Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20]>C(O)C.O1CCOCC1>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([S:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[C:12]([N+:19]([O-:21])=[O:20])[CH:13]=1
Reactant: Sc1ccncc1
Reactant: COc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: COc1ccc(Sc2ccncc2)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 21.5 %

Procedure:
1.11 g of 4-mercaptopyridine was dissolved in 5 ml of ethanol, and 52.8 mg of sodium hydride was added little by little. The mixture was stirred for 5 minutes, and then a solution of 1.87 g of 4-chloro-3-nitroanisole in 5 ml of dioxane was added. The mixture was heated under reflux at 100° C. for 15 hours. The solvent was evaporated, and 2N hydrochloric acid was added to the residue. The residue was washed with ether, made alkaline by adding an aqueous solution of sodium hydroxide, and extracted with methylene chloride. The extract was washed with a saturated aqueous solution of sodium chloride. The solvent was evaporated. The resulting residue was subjected to silica gel column chromatography. The column was eluted with a 5:3 mixture of hexane and acetone, and the eluate was recrystallized from acetone-hexane to give 562 mg (yield 21.4%) of 4-(4-methoxy-2-nitrophenyl)thiopyridine as orange needles having a melting point of 57° to 59° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N-:10]=[N+:11]=[N-:12].[Na+].C([Sn](Cl)(CCCC)CCCC)CCC.Cl>C1(C)C(C)=CC=CC=1.O1CCCC1>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]1[NH:12][N:11]=[N:10][N:5]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccccc1Br
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1C
Product: Brc1ccccc1-c1nnn[nH]1
Reaction time: 2 h
Yield: 76 %

Procedure:
A 64 g (350 mmol) sample of 2-bromobenzonitrile (Aldrich) was dissolved in 650 mL of xylene and treated with 22.75 g (350 mmol) of sodium azide and 95 mL (350 mmol) of tributyltin chloride at reflux for 48 h. The reaction was filtered; the filtrate was treated with 50 mL of anhydrous tetrahydrofuran (THF) and 20 g (550 mmol) of hydrogen chloride. The reaction was stirred for 2 h; filtration gave 59.6 g (76%) of 5-(2-bromophenyl)-1H-tetrazole: mp 178°-180° C.; NMR (DMSO-d6) δ7.50-7.64 (m, 2H), 7.67-7.74 (m, 1H), 7.83-7.91 (m, 1H). A 41.8 g (187 mmol) sample of this material was dissolved in 650 mL of methylene chloride and treated with 55.5 g (193 mmol) of triphenylmethyl chloride and 30 mL (220 mmol) of anhydrous triethylamine. The reaction was stirred overnight at reflux, cooled to ambient temperature, washed with water, dried (MgSO4), and concentrated in vacuo. Recrystallization from toluene/hexane gave 80.7 g (92%) of N-triphenylmethyl-5-(2-bromophenyl)-1H-tetrazole: mp 160°-162° C.; NMR (CDCl3) δ7.14-7.21 (m, 6H), 7.26-7.45 (m, 11H), 7.70 (dd, J=8 and 1.5 Hz, 1H), 7.89 (dd, J=7.5 and 2 Hz, 1H). A 34.05 g (73.0 mmol) sample of this material was dissolved in 1700 mL of THF under a nitrogen atmosphere and treated with 73 mmol of n-butyllithium in hexane. The reaction was allowed to stir for 17 min and then was treated with 24.9 mL (220 mmol) of trimethyl borate. The reaction was allowed to come to ambient temperature overnight while stirring, quenched with 10 mL of methanol, and concentrated in vacuo. The residue was dissolved in 1M NaOH and extracted with toluene to remove any unreacted starting material. The pH was adjusted to 6 with 6M HCl and the product extracted with toluene and dried (MgSO4). Hexane was added and the solution was placed in the freezer overnight. Filtration provided 31.3 g (99%) of 2-(N-triphenylmethyltetrazol-5-yl)phenylboronic acid: NMR (CDCl3) δ7.13-7.21 (m, 7H), 7.33-7.42 (m, 8H), 7.49-7.55 (m, 2H), 8.15-8.19 (m, 1H), 8.21-8.26 (m, 1H).
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=[CH:10][C:11]=2[OH:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:28]([O:30][CH3:31])=[O:29]>ClCCl>[CH:1]1([C:6]2[CH:7]=[C:8]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=[CH:10][C:11]=2[O:12][C:28]([O:30][CH3:31])=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)Cl
Reactant: CCOC(=O)CCc1ccc(O)c(C2CCCC2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCc1ccc(OC(=O)OC)c(C2CCCC2)c1
Reaction time: 1 h
Yield: 87.8 %

Procedure:
To a solution of ethyl 3-(3-cyclopentyl-4-hydroxy-phenyl)propanoate (857 mg, 3.27 mmol) and triethylamine (911 μL, 6.53 mmol) in dichloromethane (5 mL) under a N2 atmosphere at 0° C. was added methyl chloroformate (463 mg, 377 μL, 4.90 mmol) dropwise. After 1 h, the reaction mixture was partitioned between dichloromethane/water, separated and the aqueous layer was extracted once more with dichloromethane. The combined organics were dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (0-30% ethyl acetate/hexanes) provided ethyl 3-(3-cyclopentyl-4-methoxycarbonyloxy-phenyl)propanoate (920 mg, 88% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 7.20 (d, J=1.7 Hz, 1H), 7.09-7.03 (m, 2H), 4.04 (q, J=7.1 Hz, 2H), 3.82 (s, 3H), 3.03-2.96 (m, 1H), 2.83 (t, J=7.6 Hz, 2H), 2.61 (t, J=7.6 Hz, 2H), 1.93-1.86 (m, 2H), 1.77-1.72 (m, 2H), 1.66-1.58 (m, 2H), 1.54-1.47 (m, 2H), 1.15 (t, J=7.1 Hz, 3H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26]([OH:28])=O)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:30]=[C:31]([NH2:36])[C:32]([CH3:35])([CH3:34])[CH3:33]>>[C:32]([C:31]1[N:36]=[C:26]([CH:12]2[CH2:13][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:20][CH:21]=3)[CH2:15][N:10]([C:8]([N:5]3[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]3)=[O:9])[CH2:11]2)[O:28][N:30]=1)([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)C(N)=NO
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Product: CC(C)(C)c1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCC(O)CC3)C2)n1

Procedure:
100 mg (0.250 mmol) of 1-[(4-hydroxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 99A) and 31.9 mg (0.275 mmol) of N′-hydroxy-2,2-dimethylpropanimidamide were reacted according to the General Method 1. Yield: 55.6 mg (46% of theory).
Reaction SMILES: C(BC(C(C)C)C)(C(C)C)C.[CH2:12]([C:15]1([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[O:20][C:19](=[O:21])[N:18]([N:22]([CH3:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][CH2:16]1)[CH:13]=[CH2:14].C1C[O:40]CC1>>[F:36][C:33]1[CH:32]=[CH:31][C:30]([C:15]2([CH2:12][CH2:13][CH2:14][OH:40])[O:20][C:19](=[O:21])[N:18]([N:22]([CH3:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:17][CH2:16]2)=[CH:35][CH:34]=1
Reactant: C=CCC1(c2ccc(F)cc2)CCN(N(C)c2ccccc2)C(=O)O1
Reactant: C1CCOC1
Agent: CC(C)C(C)BC(C)C(C)C
Product: CN(c1ccccc1)N1CCC(CCCO)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
At 0° C., 2M 2-methyl-2-butene in THF (15 mL, 30 mmol) was added to BH3.DMS (1.5 mL, 15 mmol, 10M) in THF (3 mL) and stirred for 1 h to afford a 0.83 M THF solution of disiamylborane. In a separate flask, disiamylborane (0.1 mL, 0.08 mmol) was added to 6-allyl-6-(4-fluorophenyl)-3-(methyl(phenyl)amino)-1,3-oxazinan-2-one (6 mg, 0.018 mmol) in THF (1 mL) at 0° C. The reaction was warmed to rt overnight. The reaction was cooled to 0° C. and quenched with H2O (1 mL) and stirred for 15 min at rt. NaBO3 (22 mg, 0.22 mmol) was added and the reaction was stirred for 2 h. The solvent was evaporated and the crude material purified by prep HPLC to afford 6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-(methyl(phenyl)amino)-1,3-oxazinan-2-one (1.16 mg). LC/MS Method 1 tR=1.51 min m/z=359 (M+1).
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[N:21]=[C:20]([S:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=3[F:39])[N:19]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:39][C:33]1[C:34]([F:38])=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][S:30][C:20]1[N:19]=[C:18]([NH:17][S:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)(=[O:15])=[O:16])[CH:23]=[C:22]([O:24][CH2:25][C:26]([F:29])([F:27])[F:28])[N:21]=1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)Nc2cc(OCC(F)(F)F)nc(SCc3cccc(F)c3F)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1cc(OCC(F)(F)F)nc(SCc2cccc(F)c2F)n1)N1CCNCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-[[[2-[[(2,3-difluorophenyl)methyl]thio]-6-(2,2,2-trifluoroethoxy)-4-pyrimidinyl]amino]sulfonyl]-1-piperazinecarboxylic acid-1,1-dimethylethyl ester (the product from step i) (0.21 g) in DCM (2 mL) was added trifluoroacetic acid (2 mL) and the reaction mixture was stirred at ambient temperature for 4 h. The reaction mixture was evaporated, the residue was azeotroped with Et2O (×2) and then purified by reverse phase HPLC eluting with acetonitrile/aq. 0.2% trifluoroacetic acid mixtures to give title compound as a white solid.
Reaction SMILES: [I-:1].[CH2:2]([P+:6]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:7][CH2:8][OH:9])[CH2:3][CH2:4][CH3:5].COC1C=CC(O)=CC=1.[C:27](Cl)(=[O:31])[C:28]([CH3:30])=[CH2:29].II>C(#N)C>[I-:1].[CH2:10]([P+:6]([CH2:2][CH2:3][CH2:4][CH3:5])([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:7][CH2:8][O:9][C:27](=[O:31])[C:28]([CH3:30])=[CH2:29])[CH2:11][CH2:12][CH3:13]
Reactant: CCCC[P+](CCO)(CCCC)CCCC
Reactant: C=C(C)C(=O)Cl
Agent: COc1ccc(O)cc1
Agent: II
Agent: [I-]
Solvent: CC#N
Product: C=C(C)C(=O)OCC[P+](CCCC)(CCCC)CCCC
Reaction time: 2 h

Procedure:
Into a 1 L-four-necked flask equipped with a stirrer, a thermometer and a distillation line, was added the obtained tri-n-butyl(2-hydroxyethyl)phosphonium iodide dissolved in 500 ml of acetonitrile. The solution was heated under a normal pressure with stirring and about 200 ml of acetonitrile was distilled. A condenser having a calcium chloride tube was installed, 1.5 g of hydroquinone monomethyl ether was added as a polymerization inhibitor, and 76.4 g (0.731 mol) of methacryloyl chloride was added thereto dropwise at 50° C. over 2 hours through a dropping funnel, then the solution was maturated for 3 hours at the same temperature. Upon dropping, yellow coloration that was believed to have been caused by isolation of iodine occurred.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[F:11][C:12]1[CH:13]=[C:14]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][C:19]=2[CH:28]([NH2:30])[CH3:29])[CH:15]=[CH:16][CH:17]=1.C(N(CC)C(C)C)(C)C>C(O)C>[F:11][C:12]1[CH:13]=[C:14]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][C:19]=2[CH:28]([NH:30][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:29])[CH:15]=[CH:16][CH:17]=1
Reactant: CC(N)c1ccc2ccccc2c1-c1cccc(F)c1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(Nc1ncnc2[nH]cnc12)c1ccc2ccccc2c1-c1cccc(F)c1

Procedure:
A mixture of 6-bromo-9H-purine (0.02696 g, 0.1355 mmol), 1-[1-(3-fluorophenyl)-2-naphthyl]ethanamine (0.030 g, 0.11 mmol), and N,N-diisopropylethylamine (0.024 mL, 0.14 mmol) in ethanol (0.9 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resultant residue was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/minute) to give the product as a TFA salt. LCMS calculated for C23H19FN5(M+H)+: m/z=384.2; found: 384.3. 1H NMR (DMSO-d6, 400 MHz) δ 8.92 (1H, br s), 8.30 (2H, m), 7.97 (1H, d, J=9.2 Hz), 7.90 (1H, d, J=7.6 Hz), 7.79 (1H, m), 7.57 (1H, m), 7.47 (1H, m), 7.40 (2H, m), 7.31 (1H, m), 7.19 (2H, m), 5.23 (1H, m), 1.49 (3H, m) ppm. 19F NMR (DMSO-d6, 376.28 MHz) δ −74.6 ppm.
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Cl-:11]>N1C=CC=CC=1>[C:1]([Cl:11])(=[O:10])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: O=C(O)c1ccccc1O
Reactant: [Cl-]
Solvent: c1ccncc1
Product: O=C(Cl)c1ccccc1O

Procedure:
In the first step, salicylic acid is mixed with thionyl (or oxalyl) halide, most preferably chloride, (molar ratio in the general range of from 1:1 to 2:1) in an anhydrous, typically non-polar, solvent, in the presence of pyridine catalyst, at a temperature of from 20 to 45° C. for 0.5-2 hours. At the end of this reaction, salicylic acid chloride id obtained. Optionally, the solvent is distilled at least partially.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:10][CH2:11][CH2:12][C:13](Cl)=[O:14].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:10][CH2:11][CH2:12][C:13]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[CH2:1][CH2:2][CH2:3]2)=[O:14]
Reactant: O=C(Cl)CCCl
Reactant: c1ccc2c(c1)CCC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CCCl)c1ccc2c(c1)CCC2
Temperature: 25 °C
Yield: 53.2 %

Procedure:
To a stirred solution of indane (300 grams) and 3-chloropropionoyl chloride (323 grams) in methylene chloride (2 L) at 0° C. was added aluminum chloride (376 grams) over a period of 3 hours. Once the addition was complete, the cooling bath was removed and the mixture was warmed to room temperature and stirred until hydrogen chloride evolution ceased. The reaction was quenched by pouring onto a mixture of 3.5 kg of ice and 700 mL of concentrated hydrochloric acid. The layers were separated, and the aqueous phase was extracted with methylene chloride. The combined methylene chloride layers were washed with water, saturated sodium bicarbonate solution and brine. The organic phase was dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was recrystallized from hexane to afford 282 grams of a yellow solid, m.p. 63.5-65.1° C.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[N+:9]([C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1)([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([O:18][C:14]2[CH:13]=[C:12]([N+:9]([O-:11])=[O:10])[CH:17]=[CH:16][CH:15]=2)[CH:7]=1
Reactant: Cc1ccnc(F)c1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccnc(Oc2cccc([N+](=O)[O-])c2)c1
Temperature: 130 °C
Reaction time: 24 h
Yield: 40.7 %

Procedure:
A suspension of 2-fluoro-4-methylpyridine (1.11 g), 3-nitrophenol (1.67 g) and potassium carbonate (1.80 g) in N,N-dimethylformamide (10 ml) was stirred at 130° C. for 24 hours. After cooling, the mixture was poured into water and stirred for 30 minutes. The precipitate was collected by filtration and dried to give 3-(4-methylpyridin-2-yloxy)-nitrobenzene (935 mg).
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]([F:16])([F:15])[F:14])=[N:11][NH:10][C:9](=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:20])=O.C(=O)([O-])O.[Na+].ClCCl>C(#N)C>[Cl:20][C:9]1[N:10]=[N:11][C:12]([C:13]([F:16])([F:15])[F:14])=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(-c2ccccc2)c(C(F)(F)F)n[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: FC(F)(F)c1nnc(Cl)cc1-c1ccccc1
Yield: 12768.7 %

Procedure:
To a stirred solution of 5-phenyl-6-trifluoromethyl-2H-pyridazine-3-one (D2) (20.66 g, 0.086 mol) in acetonitrile (150 ml) was added phosphorous oxychloride (20 ml, 0.215 mmol) and the reaction heated at reflux for 1 h. After this period, the reaction mixture was poured into a saturated solution of sodium hydrogen carbonate, ice and dichloromethane. Further solid sodium hydrogen carbonate was then added until gas evolution had ceased. The organic layer was then separated, dried (Na2SO4) and the solvents evaporated in vacuo. The crude residue was then filtered through silica gel, eluting with dichloromethane, in order to remove the minor isomer. After evaporation of the solvent, the crude product was then re-purified by column chromatography (silica; 0-25% ethyl acetate/heptane) to yield D3 (7.1 g, 32%). C11H6ClF3N2 requires 258; Found 259 (MH+).
Reaction SMILES: [C:1]1([N:7]2C(=O)C3=CNC4C=CC=CC=4C3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([F:33])=[C:29]([F:32])[CH:30]=2)[N:25]=[CH:24][C:23]=1[C:34]([O:36]CC)=O.C1(NN)C=CC=CC=1>>[F:33][C:28]1[C:29]([F:32])=[CH:30][C:31]2[C:22]3[C:23]([C:34](=[O:36])[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)=[CH:24][NH:25][C:26]=2[CH:27]=1
Reactant: CCOC(=O)c1cnc2cc(F)c(F)cc2c1Cl
Reactant: O=c1c2c[nH]c3ccccc3c-2nn1-c1ccccc1
Solvent: NNc1ccccc1
Product: O=c1c2c[nH]c3cc(F)c(F)cc3c-2nn1-c1ccccc1

Procedure:
The title compound was prepared following the procedure described in Step 3 for the synthesis of 4a, using 3c and phenyl hydrazine. 1H NMR (DMSO-d6) δ (ppm):7.18 (1H, t, J=7.82 Hz), 7.43 (2H, dd, J=8.30, 7.33 Hz), 7.75 (1H, dd, J=11.22, 7.32 Hz), 8.18, 3H, m), 8.90 (1H, s). m/z 298.2 (MH+).
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].[CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[CH2:6]>>[C:1]([O:4][CH2:6][CH2:5][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)(=[S:3])[CH3:2]
Reactant: CC(O)=S
Reactant: C=Cc1ccccn1
Product: CC(=S)OCCc1ccccn1
Temperature: 5 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
Into a 100-mL four-necked flask equipped with a nitrogen gas introduction tube, thermometer, Dimroth condenser, and dropping funnel was introduced 15.22 g (0.20 mol) of thioacetic acid (manufactured by Tokyo Kasei Kogyo Co., Ltd.). The contents began to be stirred, and nitrogen was introduced. Thereafter, the contents were cooled to 5° C. or lower with an ice bath, and 21.03 g (0.20 mol) of 2-vinylpyridine was added dropwise thereto through the dropping funnel over 1 hour. After completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for further 1 hour and reacted. After completion of the reaction, the liquid reaction mixture was subjected to vacuum distillation under the conditions of a bath temperature of 120° C. and a pressure of 0.8 kPa to obtain 27.8 g of 2-pyridylethyl thioacetate. As a result of analysis by gas chromatography, the 2-pyridylethyl thioacetate was found to have a purity of 96.8% and the yield thereof was found to be 78.2%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=O.C[N:20]1[C:24](=[O:25])[CH2:23][S:22][C:21]1=[S:26].NCCC(O)=O>C(O)(=O)C>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1/[CH:13]=[C:23]1/[C:24](=[O:25])[NH:20][C:21](=[S:26])[S:22]/1
Reactant: CN1C(=O)CSC1=S
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C=O)c1Cl
Agent: NCCC(=O)O
Solvent: CC(=O)O
Product: Cc1ccc(Cl)c(Nc2ccccc2/C=C2\SC(=S)NC2=O)c1Cl
Temperature: 25 °C
Yield: 65.9 %

Procedure:
To a room temperature solution of 2-[(2,6-dichloro-3-methylphenyl)amino]benzaldehyde (276 mg, 0.99 mmols) and 3-methylrhodanine (166 mg, 1.13 mmols) in 15 mL of acetic acid is added β-alanine (102 mg, 1.14 mmols). The solution is heated at reflux for 3.5 h. The solution is cooled to room temperature and the resulting precipitate is collected by filtration to provide 258 mg (64%) of (Z)-5-[[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]methylene]-2-thioxo-4-thiazolidinone as a bright orange solid; mp=175°-176° C. Calc'd for C18H14Cl2N2OS2:
Reaction SMILES: O1CCCC1.[CH3:6][S:7]([NH:10][C:11]1[CH:23]=[CH:22][C:14]2[O:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20][O:21][C:13]=2[CH:12]=1)(=[O:9])=[O:8].[CH3:24][S:25]([NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)(=[O:27])=[O:26]>N1C=CC=CC=1>[CH3:6][S:7]([NH:10][C:11]1[CH:23]=[CH:22][C:14]2[O:15][CH2:16][CH2:17][N:18]([C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:29]([NH:28][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:30][CH:31]=3)[CH2:19][CH2:20][O:21][C:13]=2[CH:12]=1)(=[O:8])=[O:9]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)OCCNCCO2
Reactant: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc(C(=O)N2CCOc3ccc(NS(C)(=O)=O)cc3OCC2)cc1

Procedure:
To tetrahydrofuran add 9-[(methylsulfonyl)amino]-3,4,5,6-tetrahydro-2H-1,7,4-benzodioxazonine, pyridine, and 4-[(methylsulfonyl)amino]benzoyl chloride. Monitor the progress of the reaction by thin-layer chromatography. Upon completion, remove the solvent in vacuo. Partition the residue between aqueous NaHCO3 and EtOAc. Separate the layers and wash the organic layer with 1M aqueous HCl. Separate and dry (Na2SO4) the organic layer. Remove the solvent in vacuo to obtain the title compound.
Reaction SMILES: [C:1](=[O:12])([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])OC(C)(C)C.[OH:13][CH:14]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]1.CC(C)(N)CN>O.C(O)(C)(C)C>[C:8]([O:7][C:1]([N:16]1[CH2:17][CH2:18][CH2:19][CH:14]([OH:13])[CH2:15]1)=[O:12])([CH3:9])([CH3:10])[CH3:11]
Reactant: OC1CCCNC1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CC(C)(N)CN
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCCC(O)C1
Reaction time: 16 h

Procedure:
Di-t-butyl carbonate (11.9 g.) was added to a solution of 3-hydroxypiperidine (5.0 g.) in water (10 ml.) and t-butanol (5 ml.) at ambient temperature, and the mixture was stirred for 16 hr. at ambient temperature. 1,1-Dimethylethylenediamine (1.5 ml.) was added and the mixture was stirred at ambient temperature for 1 hr. The solution was poured into water (150 ml.) and extracted with diethyl ether (3×50 ml.). The diethyl ether extract was washed successively with 1 M-hydrochloric acid (50 ml.), saturated sodium carbonate solution (50 ml.) and brine (50 ml.), and then dried (MgSO4). The solvent was evaporated to give 1-t-butoxycarbonyl-3-hydroxypiperidine, which was used without further purification.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:4].O.[OH-].[Li+]>C1COCC1>[CH2:14]([O:13][C:11]([N:6]1[CH2:7][CH2:8][CH2:9][CH2:10][C@H:5]1[C:3]([OH:4])=[O:2])=[O:12])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)[C@@H]1CCCCN1C(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H]1CCCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirred solution of (S)-1-(benzyloxy-carbonyl)-2-piperidinecarboxylic acid methyl ester (2.00 g, 7.21 mmol) in THF (20 ml) at room temperature was treated with water (10 ml). Lithium hydroxide (190 mg, 7.93 mmol) was added and the resulting mixture stirred at room temperature for 3 hr. An additional quantity of lithium hydroxide (40 mg, 1.67 mmol) was added and the resulting mixture was stirred for 2 hr prior to the removal of the organic solvent. The resulting solution was washed with diethyl ether and the remaining aqueous layer was made acidic with 2 N HCl prior to a second extraction step with ethyl acetate. The organic layer was then recovered, dried (Na2SO4), filtered and concentrated to reveal a colorless oil (1.9927 g, 105%) which crystallized upon standing: 1H NMR (400 MHz, CDCl3) δ 1.30-1.88 (5H, m), 2.22-2.41 (1H, m), 3.00-3.21 (1H, m), 4.08-4.25 (1H, m), 4.91-5.30 (3H, m), 7.27-7.48 (5H, m).