Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:54])[N:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:5])[CH3:3].[C:55]([O:59][C:60]([NH:62][CH2:63][C:64]([NH:66][CH2:67][C:68](O)=[O:69])=[O:65])=[O:61])([CH3:58])([CH3:57])[CH3:56]>ClCCl>[C:55]([O:59][C:60]([NH:62][CH2:63][C:64]([NH:66][CH2:67][C:68]([NH:1][C@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:54])[N:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:5])[CH3:3])=[O:69])=[O:65])=[O:61])([CH3:58])([CH3:57])[CH3:56]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](C)N
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](C)NC(=O)CNC(=O)CNC(=O)OC(C)(C)C
Yield: 76 %

Procedure:
from N-(2-L-alanyl-amino-2-deoxy-β-D-glucopyranosyl)-N-octadecyl-oleamide and N-tert-butyloxycarbonyl-glycyl-glycine. Yield 76%. [α]D =+14.9° (c=1.05, dichloromethane).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)=[O:9])[CH:3]=1.[CH:20]1([NH:26][CH2:27][CH2:28][O:29][CH3:30])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([N:26]([CH2:27][CH2:28][O:29][CH3:30])[C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[NH:16][N:15]=[CH:14]4)=[O:9])[CH:3]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(Nc1ccc2[nH]ncc2c1)c1cc(Cl)ncn1
Reactant: COCCNC1CCCCC1
Product: COCCN(c1cc(C(=O)Nc2ccc3[nH]ncc3c2)ncn1)C1CCCCC1

Procedure:
Following the general method as outlined in Example 20, starting from 6-chloro-pyrimidine-4-carboxylic acid (1H-indazol-5-yl)-amide (Intermediate 16) and cyclohexyl-(2-methoxy-ethyl)-amine (Intermediate 26), the title compound was obtained as a yellow solid.
Reaction SMILES: [F:1][CH:2]([C:7]([O:9]C)=[O:8])[C:3]([O:5]C)=[O:4].C=O.FF.C1N2CN3CN(C2)CN1C3.[O:25]1COCO[CH2:26]1.C(=O)([O-])O.[K+].C(=O)([O-])O.[Na+]>>[OH:25][CH2:26][C:2]([F:1])([C:7]([OH:9])=[O:8])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(F)C(=O)OC
Reactant: C1OCOCO1
Agent: C1N2CN3CN1CN(C2)C3
Agent: C=O
Agent: FF
Product: O=C(O)C(F)(CO)C(=O)O

Procedure:
In the first process step, dimethyl α-fluoromalonate is subjected to hydroxymethylation with formaldehyde. (Dimethyl α-fluoromalonate is a known compound; see Journal of Fluorine Chemistry 25 (1984), 203-212.) The formaldehyde is preferably used in the form of an aqueous solution which has a formaldehyde content of 30 to 40 percent by weight. The formaldehyde is used in an amount of 1 to 10 moles, preferably 1.1 to 3 moles (based on 1 mole of dimethyl α-fluoromalonate). Instead of formaldehyde, it is also possible to use paraformaldehyde, hexamethylenetetramine or 1,3,5-trioxane. It is advantageous to carry out the reaction in the presence of a basic catalyst which is then used in an amount of 2 to 50, preferably 5 to 15, mol % (based on dimethyl α-fluoromalonate). The catalyst used is in particular an alkali metal hydrogencarbonate, for example potassium hydrogencarbonate and sodium hydrogencarbonate. The reaction is carried out at a temperature of 5° to 40° C., preferably of 15° to 30° C. The resulting dimethyl ester of α-hydroxymethyl-α-fluoromalonic acid is then isolated out of the reaction mixture, preferably by salting out or extraction by means of a water-nonmiscible organic solvent. A suitable solvent is in particular an aliphatic chlorohydrocarbon having 1 to 4 carbon atoms, for example dichloromethane, trichloromethane, tetrachloromethane, 1,1-dichloroethane, 1,2-dichloroethane. A combination of salting out and extraction is particularly advantageous; therein the reaction mixture has first added to it a saturated salt solution (ammonium sulfate, sodium chloride), and this mixture is then extracted. By evaporating the solvent, α-hydroxymethyl-α-fluoromalonic acid is obtained as a colorless solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]([NH:7][NH2:8])=O)[CH3:3].Cl.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:16][N:17]=[C:18]=[S:19]>CCO>[CH3:1][N:2]([CH2:4][C:5]1[N:17]([CH3:16])[C:18]([SH:19])=[N:8][N:7]=1)[CH3:3]
Reactant: CN=C=S
Reactant: CN(C)CC(=O)NN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Product: CN(C)Cc1nnc(S)n1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.8 %

Procedure:
N,N-dimethylglycine hydrazide hydrochloride (50 g, 0.263 mol) was stirred for 5 min in EtOH (525 mL). To this suspension was added Cs2CO3 (62.5 g, 0.192 mol) and the mixture was stirred at room temperature for 15 min. Methyl isothiocyanate (19.25 g, 0.263 mol) in EtOH (270 mL) was added to the pot and the reaction mixture was brought to reflux. The reflux condenser was removed and the EtOH was allowed to evaporate under atmospheric pressure (oil bath temperature 105–110° C.) over 3 h to give a purple paste. The reaction was removed from heat and allowed to sit at room temperature overnight (18 h), during which time the paste became a solid. The solid was mixed with CH2Cl2 (1.5 L) and filtered. The organic filtrate was concentrated under reduced pressure to give 31 g of a crude yellow oil. The oil was purified by column chromatography through silica gel, eluting with 4:1 CH2Cl2/MeOH to afford 15.3 g (34.9%) of the desired product.
Reaction SMILES: CN(C)C=O.Br[C:7]1[CH:8]=[C:9]([S:13]([NH2:16])(=[O:15])=[O:14])[CH:10]=[CH:11][CH:12]=1.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19].C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[CH3:17][Si:18]([C:21]#[C:22][C:7]1[CH:8]=[C:9]([S:13]([NH2:16])(=[O:15])=[O:14])[CH:10]=[CH:11][CH:12]=1)([CH3:20])[CH3:19]
Reactant: C#C[Si](C)(C)C
Reactant: NS(=O)(=O)c1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)C#Cc1cccc(S(N)(=O)=O)c1
Yield: 85.3 %

Procedure:
A dimethylformamide (30 mL) solution of 3-bromobenzenesulfonamide (13.7 g), trimethylsilylacetylene (5.18 g), copper(I) iodide (65 mg), bis(triphenylphosphine)palladium(II) dichloride (400 mg), triphenylphosphine (300 mg) and triethylamine (15.0 mL) was stirred at 80° C. for 6 hours. Thereafter, the reaction solution was added to water, and the obtained solution was then extracted with ethyl acetate. The organic layer was successively washed with water and a saturated saline, and was then dried over anhydrous magnesium sulfate, followed by vacuum concentration. The residue was purified by column chromatography (silica gel 60 N, hexane:ethyl acetate=4:1 to 3:1), so as to obtain the title compound (11.4 g) in the form of a light brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([O-])=O.[Cl-].[NH4+]>[Fe].C(O)C.O>[N:15]1([CH2:14][CH2:13][N:8]2[C:9]3[C:5](=[C:4]([NH2:1])[CH:12]=[CH:11][CH:10]=3)[CH:6]=[N:7]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1cccc2c1cnn2CCN1CCCCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cccc2c1cnn2CCN1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 4-Nitro-1-(2-piperidin-1-yl-ethyl)-1H-indazole (mmol), iron powder (mmol), and ammonium chloride (mmol) in a 4:1 solution of ethanol/H2O was heated to reflux for 2 hours, cooled to room temperature and concentrated under reduced pressure. The residue was stirred in triethylamine/ethyl acetate (1/4, 30 mL) for 15 minutes and filtered through a plug of silica gel which was rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated under reduced pressure to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.36 (m, 2 H), 1.44 (m, 4 H), 2.37 (m, 4 H), 2.66 (t, J=6.95 Hz, 2 H), 4.33 (t, J=6.95 Hz, 2 H), 5.71 (m, 2 H), 6.12 (m, 1 H), 6.66 (m, 1 H), 6.99 (m, 1 H), 8.02 (m, 1 H); MS (DCI/NH3) m/z 245 [M+H]+.
Reaction SMILES: BrCC(N1C[CH2:9][N:8]([C:11](=O)[C:12]2[CH:17]=[C:16](C)[CH:15]=[C:14](C)[CH:13]=2)[CH2:7][CH:6]1[C:21]1[CH:26]=[CH:25]C(Cl)=C(Cl)C=1)=O.Cl.[O:30]1CCOCC1.[OH-].[Na+]>C(Cl)Cl.O>[CH2:11]([N:8]1[CH2:7][CH2:6][C:21](=[O:30])[CH:26]([CH3:25])[CH2:9]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C1COCCO1
Reactant: Cc1cc(C)cc(C(=O)N2CCN(C(=O)CBr)C(c3ccc(Cl)c(Cl)c3)C2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC1CN(Cc2ccccc2)CCC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of compound 3 (Ar2 =3,4-dichlorophenyl) (16 g, 28.49 mmol) in CH2Cl2 (142.5 mL) at 0° C. was added 4N HCl-dioxane solution (71.24 mL, 284.9 mmol) through a dropping funnel. The reaction was gradually warmed up to RT and stirred for 4 h. After completion the solvents were evaporated to give a light yellow solid which was dissolved in H2O (400 mL) and brought to pH 10 with 1N NaOH. The product was extracted from basic aqueous solution with CH2Cl2 (200 mL, 4×), dried over MgSO4, filtered and concentrated to give compound 4 (Ar2 =3,4-dichlorophenyl) as a light yellow solid (12.5 g, 27.09 mmol, 95%). FAB MS [M+1]+ 35 Cl 461.1 Compound 4 was the key intermediate which was used to couple with various aromatic acid for the synthesis of many compounds.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:12][S:13](O)(=[O:15])=[O:14]>>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([S:13]([Cl:12])(=[O:15])=[O:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=S(=O)(O)Cl
Reactant: Fc1ccc2ccccc2n1
Product: O=S(=O)(Cl)c1cccc2ccc(F)nc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 2-fluoroquinoline (1.3 g, 8.9 mmol) in chlorosulfonic acid (15 mL) was stirred at −5-0° C. for 15 minutes and at 130° C. overnight. The resulting reaction mixture was poured into an ice-water mixture (300 mL), stirred at room temperature for 20 min, and extracted with EtOAc. The organic layer was then washed with brine, dried over Na2SO4 and solvent was removed. The residue was purified by column chromatography using a gradient elution from 100% PE to PE/EtOAc (100:6) to afford 1.1 g of title compound. 1H NMR (CHLOROFORM-d) δ: 8.56 (d, J=7.5 Hz, 1H), 8.43 (t, J=8.3 Hz, 1H), 8.25 (d, J=8.3 Hz, 1H), 7.72 (t, J=7.8 Hz, 1H), 7.32 (dd, J=8.9, 3.0 Hz, 1H). LC-MS: m/z 246.3 (M+H)+
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[N:12][S:13][CH:14]=2)=[CH:6][CH:5]=1.[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:16]1.C(=O)([O-])[O-].[Na+].[Na+].C(N(C(C)C)CC)(C)C.[I-].[Na+]>C(Cl)Cl.CC(CC(C)C)=O>[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]([N:24]2[CH2:25][CH2:26][N:27]([CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][C:7]([C:10]4[N:11]=[N:12][S:13][CH:14]=4)=[CH:6][CH:5]=3)[CH2:28][CH2:29]2)=[N:16]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: ClCCc1ccc(-c2csnn2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)CC(C)C
Product: c1ccc2c(N3CCN(CCc4ccc(-c5csnn5)cc4)CC3)nsc2c1

Procedure:
To a 100 ml round-bottomed flask equipped with condenser and N2 inlet were added 0.90 g (4 mmol) 4-(4-(2-chloroethyl)phenyl)-1,2,3-thiadiazole, 0.88 g (4 mmol) N-benzisothiazolylpiperazine, 0.84 g (8 mmol) sodium carbonate, 1.39 ml (8 mmol) diisopropylethyl amine, 2 mg sodium iodide, and 40 ml methylisobutyl ketone. The reaction was refluxed 2.5 days, cooled, filtered, and the filtrate evaporated. The residue was chromatographed on silica gel using ethyl acetate/methylene chloride as eluent to afford an oil, which was taken up in methylene chloride and precipitated by addition of ether saturated with HCl. The solid was filtered, washed with ether, dried under nitrogen, washed with acetone, and dried to afford a white solid, m.p. 257°-259° C., 1.02 g (57.4%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=1)O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-]>C(OCC)C>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH3:16])=[CH:13][CH:14]=1
Reactant: CCc1ccc(C(O)c2sccc2Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: CCc1ccc(Cc2sccc2Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
A solution of the above 3-bromo-2-thienyl-4-ethylphenylmethanol (12.4 g) in diethyl ether (10 ml) was added dropwise into a suspension of lithium aluminum hydride (2.6 g) and aluminum chloride (9.0 g) in diethyl ether (35 ml) at 0° C. Subsequently, the mixture was stirred at room temperature overnight, and then poured onto ice. The mixture was extracted with diethyl ether, washed with a saturated aqueous sodium hydrogen carbonate solution, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane) to give 3-bromo-2-(4-ethylphenylmethyl)thiophene (8.77 g) as colorless oil. APCI-Mass m/Z 279/281 (M+H).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([N+:16]([O-])=O)=[C:9]([O:14][CH3:15])[CH:10]=2)[CH2:5]1)[CH3:3].[H][H]>C(OCC)(=O)C.[Pd].CO>[CH3:3][CH:2]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([NH2:16])=[C:9]([O:14][CH3:15])[CH:10]=2)[CH2:5]1)[CH3:1]
Reactant: COc1cc2c(cc1[N+](=O)[O-])CN(C(C)C)CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1N)CN(C(C)C)CC2
Yield: 100 %

Procedure:
2-(1-methylethyl)-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroisoquinoline (0.24 g, 0.94 mmol) was dissolved in ethyl acetate (5 mL), treated with 10% palladium on carbon (50 mg, Aldrich), and then diluted with methanol (10 mL). The mixture was stirred under 60 psi of hydrogen pressure for 16 h in a Fischer-Porter apparatus. The pressure was released, the reaction vessel evacuated, and back-filled with nitrogen twice. The mixture was filtered through celite and the filtrate was concentrated to provide 2-(1-methylethyl)-6-(methyloxy)-1,2,3,4-tetrahydro-7-isoquinolinamine (206 mg, 0.94 mmol, 100%). 1H NMR (400 MHz, CDCl3) δ ppm 1.13 (d, J=6.6 Hz, 6 H), 2.71-2.81 (m, 4 H), 2.87 (tt, J=6.5, 6.5 Hz, 1 H), 3.59 (s, 2 H), 3.63 (bs, 2 H), 3.81 (s, 3 H), 6.40 (s, 1 H), 6.50 (s, 1 H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C@H:10]([OH:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Cl:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=1.[H-].[Na+].C(=O)([O-])O.[Na+]>O1CCOCC1.C(OCC)(=O)C>[Cl:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16]([O:12][C@@H:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH3:11])[N:15]=1
Reactant: Clc1cncc(Cl)n1
Reactant: C[C@@H](O)c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@@H](Oc1cncc(Cl)n1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 89.4 %

Procedure:
To a solution of (R)-1-(3-nitrophenyl)ethanol (167 mg, 1 mmol) and 2,6-dichloropyrazine (164 mg, 1.1 mmol) in dioxane was added sodium hydride (88 mg, 60% oil dispersion, 2.2 mmol) in one portion and the mixture was heated at reflux for 4 hours. After this time the mixture was allowed to cool to room temperature and was poured into saturated aqueous sodium hydrogen carbonate (25 mL) and ethyl acetate (25 mL). The two phases were separated and the aqueous phase was extracted with ethyl acetate (25 mL). The combined organic phases were washed with brine (25 mL), dried (Na2SO4) and concentrated under reduced pressure to give (R)-2-chloro-6-(1-(3-nitrophenyl)ethoxy)pyrazine (250 mg, 89%) as an orange oil.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH:19][C:20]12[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH:23]3[NH:30][CH3:31])[CH2:21]1)[CH2:27]2.CCN(C(C)C)C(C)C>S(Cl)(Cl)=O.C(Cl)Cl.CN(C=O)C>[OH:19][C:20]12[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH:23]3[N:30]([CH3:31])[C:13](=[O:15])[C:12]3[CH:16]=[CH:17][CH:18]=[C:10]([O:9][CH2:1][CH2:2][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH:11]=3)[CH2:21]1)[CH2:27]2
Reactant: CNC1C2CC3CC1CC(O)(C3)C2
Reactant: O=C(O)c1cccc(OCCc2ccccc2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C(=O)c1cccc(OCCc2ccccc2)c1)C1C2CC3CC1CC(O)(C3)C2
Temperature: 20 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
3-Phenethyloxy-benzoic acid (4.2 g, 17 mmol) was dissolved in thionylchloride (30 ml), and the mixture was stirred at 20° C. overnight. The solvent was removed, and 108 mg (0.41 mmol) of this acid chloride was added to a solution of 1-hydroxy-4-methylaminoadamantane (75 mg, 0.41 mmol) and DIPEA (0.14 ml, 0.83 mmol) in DCM/DMF (1:1, 4 ml). After stirring the reaction mixture at 20° C. overnight, the solution was concentrated in vacuo and purified by preparative LC-MS to give 95 mg of the title compound as a mixture of two isomers. 1H NMR (400 MHz, CDCl3): δ 7.21-7.36 (m, 6H), 6.89-7.00 (m, 3H), 4.10-4.23 (m, 3H), 3.05-3.16 (m, 5H), 2.54 (d, 2H), 2.24 (d, 1H), 1.49-2.04 (m, 11H).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH:5]=[C:4]([CH3:9])[O:3]1.CC(O)C>CC(C)=O>[C:6]([O:7][CH:2]([CH3:10])[CH3:1])(=[O:8])[CH2:5][C:4]([CH3:9])=[O:3]
Reactant: CC1=CC(=O)OC(C)(C)O1
Solvent: CC(C)O
Solvent: CC(C)=O
Product: CC(=O)CC(=O)OC(C)C
Yield: 90.2 %

Procedure:
A solution of 2,2,6-trimethyl-4H-1,3-dioxin-4-one (53)70 (74 g, 0.5 mol) and 2-propanol (30 g, 0.5 mol) was heated at 135° C. for 20 h. The acetone formed during the reaction was removed with a rotary evaporator. The residue was distilled to provide 65 g (0.451 mol, 90%) of 54 as a clear, colorless liquid: bp 185°-187° C.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])[CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H].CCCCCC>O1CCCC1.CO.C(OCC)C.[C].[Pd]>[NH2:1][C:4]1[CH:24]=[CH:23][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])[CH:10]=2)=[CH:6][CH:5]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1)N1CCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOCC
Solvent: CCCCCC
Product: Nc1ccc(Oc2ccnc(NC(=O)N3CCCC3)c2)cc1
Reaction time: 8 h
Yield: 90.8 %

Procedure:
Pyrrolidine-1-carboxylic acid [4-(4nitrophenoxy)pyridin-2-yl]amide (636 mg) was dissolved in tetrahydrofuran (18 ml)-methanol (18 ml), and then 10% palladium carbon (412 mg) was added thereto under a nitrogen atmosphere, followed by replacing with hydrogen inside the system and stirring overnight. After replacing with nitrogen inside the system, the reaction mixture was filtered to remove the catalyst, which was washed with methanol. The filtrate was concentrated under a reduced pressure to give a residue, which was suspended in diethyl ether (10 ml)-hexane (10 ml). The solid was filtered off, and dried in vacuum to provide the titled compound (524.9 mg, 90.7%).
Reaction SMILES: [Mg].[CH2:2]([C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)[CH2:3][CH2:4][CH2:5][CH3:6].[C:20](=[S:22])=[S:21].Cl>C1COCC1>[CH2:2]([C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][C:16]([C:20]([SH:22])=[S:21])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(Br)cc2)CC1
Reactant: S=C=S
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](c2ccc(C(=S)S)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension prepared by suspending 0.95 g (39 mmol) of magnesium in 200 ml of THF was added dropwise a solution prepared by dissolving 9.28 g (30 mmol) of 4-(trans-4-n-pentylcyclohexyl)bromobenzene in 80 ml of THF, at room temperature while being stirred in 1 hour, and then heated to reflux for 2 hours to prepare a Grignard reagent. To this solution was added dropwise 5.7 g (75 mmol) of carbon disulfide at room temperature in 30 min and stirred as it was overnight. To this reaction solution was added 150 ml of 1M hydrochloric acid to terminate the reaction and extracted with 350 ml of toluene. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under a reduced pressure, and the residue was recrystallized from heptane to obtain 4.74 g of 4-(trans-4-n-pentylcyclohexyl)phenyldithiocarboxylic acid (yield 51.5%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[SH:10].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[C:16](O)=O>C(Cl)Cl>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:16]2[S:10][C:3]3[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=3[N:1]=2)[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23]
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: COc1ccc(N)c(S)c1
Solvent: ClCCl
Product: COc1ccc2nc(-c3ccc([N+](=O)[O-])c(OC)c3)sc2c1
Temperature: 150 °C
Yield: 32.4 %

Procedure:
A thoroughly mixed paste of 2-amino-5-methoxybenzenethiol (2.0 g, 12.88 mmol) and 3-methoxy-4-nitrobenzoic acid (2.54 g, 12.88 mmol) in trimethylsilylpolyphosphate (10 ml) was stirred and heated at 150° C. under an atmosphere of argon for 2 h. On cooling to room temperature, the reaction mixture was suspended in DCM (300 ml) and adsorbed onto flash silica and initially purified using a plug of flash silica eluting with DCM, then DCM/EtOAc (6:1). Further purification of the collected fractions by flash chromatography (20:1 DCM/Hexane) gave the title compound (1.32 g, 32%) as a yellow solid.
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[CH3:38][C:39]1[C:47]([C:48](O)=[O:49])=[CH:46][CH:45]=[C:44]2[C:40]=1[CH:41]=[N:42][NH:43]2>CN(C)C=O.C(OCC)(=O)C>[CH3:38][C:39]1[C:47]([C:48]([NH:8][CH:5]2[CH2:6][CH2:7][O:2][CH2:3][CH2:4]2)=[O:49])=[CH:46][CH:45]=[C:44]2[C:40]=1[CH:41]=[N:42][NH:43]2
Reactant: NC1CCOCC1
Reactant: Cc1c(C(=O)O)ccc2[nH]ncc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)NC2CCOCC2)ccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 12.4 %

Procedure:
Tetrahydro-2H-pyran-4-ylamine monohydrochloride (228 mg, 1.66 mmol), triethylamine (0.5 ml, 3.59 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide monohydrochloride (367 mg, 1.91 mmol) and hydroxybenzotriazole (190 mg, 1.41 mmol) were added to a solution of 4-methyl-1H-indazole-5-carboxylic acid (225 mg, 1.28 mmol) in N,N-dimethylformamide (5.5 ml), and the resulting mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous sodium hydrogencarbonate solution. A small amount of the insoluble material was collected by filtration and then dried to obtain 4-methyl-N-tetrahydro-2H-pyran-4-yl-1H-indazole-5-carboxamide (41 mg). The filtrate was extracted with ethyl acetate and chloroform, and the combined organic layer was dehydrated over magnesium sulfate and then filtered. The filtrate was concentrated and the resulting residue was suspended in chloroform. The resulting suspension was filtered and the precipitate was dried to obtain 4-methyl-N-tetrahydro-2H-pyran-4-yl-1H-indazole-5-carboxamide (134 mg, 52.7%).