Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.CO.[N:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[C:13]([OH:15])=[O:14].[C:16](=O)([O-])O.[Na+]>O>[N:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: O=C(O)c1cnccn1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cnccn1
Temperature: 61 °C
Yield: 74.6 %

Procedure:
106.6 g of thionyl chloride was added dropwise over 1 hour to 1200 ml of methanol under argon at 4° to 6° C. 100.1 g of pyrazinecarboxylic acid was added at 9° C. and the mixture was heated at 61° C. for 2 hours, the acid passing completely into solution. After cooling to room temperature, a solution of 145 g of sodium hydrogen carbonate in 1.4 l of water was added slowly. The methanol was distilled off on a rotary evaporator at a bath temperature of 45° C. and at 50 to 120 mbar and the residue was extracted three times with dichloromethane (400 ml, 100 ml, 100 ml). Concentration of the organic phase gave 83.15 g of crude product, which was recrystallized from ca. 250 g of diisopropyl ether. The yield of the title compound was 70.6 g plus 10.28 g from the mother liquor (total 72.5 percent). Further data concerning the title compound was:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH3:15])=[CH:8][CH:7]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22]>C(#N)C>[Br-:1].[CH2:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][N+:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[CH:7][CH:8]=1)[CH2:13][CH2:14][CH3:15]
Reactant: Cc1ccccn1
Reactant: CCCCc1ccc(CCCCBr)cc1
Solvent: CC#N
Product: CCCCc1ccc(CCCC[n+]2ccccc2C)cc1
Product: [Br-]
Yield: 74 %

Procedure:
1-(4-Bromo-butyl)-4-butyl-benzene (1 mmol) was added to a solution of 2-picoline (3 mmol) in acetonitrile, and the solution was refluxed for 24 hours. The acetonitrile was removed in a vacuum, and the resulting residue was partitioned between ether and water. The aqueous layer was washed extensively with ether until no 2-picoline was left in the aqueous layer. The resulting aqueous solution of the product was extracted with chloroform. The chloroform was removed to afford the product (74%). 1HNMR (300 MHz, CDCl3, ppm), 9.69 (d, J=6.6, 1H), 8.25-8.30 (m, 1H), 7.90-7.95 (m, 1H), 7.77 (d, J=7.8, 1H), 7.04-7.10 (m, 4H), 4.92 (t, 7.5, 2H), 2.84 (s, 3H), 2.66 (t, J=7.2, 2H), 2.56 (t, J=7.5, 2H), 1.89-1.98 (m, 2H), 1.78-1.86 (m, 2H), 1.51-1.59 (m, 2H), 1.27-1.37 (m, 2H), 0.91 (t, J=7.2, 3H).
Reaction SMILES: ClC1N2C(=O)NN=C2C(C2C=CC(Cl)=CC=2)=C(C2C=CC(Cl)=CC=2)N=1.[Cl-].[Cl-].[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][Zn+])=[CH:32][CH:31]=1.ICC.[Cl:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[N:53]=[C:52](C)[N:51]3[C:55](=[O:69])[N:56]([CH2:58][C:59]4C=CC(C(F)(F)F)=CC=4)[N:57]=[C:50]3[C:49]=2[C:70]2[CH:75]=[CH:74][C:73]([Cl:76])=[CH:72][CH:71]=2)=[CH:44][CH:43]=1>>[Cl:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[N:53]=[C:52]([CH2:34][C:33]3[CH:36]=[CH:37][C:30]([O:29][CH3:28])=[CH:31][CH:32]=3)[N:51]3[C:55](=[O:69])[N:56]([CH2:58][CH3:59])[N:57]=[C:50]3[C:49]=2[C:70]2[CH:71]=[CH:72][C:73]([Cl:76])=[CH:74][CH:75]=2)=[CH:44][CH:43]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c2nn(Cc3ccc(C(F)(F)F)cc3)c(=O)n12
Reactant: COc1ccc(C[Zn+])cc1
Agent: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nc(Cl)n12
Agent: [Cl-]
Solvent: CCI
Product: CCn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nc(Cc3ccc(OC)cc3)n2c1=O

Procedure:
The title compound was prepared in two steps from 5-chloro-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one by nucleophilic displacement of chloride with 4-methoxybenzylzinc chloride, followed by alkylation with iodoethane, in a manner analogous to that in which 7,8-bis(4-chlorophenyl)-5-methyl-2-(4-(trifluoromethyl)benzyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one was prepared. HPLC/MS: retention time=4.571 min, [M+H]30 =505.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:35][O:36][C:37](=[O:39])[CH3:38])(=[O:3])[CH3:2].[Cr]([O-])([O-])(=O)=[O:41].[K+].[K+]>C(O)(=O)C>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([C:33](=[O:41])[CH3:34])=[CH:31][CH:32]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:35][O:36][C:37](=[O:39])[CH3:38])(=[O:3])[CH3:2]
Reactant: CCc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Reactant: O=[Cr](=O)([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(C(C)=O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 37 %

Procedure:
To a stirred solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-ethylbenzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (10 g, 10.8 mmol) in acetic acid (130 mL) at 120° C. was added potassium chromate (6.3 g, 21.4 mmol) in one portion. The mixture was stirred for 22 hours at this temperature, and the reaction was cooled to RT. The volatiles were removed under reduced pressure, ethyl acetate was added, and the solids were filtered off. The organic layer was washed with a saturated solution of sodium bicarbonate and then with brine, and dried over sodium sulfate. Concentration of the organic solution and purification of the resulting residue by silica gel column (3:1 petroleum ether:ethyl acetate) gave 2.3 g of title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.90 (d, J=8.0 Hz, 2H), 7.39 (d, J=8.4 Hz, 1H), 7.26 (d, J=8.4 Hz, 2H), 7.22 (dd, J=8.4, 2.2 Hz, 1H), 7.17 (d, J=2.0 Hz, 1H), 5.31 (t, J=9.4 Hz, 1H), 5.22 (t, J=9.8 Hz, 1H), 5.09 (t, J=9.4 Hz, 1H), 4.35 (d, J=10.0 Hz, 1H), 4.29 (dd, J=12.4, 4.8 Hz, 1H), 4.18-4.13 (m, 3H), 3.85-3.81 (m, 1H), 2.60 (s, 3H), 2.09 (s, 3H), 2.07 (s, 3H), 2.01 (s, 3H), 1.75 (s, 3H); MS ESI (m/z): 575 [M+H]+, 619 [M+HCO2]−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C@@H:7]([O:9][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 8 h

Procedure:
To a solution of trans-N-Boc-4-hydroxy proline methyl ester (17.6 g) (0.072 mol) and TEA (12.5 mL) (0.09 mol) in 100 mL of DCM at 0° C. was slowly added methanesulfonyl chloride (7 mL) (0.09 mol). The temperature was allowed to warm to 20° C., and the mixture was stirred overnight. Insoluble material was removed by filtration and the organic layer washed with water, dried over MgSO4, and evaporated in vacuo to afford the above-titled compound as an oil which solidified upon standing (24 g). NMR(CDCl3, 200 MHz): 5.22 (1H, m), 4.32-4.5 (1H, m), 3.5-3.9 (5H, m), 3.05 (3H, s), 2.5-2.73 (1H, m), 2.15-2.35 (1H, m), 1.35-1.5 (9H).
Reaction SMILES: ClCCC[N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].[OH:19][C:20]1([C:26]2[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][CH:27]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(=O)(O)[O-].[Na+].O1C[CH2:41][CH2:40][CH2:39]1>CN(C)C=O>[Br:32][C:29]1[CH:30]=[CH:31][C:26]([C:20]2([OH:19])[CH2:21][CH2:22][N:23]([CH2:39][CH2:40][CH2:41][C:10]3[C:9]4[NH:5][S:6](=[O:17])(=[O:18])[C:7]5[C:8]=4[C:13]([CH:14]=[CH:15][CH:16]=5)=[CH:12][CH:11]=3)[CH2:24][CH2:25]2)=[CH:27][CH:28]=1
Reactant: OC1(c2ccc(Br)cc2)CCNCC1
Reactant: C1CCOC1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S1(=O)Nc2c(CCCN3CCC(O)(c4ccc(Br)cc4)CC3)ccc3cccc1c23
Temperature: 100 °C

Procedure:
The experiment is carried out as in Exampe 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (2.8 g), 4-hydroxy-4-(4-bromophenyl)piperidine (2.4 g) and sodium bicarbonate (0.94 g) in a mixture of dimethylformamide (80 cc) and tetrahydrofuran (50 cc). The mixture is heated for 5 hours to a temperature of about 100° C. then cooled to a temperature of about 20° C. Stirring is maintained for 15 hours at this temperature. After purification by flash-chromatography on a silica column, under a current of argon (0.5-1.5 bar) with a mixture of dichloromethane and methanol (95-5 vol) as eluant, and recrystallization from boiling ethyl acetate (50 cc), 2-(3-[4-(4-bromophenyl)-4-hydroxypiperidino]propylnaphtho[1,8-cd]isothiazole 1,1-dioxide (1.5 g) is obtained in the form of hydrochloride, of m.p. 110 C.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][C:10]3[C:15]([C:16]=2[C:17]2[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[C:24]([F:27])([F:26])[F:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(N(CC)CC)C>[C:28]1([NH:34][C:35]([NH:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:16]3[C:15]4[C:10](=[C:11]([C:24]([F:27])([F:25])[F:26])[CH:12]=[CH:13][CH:14]=4)[N:9]=[CH:8][C:7]=3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:18]=2)=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1cccc(-c2c(-c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)Nc1cccc(-c2c(-c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from {3-[3-phenyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and phenyl isocyanate in substantially the same manner as described in Example 61 with one change: no triethylamine was used; off-white solid: mp 202-205° C.; MS (ES) m/z 481.8.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13]2=[CH:14][N:15]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])[N:16]=[C:12]2[CH:11]=[CH:10][N:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C(OCC)C>C(Cl)Cl>[Cl:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([F:23])[C:17]=1[N:15]1[CH:14]=[C:13]2[C:8]([NH2:7])=[N:9][CH:10]=[CH:11][C:12]2=[N:16]1
Reactant: CC(C)(C)OC(=O)Nc1nccc2nn(-c3c(F)cccc3Cl)cc12
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nccc2nn(-c3c(F)cccc3Cl)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.8 %

Procedure:
To a solution of [2-(2-chloro-6-fluorophenyl)-2H-pyrazolo[4,3-c]pyridin-4-yl]-carbamic acid tert-butyl ester (137 mg) in DCM (1 mL)) at 0° C. was added TFA (1 mL). The reaction mixture was stirred at room temperature for 1 hour then concentrated under reduced pressure. The resultant residue was partitioned between ethyl acetate and sodium bicarbonate (sat. aq.). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to give a colourless oil. Trituration with diethyl ether gave the title compound as a white solid (100 mg, 91% yield). LCMS (Method C): RT=0.34 min and 1.79 min, m/z: 263 [M+H+].
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:23]=[C:22]4[CH2:24][CH2:25][CH2:26][C:27](=[CH:30]N(C)C)[C:28](=O)[C:21]4=[CH:20][C:19]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.O.[NH2:42][NH2:43]>C(O)C>[C:34]1([C:19]2[CH:20]=[C:21]3[C:28]4=[N:42][NH:43][CH:30]=[C:27]4[CH2:26][CH2:25][CH2:24][C:22]3=[N:23][C:18]=2[C:15]2[CH:14]=[CH:13][C:12]([C:8]3([NH2:7])[CH2:11][CH2:10][CH2:9]3)=[CH:17][CH:16]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CN(C)C=C1CCCc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2C1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-c3n[nH]cc3CCC4)cc2)CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.3 %

Procedure:
To a solution of tert-butyl(1-(4-(6-((dimethylamino)methylene)-5-oxo-3-phenyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-2-yl)phenyl)cyclobutyl)carbamate (90 mg, 0.17 mmol) in anhydrous ethanol (2 mL) was added hydrazine hydrate (25 μL, 0.5 mmol). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours. The reaction mixture was concentrated to dryness under reduced pressure, purified by Biotage chromatography (silica, hexane:ethyl acetate, gradient elution from 99:1 to 60:40) and preparative HPLC (Method G, gradient 5 to 95% 0.1% FA/ACN in 0.1% FA/H2O, 20 minutes run) to give the desired product as a white solid (50 mg, 58% yield). 1H NMR (500 MHz, CDCl3) 7.49 (s, 1H), 7.38 (d, 2H), 7.29 (d, 2H), 7.21-7.25 (br m, 5H+1H), 3.25 (m, 2H), 2.94 (t, 2H), 2.53-2.61 (br m, 1H), 2.42-2.52 (m, 2H), 2.31-2.41 (br m, 1H), 2.14-2.21 (m, 2H), 1.98-2.10 (m, 1H), 1.74-1.85 (m, 1H), 1.30-1.43 (br s, 9H). LCMS (Method A): RT=6.09 min, M+H+=507.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.Cl[S:8]([OH:11])(=O)=[O:9].Cl.[CH2:13]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)[CH3:14].[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21]>O1CCCC1>[CH2:13]([C:15]1[S:16][C:17]([S:8]([NH:24][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:11])=[O:9])=[CH:18][CH:19]=1)[CH3:14]
Reactant: CCc1cccs1
Reactant: CC(C)(C)N
Reactant: O=S(=O)(O)Cl
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CCc1ccc(S(=O)(=O)NC(C)(C)C)s1
Yield: 53.4 %

Procedure:
222 gm (1.07 mol) of phosphorus pentachloride were added in portions while stirring and cooling to 310 gm (2.7 mol) of chlorosulfonic acid. After the evolution of hydrogen chloride had subsided, 100 gm (0.89 mol) of 2-ethyl-thiophene were added dropwise while stirring at a temperature of 20° C. When the addition was finished, the reaction mixture was poured over ice and extracted with ether. The ether solution was washed until neutral, dried and evaporated. The residue was taken up in tetrahydrofuran, and the solution was added dropwise to a solution of 169 gm (2.3 mol) of tert.butylamine in 200 ml of tetrahydrofuran. After refluxing for 3 hours, the reaction mixture was filtered to separate the precipitated tert.butylamine hydrochloride, and the filtrate was evaporated in vacuo. The residue was taken up in ether and the solution was washed with dilute hydrochloric acid and with water, dried and evaporated. 147 gm of crude product were obtained which, after purification on a silica gel column (4 kg of silica gel 40 for column chromatography, particle size 0.2-0.5 mm; eluant: cyclohexane/ethyl acetate 4:1), yielded 117.6 gm (53% of theory) of 5-ethyl-N-tert.butyl-thiophene-2-sulfonamide.
Reaction SMILES: [CH2:1]([S-:3])[CH3:2].[Na+].Cl[C:6]1[C:7]([C:12]([NH:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1.CN(C=O)C>O>[CH2:1]([S:3][C:6]1[C:7]([C:12]([NH:14][C:15]2[CH:16]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=2)=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: CC[S-]
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncccc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1cccnc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
0.89 g of sodium ethanethiolate was added to a mixture of 1.56 g of 3-chloro-N-(3,5-bistrifluoromethylphenyl)picolinamide and 3 mL of DMF, and the mixture was stirred at 60° C. for 2 hours. The reaction mixture cooled to room temperature was poured to water, and the precipitated solid was taken by filtration. The resulting solid was dissolved in ethyl acetate, and the mixture was extracted with water and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 1.64 g of 3-ethylsulfanyl-N-(3,5-bistrifluoromethylphenyl)picolinamide (hereinafter, referred to as Compound of Present Invention 10).
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[NH:23]1[CH2:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>CS(C)=O.O>[N:23]1([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:26][CH2:25][CH2:24]1
Reactant: C1CNC1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCC3)nc2c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (100 mg, 0.32 mmol) in DMSO (2 mL) was added azetidine (37 mg, 0.65 mmol) and DIEA (81 mg, 0.63 mmol). After stirring for 2 hours at 70° C., the reaction mixture was dissolved in water (50 mL), extracted with dichloromethane (3×30 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to afford a residue, which was purified via silica gel column chromatography (2% dichloromethane in petroleum ether) to afford methyl 3-(azetidin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a light yellow solid (60 mg, 56%).
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)[CH3:7])[C:2]#[CH:3].[CH3:18][O:19][C:20](=[O:26])[C:21](Br)=[CH:22][O:23][CH3:24]>C(N(CC)CC)C.O1CCCC1.[Cu]I>[CH3:18][O:19][C:20](=[O:26])[C:21](=[CH:22][O:23][CH3:24])[C:3]#[C:2][CH2:1][O:4][N:5]=[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=1)[CH3:7]
Reactant: C#CCON=C(C)c1cccc(C(F)(F)F)c1
Reactant: COC=C(Br)C(=O)OC
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC=C(C#CCON=C(C)c1cccc(C(F)(F)F)c1)C(=O)OC
Temperature: 70 °C
Reaction time: 14 h
Yield: 31.2 %

Procedure:
0.25 g of Pd(TPP)2Cl2 and also 0.1 g of copper(I) iodide are added, under an argon atmosphere, to a solution of 10.0 g of 1-(3-trifluoromethylphenyl)ethanone O-prop-2-ynyl-oxime in 150 ml of triethylamine and the mixture is heated to 70° C. 8.9 g of 2-bromo-3-methoxyacrylic acid methyl ester in 30 ml of tetrahydrofuran are then added and the mixture is stirred at 70° C. for 14 h and then filtered. The filtrate is concentrated by evaporation and chromatographed on silica gel (hexane/diethyl ether 2:1) to yield 4.6 g of the product having a melting point of 57-58° C.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([C@@H:13]([CH2:23][C@H:24]3[CH2:28][CH2:27][NH:26][CH2:25]3)[C:14]([NH:16][C:17]3[S:18][C:19]([F:22])=[CH:20][N:21]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[OH:29][NH:30][C:31](=O)[O:32]C1C=CC=CC=1.O>C(O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([C@H:13]([C:14]([NH:16][C:17]3[S:18][C:19]([F:22])=[CH:20][N:21]=3)=[O:15])[CH2:23][C@H:24]3[CH2:28][CH2:27][N:26]([C:31]([NH:30][OH:29])=[O:32])[CH2:25]3)=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(NO)Oc1ccccc1
Reactant: O=C(Nc1ncc(F)s1)[C@H](C[C@H]1CCNC1)c1ccc(S(=O)(=O)C2CC2)cc1
Solvent: CCO
Solvent: O
Product: O=C(Nc1ncc(F)s1)[C@H](C[C@H]1CCN(C(=O)NO)C1)c1ccc(S(=O)(=O)C2CC2)cc1
Reaction time: 5 h
Yield: 54.3 %

Procedure:
The (R)-2-(4-(cyclopropylsulfonyl)phenyl)-N-(5-fluorothiazol-2-yl)-3-((S)-pyrrolidin-3-yl)propanamide (39.1 mg, 92.3 μmol) obtained in Step 1 of Example 2 was dissolved in ethanol (2 mL), and phenyl N-hydroxycarbamate (56.0 mg, 366 μmol) was then added to the obtained solution. The obtained mixture was stirred for 5 hours at reflux. Thereafter, water was added to the reaction solution, and the mixed solution was then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and was then concentrated in vacuo. The obtained residue was purified by silica gel chromatography (chloroform/methanol=1%→20%) to obtain the captioned compound (24.2 mg, 54%) in the form of a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1([O:20][CH2:21][CH3:22])[CH2:9][CH2:8][N:7]([C@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[C@@H:6]([CH2:18]O)[CH2:5]1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:42]1(=[O:52])[NH:46][C:45](=[O:47])[C:44]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]12.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:21]([O:20][C:4]1([O:3][CH2:1][CH3:2])[CH2:9][CH2:8][N:7]([C@H:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:11])[C@@H:6]([CH2:18][N:46]2[C:42](=[O:52])[C:43]3=[CH:51][CH:50]=[CH:49][CH:48]=[C:44]3[C:45]2=[O:47])[CH2:5]1)[CH3:22]
Reactant: CCOC1(OCC)CCN([C@@H](C)c2ccccc2)[C@@H](CO)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC1(OCC)CCN([C@@H](C)c2ccccc2)[C@@H](CN2C(=O)c3ccccc3C2=O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 72485.8 %

Procedure:
A solution of 4,4-Diethoxy-1-((S)1-phenyl-ethyl)-(R)-2-hydroxymethyl-piperidine (65.35 g, 0.213 mmol), triphenylphosphine (61.3 g, 0.234 mol) and phthalimide (34.4 g, 0.234 mol), in tetrahydrofuran (700 ml) cooled to 0° C. was added diethyl azodicarboxylate over the course of 1.5 hour. The reaction mixture was stirred at 0° C. for another 2 hours before the solvent was removed in vacuo. The residue was dissolved in hot heptane-toluene (3:2) (650 ml) before it was cooled on an ice bath. The precipitate consisting of triphenyl phosphine oxide was filtered off and washed with heptane. The filtrate was concentrated in vacuo and the residue subjected to column chromatography using a mixture of toluene-ethyl acetate-heptane (3:1:3) as eluent. The solvent was evaporated in vacuo whereupon a viscous oil was obtained. Upon addition of light petrol ether the product crystallized to give 67.4 g (73%) of the title compound as a solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:9]([C:19](=[O:24])[NH:20][CH:21]2[CH2:23][CH2:22]2)=[N:10][O:11][C:12]=1C(=O)NC1CC1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:21]1([NH:20][C:19]([C:9]2[C:8]([NH2:7])=[CH:12][O:11][N:10]=2)=[O:24])[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)Nc1c(C(=O)NC2CC2)noc1C(=O)NC1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1conc1C(=O)NC1CC1
Temperature: 20 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
A mixture of (3-Cyclopropylcarbamoylcyclopropylcarbamoyl-isoxazol-4-yl)-carbamic acid tert-butyl ester (142 mg, 531 μmol), trifluoroacetic acid (614 μl, 7.97 mmol) in dichloromethane (3 ml) was stirred for 3 h at 20° C. The volatiles were evaporated in vacuo and the resulting crude product was poured into 50 ml dichloromethane and extracted with sodium bicarbonate (saturated aqueous solution). The aqueous phase was washed with dichloromethane and the organic layers were dried and evaporated to yield the product as light yellow oil (85 mg, 91%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]([OH:13])=[C:5]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:4]=1.[CH3:18]O>Cl>[CH3:18][O:1][CH2:2][C:3]1[CH:4]=[C:5]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:6]([OH:13])=[C:7]([C:9]([CH3:10])([CH3:11])[CH3:12])[CH:8]=1
Reactant: CO
Reactant: CC(C)(C)c1cc(CO)cc(C(C)(C)C)c1O
Agent: Cl
Product: COCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
A solution of 4-hydroxymethyl-2,6-di-t-butylphenol (0.5 g) in methanol (10 mL) containing 1 drop of concentrated hydrochloric acid was stirred at ambient temperature for 1 hour. Evaporation of the solvent gave the title compound, 0.5 g, 94% yield as a white crystalline solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:21]>C1(C)C=CC=CC=1>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[C:10]([Cl:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Nc1ccccc1C(F)(F)F)c1ccccc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccccc1N=C(Cl)c1ccccc1
Yield: 101.5 %

Procedure:
Using the procedure of Step B of Example 6, 26.52 g of the product of Step A and 22.9 g of phosphorus pentachloride were reacted in 160 ml of dry toluene to obtain 28.8 g of N-(2-trifluoromethylphenyl)-benzenecarboximidoyl chloride as an oil which was used as is for the next step.