Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O=[C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH:10]([C:20]([NH:22][CH:23]2[CH2:25][CH2:24]2)=O)[CH2:9]1.O.[OH-].[Na+]>O1CCCC1>[C:14]1([CH2:13][N:12]2[CH2:8][CH2:9][CH:10]([CH2:20][NH:22][CH:23]3[CH2:25][CH2:24]3)[CH2:11]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(NC1CC1)C1CC(=O)N(Cc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(CN2CCC(CNC3CC3)C2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 8.2 g (0.20 mole) of lithium aluminum hydride in 150 ml of dry tetrahydrofuran was added portionwise 18.0 g (70.0 mmole) of solid 5-oxo-1-(phenylmethyl)-N-cyclopropyl-3-pyrrolidinecarboxamide. When the addition was complete, the reaction mixture was stirred at room temperature for 18 hours and then at reflux for two hours. After cooling to room temperature, the mixture was treated dropwise, successively, with 8 ml of water, 8 ml of 15% aqueous sodium hydroxide and 24 ml of water, titrating the final addition to produce a granular precipitate. The solid was removed by filtration, washed with tetrahydrofuran and the filtrate evaporated in vacuo to give 16.0 g of 1-(phenylmethyl)-N-cyclopropyl-3-pyrrolidinemethanamine, as a heavy oil. This was used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[OH:15].FC1C=CC([N+]([O-])=O)=CC=1O.CN1CCNCC1.[CH2:34]1[C:42]2[C:37](=[CH:38][C:39]([N:43]3[C:48]4[N:49]=[C:50](S(C)(=O)=O)[N:51]=[CH:52][C:47]=4[C:46](=[O:57])[C:45]([C:58]([NH2:60])=[O:59])=[CH:44]3)=[CH:40][CH:41]=2)[CH2:36][CH2:35]1>>[OH:15][C:3]1[CH:4]=[C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]2)[CH:6]=[CH:7][C:2]=1[NH:1][C:50]1[N:51]=[CH:52][C:47]2[C:46](=[O:57])[C:45]([C:58]([NH2:60])=[O:59])=[CH:44][N:43]([C:39]3[CH:38]=[C:37]4[C:42](=[CH:41][CH:40]=3)[CH2:34][CH2:35][CH2:36]4)[C:48]=2[N:49]=1
Reactant: CN1CCN(c2ccc(N)c(O)c2)CC1
Reactant: CS(=O)(=O)c1ncc2c(=O)c(C(N)=O)cn(-c3ccc4c(c3)CCC4)c2n1
Agent: CN1CCNCC1
Agent: O=[N+]([O-])c1ccc(F)c(O)c1
Product: CN1CCN(c2ccc(Nc3ncc4c(=O)c(C(N)=O)cn(-c5ccc6c(c5)CCC6)c4n3)c(O)c2)CC1
Yield: 40 %

Procedure:
Using the procedure outlined in Example 23 (c), the title compound was prepared from 2-amino-5-(4-methyl-piperazin-1-yl)-phenol (5 mg, prepared using the procedure outlined in Example 1 (F) from 1-fluoro-2-hydroxy-4-nitrobenzene and 1-methyl-piperazine) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide (from Example 23 (b), 7 mg). Purification by preparative HPLC (32 mL/min, 5-100% H2O/MeCN (0.01% TFA, v/v) gradient over 10 min) followed by a basic aqueous work-up gave the title compound as a yellow solid (3.7 mg, 40%). 1H NMR (400 MHz, CD3OD) δ (ppm): 9.25 (br, 1H), 8.73 (s, 1H), 7.44 (d, J=8.4 Hz, 2H), 7.36 (s, 1H), 7.25 (d, J=7.1 Hz, 1H), 6.45 (s, 1H), 6.02 (br, 1H), 3.20 (br, 2H), 3.03 (m, 6H), 2.65 (s, 3H), 2.22 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C28H29N7O3: 512.23 (M+H), Found: 512.1.
Reaction SMILES: [C:1]([NH:9][NH:10][C:11]([C:13]1[CH:25]=[CH:24][C:23]2[C:22]3[C:17](=[CH:18][C:19]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:20][CH:21]=3)[CH2:16][C:15]=2[CH:14]=1)=O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1.[OH-].[Na+]>O1CCCC1>[CH2:26]([C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[C:15](=[CH:14][C:13]([C:11]4[S:43][C:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[N:9][N:10]=4)=[CH:25][CH:24]=3)[CH2:16][C:17]=2[CH:18]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCc1ccc2c(c1)Cc1cc(C(=O)NNC(=O)CCCCCC)ccc1-2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc2c(c1)Cc1cc(-c3nnc(CCCCCC)s3)ccc1-2
Temperature: 0 °C
Yield: 61.8 %

Procedure:
In a 30 ml-round-bottomed flask, 0.65 g (1.45 mM) of N-heptanoyl-N'-(7-octyl-2-fluorenecarbonyl)hydrazine, 0.62 g (1.53 mM) of Lawesson's reagent and 10 ml of tetrahydrofuran were placed, followed by heat-refluxing for 1.5 hours. After the reaction, the reaction mixture was poured into a solution of 0.45 g of sodium hydroxide in 100 ml of ice water to precipitate a crystal. The crystal was recovered by filtration, washed with water and dissolved in toluene, followed by washing with water, drying with anhydrous sodium sulfate and distilling-off of the solvent. The residue was purified by silica gel column chromatography (eluent: toluene) and recrystallized two times from a mixture solvent of toluene-methanol to obtain 0.40 g of 2-octyl-7-(5-hexyl-1,3,4-thiadiazole-2-yl)fluorene (Yield: 61.8%). ##STR87##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14](O)=[O:15])[C:9]2=[O:17])=[CH:4][CH:3]=1.O=S(Cl)[Cl:20]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([Cl:20])=[O:15])[C:9]2=[O:17])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cccn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (prepared according to: J. Med. Chem. (2008), 51, 5330-5341) (0.257 g, 1.1 mmol) in SOCl2 (2.409 mL, 33.0 mmol) was heated to 60° C. for 35 min, cooled to RT and concentrated to dryness. The residue was co-evaporated with toluene (2×) to afford 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonyl chloride (100% yield assumed) as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[N:5]2[CH:15]=[C:16]([CH2:18][OH:19])[N:17]=[C:4]2[CH:3]=1.[CH3:20][S:21]([NH:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)(=[O:23])=[O:22]>>[OH:19][CH2:18][C:16]1[N:17]=[C:4]2[CH:3]=[C:2]([C:29]3[CH:30]=[C:25]([NH:24][S:21]([CH3:20])(=[O:22])=[O:23])[CH:26]=[CH:27][CH:28]=3)[N:7]=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=3)[N:5]2[CH:15]=1
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Reactant: Cc1cc(Nc2nc(Cl)cc3nc(CO)cn23)n[nH]1
Product: Cc1cc(Nc2nc(-c3cccc(NS(C)(=O)=O)c3)cc3nc(CO)cn23)n[nH]1

Procedure:
The title compound was synthesized using (7-chloro-5-(5-methyl-1H-pyrazol-3-ylamino)imidazo[1,2-c]pyrimidin-2-yl)methanol and 3-(methylsulfonamido)phenyl boronic acid using the procedure described in Example 278. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.32 (s, 3H) 3.06 (s, 3H) 4.70 (s, 2H) 6.75 (s, 1H) 7.31 (dd, J=7.96, 1.64 Hz, 1H) 7.50-7.61 (m, 2H) 7.89 (d, J=8.08 Hz, 1H) 8.15 (s, 1H) 8.57 (s, 1H) 10.02 (s, 1H) 10.97 (s, 1H) 12.37 (s, 1H); ESI-MS: m/z calc'd for C18H19N7O3S 413.45; found 414.3 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[C:16](OCC)(=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:14]3[N:15]=[C:16]2[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4][CH:3]=1
Reactant: Nc1cccnc1Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C(=O)OCC
Product: CCOC(=O)c1nc2cccnc2n1-c1ccc(Cl)cc1
Temperature: 140 °C
Reaction time: 18 h

Procedure:
A mixture of N2-(4-chlorophenyl)pyridine-2,3-diamine (C9) (1.8 g, 8.2 mmol) and diethyl ethanedioate (18 g, 123 mmol) was stirred at 140° C. for 18 hours. Purification using silica gel chromatography (Gradient: 16% to 50% ethyl acetate in petroleum ether) provided the product as a brown solid, containing approximately 30% of a contaminant by 1H NMR analysis. Yield: 250 mg, 0.83 mmol, 10%. 1H NMR (400 MHz, CD3OD), product peaks only: δ 8.49 (dd, J=4.8, 1.5 Hz, 1H), 8.31 (dd, J=8.2, 1.4 Hz, 1H), 7.61 (br d, J=8.9 Hz, 2H), 7.52 (dd, J=8.2, 4.6 Hz, 1H), 7.49 (br d, J=8.9 Hz, 2H), 4.34 (q, J=7.2 Hz, 2H), 1.25 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:44])[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16]([CH2:19][CH2:20][CH2:21][C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])(=O)=[O:17])[C:5](=[O:29])[N:4]([C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-])=O)=[C:32]([C:39]([F:42])([F:41])[F:40])[CH:31]=2)[C:3]1=[O:43].NC1C=CC(N2C(=O)C(C)(C)N(CCCCCCCCCSCCCC(F)(F)C(F)(F)F)C2=O)=CC=1C(F)(F)F>>[NH2:36][C:33]1[CH:34]=[CH:35][C:30]([N:4]2[C:3](=[O:43])[C:2]([CH3:1])([CH3:44])[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16]([CH2:19][CH2:20][CH2:21][C:22]([F:27])([F:28])[C:23]([F:24])([F:25])[F:26])=[O:17])[C:5]2=[O:29])=[CH:31][C:32]=1[C:39]([F:42])([F:41])[F:40]
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCS(=O)(=O)CCCC(F)(F)C(F)(F)F
Agent: CC1(C)C(=O)N(c2ccc(N)c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCSCCCC(F)(F)C(F)(F)F
Product: CC1(C)C(=O)N(c2ccc(N)c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F

Procedure:
The experimental protocol used is the same as that described for the synthesis of the compound of Example 3, the compound of Example 16 replacing the compound of Example 2.
Reaction SMILES: CN[CH:3]([C:15]1[C:16](=[O:27])[C:17]2[C:22]([C:23](=[O:26])[C:24]=1[OH:25])=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].S(=O)(=O)(O)O>C1(C)C(C)=CC=CC=1>[CH:3]([C:15]1[C:16](=[O:27])[C:17]2[C:22]([C:23](=[O:26])[C:24]=1[OH:25])=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCC(NC)C1=C(O)C(=O)c2ccccc2C1=O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCC=CC1=C(O)C(=O)c2ccccc2C1=O
Temperature: 120 °C
Yield: 80.8 %

Procedure:
Into a 30 ml glass autoclave, 1.00 g (2.67 mmol) of 2-(1-methylaminododecyl)-3-hydroxy-1,4-naphthoquinone, 305.6 mg (1.1 mmol times relative to the starting material) of concentrated sulfuric acid and 20 ml of xylene were charged, then heated to 120° C. under stirring and maintained at that temperature for one hour. The mixture was left to cool and then extracted with a benzene/water system. The organic layer was dried over sodium sulfate, and the solvent was distilled off. The residue was recrystallized from methanol to obtain 734.6 mg of 2-(1-dodecenyl)-3-hydroxy-1,4-naphthoquinone. Further, the filtrate of the recrystallization was analyzed by HPLC, whereby it was confirmed that the filtrate contained 12.4 mg of 2-hydroxy-1,4-naphthoquinone, 0.7 mg of the starting material and 15.5 mg of the desired product. The yield, etc. are shown in Table 3.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=2)O1>>[NH2:32][C:29]1[N:30]=[CH:31][C:26]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([Cl:17])[CH:3]=2)=[CH:27][CH:28]=1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1c2n(c3c(-c4ccc(N)nc4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, white solid (67 mg, 82%), MS (ISP) m/z=327.5 [(M+H)+], mp 250° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (71.5 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1OS(C(F)(F)F)(=O)=O)[O:8][CH:7]([C:20]([F:23])([F:22])[F:21])[C:6]([C:24]([O:26]CC)=[O:25])=[CH:5]2.[C:29](=O)([O-])[O-].[K+].[K+].CN(C=O)C.O.[OH-].[Li+]>C1COCC1.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.C(O)C.O.CCOC(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:29])[O:8][CH:7]([C:20]([F:23])([F:21])[F:22])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C1=Cc2cc(C)c(OS(=O)(=O)C(F)(F)F)cc2OC1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc2c(cc1C)OC(C(F)(F)F)C(C(=O)O)=C2
Temperature: 110 °C
Reaction time: 2 h

Procedure:
To the mixture of ethyl 6-methyl-2-(trifluoromethyl)-7-{[(trifluoromethyl) sulfonyl]-oxy}-2H-chromene-3-carboxylate (0.3 g, 0.7 mmol), potassium carbonate(0.378 g, 2.73 mmol), tetrakis(triphenylphosphine)palladium (0) (81 mg, 0.07 mmol) and 3 mL of anhydrous DMF was added trimethylboraxine(292 uL, 2.1 mmol). The resulting mixture was heated to 110° C., and stirred at 110° C. for two hrs. LC-MS indicated that the reaction was done. To the reaction was added 100 mL of EtOAc, the resulting organic solution was washed with brine, and dried over anhydrous magnesium sulfate. After removing the volatiles, the residue was purified on silica gel column with 1:9 EtOAc/hexane. It gave a white solid, about 180 mg. The purified white solid was dissolved in 3 mL of THF, to the resulting solution was added lithium hydroxide hydrate (118 mg, 2.8 mmol), 3 mL of water and 3 mL of ethanol, the resulting solution was heated to 80° C. and stirred for 45 min. After cooling to room temperature, the volatiles were removed on rotavapor, the residue was diluted with water, and acidified in ice bath with ice cold dilute hydrochloric acid. Plenty of white precipitates were formed. The solid was filtered and washed with water, and dried in vacuum. The crude product was then purified on reverse phase HPLC. It gave a white solid, 70 mg. 1H NMR (CDCl3/CD3OD/300 MHz) 7.73(s, 1H), 6.97(s, 1H), 6.79(s, 1H), 5.65(q, J=6.6 Hz), 2.25(s, 3H), 2.19(s, 3H). 13C NMR(CDCl3/ CD3OD/300 MHz) 167.0, 151.8, 143.2, 138.3, 131.0, 130.4, 123.9(q, J=287.9 Hz), 117.1, 116.9, 115.2, 70.7(q, J=32.7 Hz), 20.5, 18.9. 19F NMR(CDCl3/ CD3OD/300 MHz) −78.97(d, J=6.5 Hz). LC-MS (ES+):273.2 (M+1, 100). High resolution Mass (ES−): m/z calc. For C13H10F3O3: 271.0582(M−H), found: 271.0563.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:8]=[N:9][N:10]([CH3:22])[C:11]=1[S:12]([NH:15][C:16]([NH:18][CH:19]([CH3:21])[CH3:20])=S)(=[O:14])=[O:13])=[O:5])[CH3:2].C(N(CC)CC)C.C(Cl)(Cl)=O>C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[C:7]2[CH:8]=[N:9][N:10]([CH3:22])[C:11]=2[S:12](=[O:14])(=[O:13])[N:15]=[C:16]1[NH:18][CH:19]([CH3:21])[CH3:20])=[O:5])[CH3:2]
Reactant: CCOC(=O)Nc1cnn(C)c1S(=O)(=O)NC(=S)NC(C)C
Agent: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)N1C(NC(C)C)=NS(=O)(=O)c2c1cnn2C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
To a stirred solution of N-(4-ethoxycarbonylamino-1-methyl-5-pyrazolesulfonyl)-N'-isopropylthiourea (0.37 g) and triethylamine (0.45 ml) in 5 ml of dry THF at 0° C. was added 1.0 ml of a 20% solution of phosgene in toluene. The mixture was stirred at 0° C. for 30 min. and then evaporated to dryness. The residue was triturated with 10 ml of water, filtered off, rinsed on the filter with water and dried to give 0.27 g (82%) of the title compound; m.p. 141°-145° C.
Reaction SMILES: [O:1]([C:8]1[C:9]([NH:21][C:22]2[S:26][N:25]=[C:24]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[N:23]=2)=[N:10][CH:11]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34].C1COCC1>O>[O:1]([C:8]1[C:9]([NH:21][C:22]2[S:26][N:25]=[C:24]([CH:27]3[CH2:32][CH2:31][N:30]([C:33](=[O:35])[CH3:34])[CH2:29][CH2:28]3)[N:23]=2)=[N:10][CH:11]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Oc2cc(Sc3ccccn3)cnc2Nc2nc(C3CCNCC3)ns2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N1CCC(c2nsc(Nc3ncc(Sc4ccccn4)cc3Oc3ccccc3)n2)CC1
Reaction time: 3 h
Yield: 54.5 %

Procedure:
3-Phenoxy-N-(3-(piperidin-4-yl)-1,2,4-thiadiazol-5-yl)-5-(pyridin-2-ylthio) pyridin-2-amine (0.075 g, 0.16 mmol), TEA (0.090 mL, 0.65 mmol), and acetic anhydride (0.017 g, 0.16 mmol) were added to THF and stirred for 3 hr. Water was added and extracted with CH2Cl2. The organic layer was dried, filtered, and concentrated. The residue was purified by silica gel (5% MeOH in CH2Cl2) to provide the title compound (0.044 g, 54% yield). 1H NMR (d6-DMSO) δ 12.34 (s, 1H), 8.38 (m, 2H), 7.67 (dt, 1H), 7.48 (d, 1H), 7.42 (t, 2H), 7.21-7.11 (m, 5H), 4.32 (d, 1H), 3.84 (d, 1H), 3.19 (m, 1H), 3.05 (m, 1H), 2.76 (t, 1H), 2.01 (m, 5H), 1.74 (m, 1H), 1.59 (m, 1H).
Reaction SMILES: [OH-].[Na+].Cl.Cl.[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][S:12][C:13](=N)N)[CH:6]=1.BrC[CH2:18][CH2:19][CH2:20][Cl:21]>O>[Cl:21][CH2:20][CH2:19][CH2:18][CH2:13][S:12][CH2:11][C:7]1[CH:6]=[N:5][CH:10]=[CH:9][CH:8]=1
Reactant: N=C(N)SCc1cccnc1
Reactant: ClCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: ClCCCCSCc1cccnc1
Temperature: 70 °C
Reaction time: 15 h
Yield: 70.8 %

Procedure:
A 10 N aqueous solution of sodium hydroxide (144 cc) is added dropwise, in the course of 25 minutes and whilst keeping the temperature below 12° C., to a solution of 2-(pyrid-3-ylmethyl)-isothiourea dihydrochloride (173 g) in distilled water (330 cc), cooled to 4° C. After heating for 25 minutes at 70° C. and then cooling to 11° C., a 10 N aqueous solution of sodium hydroxide (89 cc) and then 1-bromo-4-chlorobutane (123.5 g) are added, whilst stirring, and stirring is continued for 15 hours at a temperature of about 20° C. The reaction mixture is then extracted four times with methylene chloride (560 cc in total); the organic extracts are combined, washed twice with distilled water (800 cc in total), dried over anhydrous sodium sulphate and filtered. The solution is poured onto neutral silica gel (150 g) contained in a column of diameter 3.7 cm; the column is eluted with methylene chloride (2500 cc). The first fraction (600 cc) is discarded. The second (2500 cc) is concentrated to dryness under reduced pressure (25 mm Hg; 3.4 kPa) without exceeding 30° C. Pyrid-3-ylmethyl 4-chlorobutyl sulphide (110 g) is thus obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:5][O:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([I:14])[CH:9]=1.[C:20](Cl)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([O:1][CH2:2][C:3]1[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:5][O:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([I:14])[CH:9]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1noc(-c2cccc(I)c2)c1CO
Solvent: c1ccncc1
Product: CCOC(=O)c1noc(-c2cccc(I)c2)c1COC(C)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
A solution of ethyl 4-(hydroxymethyl)-5-(3-iodophenyl)isoxazole-3-carboxylate (1.50 g, 4.03 mmol) in pyridine (5 mL) was stirred for 10 min. followed by cooling to 0° C. and slowly adding acetyl chloride (379 mg, 4.83 mmol). The mixture was allowed to come to ambient temperature and stirred for 2 hours. The solvent was removed under vacuo and the mixture purified by column chromatography (0–30% ethyl acetate in hexanes) to provide the titled compound (1.65 g, 99%).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17].CCOC(C)=O>C1COCC1>[CH3:8][C:7]1[C:2]([Sn:18]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:14][CH2:15][CH2:16][CH3:17])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccnc1Br
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ncccc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.8 %

Procedure:
To 2-bromo-3-methylpyridine (1.3 mL, 11.7 mmol) in THF (35 mL) at −78° C. was added n-BuLi (2.5 M in hexanes, 5.6 mL, 14 mmol). After 30 min, tri-n-butyltin chloride (3.8 mL, 14 mmol) was added. After 1 h at −78° C., the reaction was allowed to warm to rt. EtOAc was added and the reaction mixture was washed with 10% aq KF. The organic layer was dried (MgSO4). Purification via silica gel chromatography (0-15% EtOAc in heptane) gave the title compound (1.2 g, 27%). MS (ESI) mass calcd. for C18H33NSn, 382.2; m/z found 384.0 [M+H]+.
Reaction SMILES: [C:1]([Cl:7])(=[O:6])[CH2:2][CH:3]=[CH:4][CH3:5].C=CC=C.Cl>O>[CH2:1]=[CH:2][CH:3]=[CH2:4].[C:1]([Cl:7])(=[O:6])[CH:2]=[CH:3][CH2:4][CH3:5]
Reactant: CC=CCC(=O)Cl
Agent: C=CC=C
Agent: Cl
Solvent: O
Product: CCC=CC(=O)Cl

Procedure:
combining the separated mixture containing 3-pentenoylchloride and chlorobutenes with water, butadiene, and hydrochloric acid to form a mixture where the ratio of butadiene to pentenoylchloride is 1:1 to 6:1 and the molar ratio of water to 3-pentenoylchloride is 1:1 to 15:1, and reacting this mixture at a temperature in the range of about 0 degrees C. to 100 degrees C., and at a pressure of about 50 to 600 psig to form a two phase mixture comprising an organic phase containing 3-pentenoic acid, chlorovaleric acid, and additional chlorobutene selected from the group consisting of 3-chloro-1-butene and 1-chloro-2-butene, and an aqueous phase,
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH:16]([OH:21])[CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].S(OC)(O[CH3:28])(=O)=O>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH:16]([O:21][CH3:28])[CH2:15]2)(=[O:12])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COS(=O)(=O)OC
Reactant: O=C(O)c1cc(S(=O)(=O)N2CCC(O)C(O)C2)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC1CN(S(=O)(=O)c2ccc(Cl)c(C(=O)O)c2)CCC1O
Temperature: 25 °C

Procedure:
2-Chloro-5-(3,4-dihyroxypiperidinosulfonyl)benzoic acid (4.0 g.) is heated for 16 hours at 90° C. with water (15 ml.), NaOH (1.0 g.) and dimethyl sulfate (0.5 ml.). Dimethyl sulfate and NaOH are added during the course of the reaction to maintain basicity. After cooling to room temperature, the reaction mixture is washed with ether and the aqueous phase is acidified with concentrated hydrochloric acid and decanted from the precipitated gum. The gum is dissolved in ethyl acetate and chromatographed on a silica gel column. The product fractions in the column effluent are identified by paper chromatography, with development in a solvent system of ethyl acetate-acetic acid. Concentration of the column fraction yields the product, m.p. 170°-174° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[CH2:13][CH:12]([C:16]([OH:18])=[O:17])[CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].S(Cl)(Cl)=O.[CH2:23](O)[CH3:24]>>[CH2:23]([O:17][C:16]([CH:12]1[CH2:13][C:14](=[O:15])[N:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=2)[CH2:11]1)=[O:18])[CH3:24]
Reactant: CCO
Reactant: CC(C)c1ccc(N2CC(C(=O)O)CC2=O)cc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C1CC(=O)N(c2ccc(C(C)C)cc2)C1
Temperature: 57.5 °C
Yield: 100 %

Procedure:
A mixture of 1-(4-isopropyl-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid obtained in step 1 (0.6 g, 2.42 mmol), thionyl chloride (0.35 g, 2.90 mmol), and ethanol (10 ml) was heated at 55-60° C. for 2 hours. The mixture was cooled and solvent was removed. The residue was dissolved in ethyl acetate (20 ml). The organic layer was washed with saturated NaHCO3 and saturated brine solution (20 ml). The organic layer was dried over Na2SO4 and evaporated to obtain 1-(4-isopropyl-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid ethyl ester as yellow oil (0.7 g, 100%).