:18])[CH:14]=[C:13]([NH:19][C:20]3[CH:25]=[N:24][CH:23]=[CH:22][N:21]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1.[C:26](Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[CH:16]=[C:15]([CH2:17][O:18][CH3:26])[CH:14]=[C:13]([NH:19][C:20]3[CH:25]=[N:24][CH:23]=[CH:22][N:21]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](Nc1cc(CO)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COCc1cc(Nc2cnccn2)nc(N[C@@H](C)c2ccc(F)cc2)c1
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
20 mg of (S)-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}methanol (Example 140) was dissolved in methylene chloride, and 59 mg of carbon tetrabromide and 47 mg of triphenylphosphine were added under ice-cooling, and the mixture was stirred for 30 minutes. Subsequently, 90 μl of 9.8M sodium methoxide/methanol solution was added thereto, and the mixture was stirred overnight. The reaction solution was diluted with ethyl acetate and was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled of f under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 7 mg of the objective compound as yellow powder.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:15][CH:16]([CH3:18])[CH3:17])=[C:10]([CH:14]=1)[C:11]([OH:13])=O)(=[O:5])=[O:4])[CH3:2].Cl.[F:20][C:21]([F:34])([F:33])[C:22]1[S:26][C:25]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:24][CH:23]=1>>[CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:15][CH:16]([CH3:18])[CH3:17])=[C:10]([C:11]([N:30]2[CH2:31][CH2:32][N:27]([C:25]3[S:26][C:22]([C:21]([F:34])([F:20])[F:33])=[CH:23][N:24]=3)[CH2:28][CH2:29]2)=[O:13])[CH:14]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(OC(C)C)c(C(=O)O)c1
Reactant: FC(F)(F)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: CCS(=O)(=O)c1ccc(OC(C)C)c(C(=O)N2CCN(c3ncc(C(F)(F)F)s3)CC2)c1
Yield: 21 %

Procedure:
Prepared in analogy to example 1 (b) from 5-ethanesulfonyl-2-isopropoxy-benzoic acid (Example A18) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58(c)). The crude material was purified by reversed phase HPLC (acetonitrile/water) followed by trituration in ether to yield the title compound as an off-white crystalline solid (yield 21%). MS (m/e): 492.1 (M+H+, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]([C:13]([NH:15][CH2:16][CH2:17]Cl)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:21][C:22]1([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]([C:13]([NH:15][CH2:16][CH2:17][N:25]2[CH2:26][CH2:27][C:22]([OH:21])([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)[CH2:23][CH2:24]2)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCCl)c1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccc(CC2(O)CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: Cc1ccc(CC2(O)CCN(CCNC(=O)c3ccc(OCc4ccccc4)cc3)CC2)cc1
Temperature: 60 °C
Reaction time: 15 h
Yield: 18.7 %

Procedure:
A mixture of 4-benzyloxy-N-(2-chloro-ethyl)-benzamide (2.0 g, 6.9 mmol), 4-hydroxy-4-(4-methyl-benzyl)-piperidine (1.06 g, 5.18 mmol), potassium carbonate (1.43 g, 10.35 mmol) and 2-butanone (40 ml) was stirred for 15 h at 60° C. After the addition of water, the mixture was extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (silica gel, methylene chloride methanol from 95:5 to 9:1) to give 4-benzyloxy-N-[2-[4-hydroxy-4-(4-methyl-benzyl)-piperidin-1-yl]-ethyl]-benzamide (445 mg, 19%) as a light yellow solid. MS: me/e =459 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7]([CH3:14])([CH3:13])[CH:6]=[C:5]2[C:15]([F:18])([F:17])[F:16].O[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:38]=[CH:37][C:27]([O:28][C:29]([CH3:36])([CH2:34][CH3:35])[C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:38]=[CH:37][C:27]([O:28][C:29]([CH3:36])([CH2:34][CH3:35])[C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=1)[O:8][C:7]([CH3:14])([CH3:13])[CH:6]=[C:5]2[C:15]([F:16])([F:18])[F:17]
Reactant: CC1(C)C=C(C(F)(F)F)c2cc(Cl)c(O)cc2O1
Reactant: CCC(C)(Oc1ccc(OCCCO)cc1)C(=O)OC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(C)(Oc1ccc(OCCCOc2cc3c(cc2Cl)C(C(F)(F)F)=CC(C)(C)O3)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.8 %

Procedure:
To a solution of 6-Chloro-2,2-dimethyl-4-(trifluoromethyl)-2H-chromen-7-ol (0.66 g, 2.95 mmol), methyl 2-(4-(3-hydroxypropoxy)phenoxy)-2-methylbutanoate (1.0 g, 2.97 mmol) and triphenylphosphine (0.85 g, 3.24 mmol) in 25 mL THF is added diethyl azodicarboxylate (0.56 g, 3.21 mmol)(slight exotherm) and the reaction mixture is stirred at ambient temperature overnight (16 h). After concentrating under reduced pressure, the residue obtained is chromatographed over silica gel to provide methyl 2-(4-(3-((6-chloro-2,2-dimethyl-4-(trifluoromethyl)-2H-chromen-7-yl)oxy)propoxy)phenoxy)-2-methylbutanoate (0.99 g).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([O:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=[O:15])[CH:9]=2)[CH:4]=[N:3][CH:2]=1.[CH2:17](O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[N:3]1[CH:4]=[C:5]([O:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH:9]=2)[CH:6]=[N:1][CH:2]=1
Reactant: O=C(O)c1cc(Oc2cncnc2)ccn1
Reactant: OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1cc(Oc2cncnc2)ccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 37.1 %

Procedure:
4-(Pyrimidin-5-yloxy)picolinic acid (1.43 g, 6.58 mmol, 1.00 eq), benzyl alcohol (1.02 mL, 9.88 mmol, 1.50 eq), PS—PPh3 (5.51 g, 14.5 mmol, 2.20 eq) and THF (66 mL) were added to a flame-dried round-bottom flask. The mixture was cooled to 0° C. and diisopropyl azodicarboxylate (2.07 mL, 10.5 mmol, 1.60 eq) was added dropwise. The reaction was allowed to warm to rt and stirred for 1 h. The reaction was filtered and washed with EtOAc. The combined organics were concentrated in vacuo and purified by flash chromatography on silica gel to afford 750 mg (37%) of the title compound as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 9.16 (s, 1H), 8.87 (s, 2H), 8.64 (d, J=5.7 Hz, 1H), 7.66 (d, J=2.5 Hz, 1H), 7.47-7.40 (m, 2H), 7.40-7.38 (m, 1H), 7.38-7.32 (m, 3H), 5.36 (s, 1H); [M+1]+: 308.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1.[Cl:20][S:21](O)(=[O:23])=[O:22]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([S:21]([Cl:20])(=[O:23])=[O:22])[CH:14]=1
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1S(=O)(=O)Cl
Temperature: 0 °C
Yield: 81.1 %

Procedure:
6.7 g (22.0 mmol) of 4-(2,6-dichloro-4-trifluoromethylphenyl)toluene prepared in (a) was dissolved in 50 ml of chloroform, and 3.8 g (32.6 mmol) of chlorosulfonic acid was added dropwise at 0° C. with stirring. After further 3 hours of stirring at room temperature, the reaction mixture was poured into about 200 ml of ice-cold water for separation. The organic layer was washed with water twice and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 7.2 g of 5-(2,6-dichloro-4-trifluoromethylphenyl)-2-methylbenzenesulfonyl chloride (yield 81.0%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.S(=O)(=O)(O)O.[Br:15]Br.[OH-].[Na+]>O>[NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:15])=[C:4]([CH3:9])[N:3]=1
Reactant: BrBr
Reactant: Cc1cc(C)nc(N)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(N)nc(C)c1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
20 g(0.164 mole) of 2-amino-4, 6-dimethylpyridine was added into a mixture of 69 ml of water and 16.1 g(0.164 mole) of sulfuric acid and the resulting solution was cooled to 0° C., and thereto was added 8.45 ml(0.164 mole) of bromine gradually at 0° C. The resulting solution was stirred for 30 minutes, adjusted to pH 9 to 10 with aqueous sodium hydroxide solution and extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified with silica gel column chromatography to obtain 18.25 g of the title compound(yield 55%) and 5.4 g of dibromo compound(yield 11.8%).
Reaction SMILES: C([Mg]Br)C.[CH:5]1([C:11]#[CH:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[CH2:13]=[O:14]>CCOCC>[CH:5]1([C:11]#[C:12][CH2:13][OH:14])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: C#CC1CCCCC1
Reactant: C=O
Agent: CC[Mg]Br
Solvent: CCOCC
Product: OCC#CC1CCCCC1
Temperature: 25 °C

Procedure:
To a solution of ethyl magnesium bromide (prepared from 2.5 g of magnesium turning and 11.3 g of bromoethane) in ether was added dropwise a solution of 10.2 g of cyclohexylacetylene in ether and the reaction mixture was refluxed for 2 hours. The reaction mixture was cooled to ambient temperature and anhydrous formaldehyde (prepared from the thermal decomposition of 50 g of paraformaldehyde for 20 minutes) was bubbled into the mixture. After cooling, the reaction was quenched with saturated ammonium chloride and extracted with ether (2×100 ml). The combined ether extracts were washed with brine, dried over magnesium sulfate and evaporated to yield the product which was distilled under high vacuum at 68°-74° C. to yield 6.4 g as a colorless liquid.
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]2=[C:3]([C:10]#[N:11])[CH:2]=1.S(=O)(=O)(O)[OH:13]>>[N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]2=[C:3]([C:10]([NH2:11])=[O:13])[CH:2]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cnn2cccnc12
Product: NC(=O)c1cnn2cccnc12

Procedure:
As shown hereinabove a pyrazolo(1,5-a)-pyrimidine-3-carbonitrile (4) (prepared in the manner described in U.S. Pat. Nos. 4,281,000; 4,236,005 and 4,178,499) is stirred with concentrated sulfuric acid at room temperature for from 2-20 hours. The mixture is carefully poured onto ice and the precipitate is collected, neutralized with sodium hydroxide, ammonium hydroxide or saturated sodium bicarbonate and the like and washed with water to obtain the corresponding pyrazolo(1,5-a)pyrimidine-3-carboxamide compound (3).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]([F:33])([F:32])[O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:25]2[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1.O[N:35]1[C:43](=[O:44])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]1=[O:45].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[F:33][C:14]([F:13])([F:32])[O:15][C:16]1[CH:17]=[CH:18][C:19]([S:22]([N:25]2[CH2:26][CH2:27][CH:28]([O:31][N:35]3[C:43](=[O:44])[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:36]3=[O:45])[CH2:29][CH2:30]2)(=[O:23])=[O:24])=[CH:20][CH:21]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=S(=O)(c1ccc(OC(F)(F)F)cc1)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OC1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 80.3 %

Procedure:
Diethyl azodicarboxylate (8.86 g, 33.8 mmol) was added to a solution of 1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-ol (10.0 g, 30.7 mmol), 2-hydroxyisoindoline-1,3-dione (5.01 g, 30.7 mmol) and triphenylphosphine (8.86 g, 33.8 mmol) in tetrahydrofuran (100 ml) at 0° C. The reaction mixture was stirred at room temperature for 17 hours and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether: 33/67) to give 2-(1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-yloxy)isoindoline-1,3-dione (11.6 g, 80%) as a white solid: LCMS: 471 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][NH2:13])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[C:14]1([N:20]=[C:21]=[N:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[C:23]1([NH:22][C:21]([NH:13][NH:12][C:9]2[CH:10]=[CH:11][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)=[N:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1ccc(NN)cc1
Reactant: C(=Nc1ccccc1)=Nc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(NNC(=Nc2ccccc2)Nc2ccccc2)cc1
Reaction time: 1 h
Yield: 82.4 %

Procedure:
In 70 ml of tetrahydrofuran were dissolved 9.0 g of 4-ethoxycarbonylphenylhydrazine and 9.7 g of 1,3-diphenylcarbodiimide and after stirring the solution for one hour under ice-cooling, tetrahydrofuran was distilled off under reduced pressure. Then, when 70 ml of benzene and 70 ml of n-hexane were added to the residue thus formed, crystals deposited. By collecting the crystals thus deposited by filtration, 15.4 g of 1,2-diphenyl-3-(4-ethoxycarbonylphenylamino)guanidine was obtained.
Reaction SMILES: [NH2:1][S:2]([CH2:5][CH2:6][CH2:7][C:8]([OH:10])=O)(=[O:4])=[O:3].CCN(C(C)C)C(C)C.CC(C)N=C=NC(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:39]1([C:45]2[C:46]3[CH:47]=[CH:48][C:49]([C:70]([O:72][CH3:73])=[O:71])=[CH:50][C:51]=3[N:52]3[C:59]=2[C:58]2[CH:60]=[CH:61][CH:62]=[CH:63][C:57]=2[O:56][CH2:55][C@H:54]([N:64]([CH3:69])[CH2:65][CH2:66][NH:67][CH3:68])[CH2:53]3)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>CN(C=O)C>[NH2:1][S:2]([CH2:5][CH2:6][CH2:7][C:8]([N:67]([CH3:68])[CH2:66][CH2:65][N:64]([CH3:69])[C@@H:54]1[CH2:53][N:52]2[C:51]3[CH:50]=[C:49]([C:70]([O:72][CH3:73])=[O:71])[CH:48]=[CH:47][C:46]=3[C:45]([CH:39]3[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]3)=[C:59]2[C:58]2[CH:60]=[CH:61][CH:62]=[CH:63][C:57]=2[O:56][CH2:55]1)=[O:10])(=[O:4])=[O:3]
Reactant: CNCCN(C)[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Reactant: NS(=O)(=O)CCCC(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)CCN(C)C(=O)CCCS(N)(=O)=O)COc1ccccc1-3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(aminosulfonyl)butanoic acid (1.2 eq.), DIPEA (2 eq.), DIC (1.1 eq.) and HOBT (1.1 eq.) were added to a solution of methyl(7R)-14-cyclohexyl-7-{methyl[2-(methylamino)ethyl]amino}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.07 M) in DMF. The reaction was stirred under N2 at RT overnight. The mixture was then partitioned between sat. aq. NaHCO3 and EtOAc. The combined organics were washed with 1N HCl followed by brine, dried (Na2SO4), filtered and concentrated in vacuo. The product was used in the next step without further purification. (ES+) m/z 625 (M+H)+.
Reaction SMILES: CO.C[O-].[Na+].[N+](C(C)C)([O-])=[O:7].Br[CH2:13][C:14]1[C:15]([Cl:25])=[C:16]([CH:21]=[CH:22][C:23]=1[Cl:24])[C:17]([O:19][CH3:20])=[O:18]>C(OCC)(=O)C>[Cl:25][C:15]1[C:14]([CH:13]=[O:7])=[C:23]([Cl:24])[CH:22]=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1ccc(Cl)c(CBr)c1Cl
Reactant: CC(C)[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cl)c(C=O)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To methanol in a volume of 100 ml, was added 28% methanol solution of sodium methylate in an amount of 26.61 g, and to the resulting solution, was fed dropwise 2-nitro propane in an amount of 12.29 g while cooling with ice to a temperature lower than 25° C. The mixture was then added with methyl 3-bromomethyl-2,4-dichlorobenzoate in an amount of 41.16 g and stirred for 30 minutes under heating reflux. After completing reaction, the reacted-mixture was cooled and condensed under reduced pressure. A residue obtained was then dissolved in ethyl acetate in a volume of 1,000 ml, and the resulting solution was then washed with 1% aqueous solution of sodium hydroxide while cooling with ice. An organic layer resulted was washed with water and then with saturated saline solution, and was dried over anhydrous magnesium sulfate. Crystals, which were obtained after condensation of the organic layer under reduce pressure, were washed with benzene and then with n-hexane to obtain an objective compound of methyl 2,4-dichloro-3-formylbenzoate in an amount of 22.0 g in crystalline state. The melting point of this compound is in a range of from 103° to 104° C.
Reaction SMILES: N.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][C:4]=1[N:15]=[C:16]=[O:17].ClC1C=C(Cl)C(OC(OC)=O)=CC=1[N+:31]([O-])=O>C1C=CC=CC=1>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][C:4]=1[NH:15][C:16]([NH2:31])=[O:17]
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(Cl)cc1Cl
Reactant: COC(=O)Oc1cc(N=C=O)c(Cl)cc1Cl
Agent: N
Solvent: c1ccccc1
Product: COC(=O)Oc1cc(NC(N)=O)c(Cl)cc1Cl
Yield: 88 %

Procedure:
An ammonia gas was introduced while strongly stirring on cooling in an ice bath into a benzene solution (120 ml) of 2,4-dichloro-5-methoxycarbonyloxyphenyl isocyanate (5.04 g, 19.2 mmol) which has been synthesized by the identical method as the Comparative Examples 1 to 4 from 2,4-dichloro-5-methoxycarbonyloxynitrobenzene. Thirty minutes later, a white solid deposited was filtered and sufficiently washed with benzene. This product was confirmed to be the desired 2,4-dichloro-5-methoxycarbonyloxyphenyl urea (4.68 g, yield 88%) by means of spectral analyses.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].S(=O)(=O)(O)O.[CH3:19]COC(C)=O.O>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:10][CH3:19])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CC(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: COC(C)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 150 °C
Yield: 71 %

Procedure:
1-(4-fluoro-3-nitrophenyl)ethanol (870 g, 4.7 mmol) was dissolved in MeOH (10 ml) and concentrated sulfuric acid (2.5 ml, 47 mmol) was added carefully. The reaction mixture was heated at 150° C. using microwave (Biotage Initiator) for 5 minutes. After cooling to room temperature, the reaction mixture was poured into EtOAc/water. The organic layer was washed with brine, dried over MgSO4 and evaporated. The resulting material was purified by flash chromatography on silica eluting with 0% to 50% EtOAc/Hexane to afford the title compound (664 mg, yield: 71%). 1H-NMR (400 MHz, CDCl3) δ 1.45 (d, 3H) 3.27 (s, 3H) 4.36 (q, 1H) 7.28-7.32 (m, 1H) 7.56-7.63 (m, 1H) 7.98-8.04 (m, 1H)