Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:16][NH:17][CH2:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[CH2:3][O:4][CH2:5][CH:6]([OH:15])[CH2:7][NH:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13].C(N([CH2:29][CH3:30])CC)C.[C:31](Cl)(=[O:43])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>C(Cl)Cl>[O:43]=[C:31]([N:8]([CH2:9][CH2:10][CH2:11][N:12]([CH3:13])[CH3:14])[CH2:7][CH:6]([OH:15])[CH2:5][O:4][CH2:3][CH:2]([OH:1])[CH2:16][N:17]([C:31](=[O:43])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:29][CH3:30])[CH2:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCN(CC)CC
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CN(C)CCCNCC(O)COCC(O)CNCCCN(C)C
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)N(CCCN(C)C)CC(O)COCC(O)CN(CCCN(C)C)C(=O)CCCCCCCCCCC
Yield: 32.9 %

Procedure:
Bis(2-hydroxy-8-methyl-4,8-diazanonyl)ether (10 g, 0.030 mol) synthesized using a known method, triethylamine (6.1 g, 0.060 mol), and methylene chloride (200 ml) were placed in a 500 ml four-necked round flask, and the mixture was cooled on ice. Dodecanoylchloride (13 g, 0.060 mol) was added dropwise over 1 hour to the flask while the contents of the flask were stirred under nitrogen. The mixture was stirred for 24 more hours at room temperature. The solid which precipitated was removed by filtration, after which water was added for washing. Methylene chloride was removed from the organic phase under reduced pressure. The residue was purified by column chromatography (packed with Kieselgel 60 (product of Merck), eluent: chloroform/methanol=7:1 (v/v)) to obtain 6.9 g of bis(4-(1-oxododecyl)-2-hydroxy-8-methyl-4,8-diazanonyl)ether. Yield: 33 wt %.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.[NH2:44][CH2:45][C:46]1[CH:51]=[CH:50][C:49]([N:52]2[C:56]([NH:57][C:58]([NH:60][C:61]3[CH:66]=[CH:65][C:64]([O:67][C:68]4[CH:73]=[CH:72][N:71]=[CH:70][CH:69]=4)=[CH:63][CH:62]=3)=[O:59])=[CH:55][C:54]([C:74]([CH3:77])([CH3:76])[CH3:75])=[N:53]2)=[CH:48][CH:47]=1>C1COCC1.C(#N)C>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][C:10](=[O:12])[NH:44][CH2:45][C:46]1[CH:51]=[CH:50][C:49]([N:52]2[C:56]([NH:57][C:58]([NH:60][C:61]3[CH:66]=[CH:65][C:64]([O:67][C:68]4[CH:69]=[CH:70][N:71]=[CH:72][CH:73]=4)=[CH:63][CH:62]=3)=[O:59])=[CH:55][C:54]([C:74]([CH3:77])([CH3:76])[CH3:75])=[N:53]2)=[CH:48][CH:47]=1)([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccncc3)cc2)n(-c2ccc(CN)cc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(=O)NCc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccncc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.7 %

Procedure:
To a solution of N-Boc-glycine (260 mg, 1.48 mmol), EDCl (283 mg, 148 mmol) and HOBT (200 mg, 1.48 mmol) in THF/acetonitrile (50:50, 5 mL) was added N,N-diisopropylethylamine (380 mg, 2.96 mmol), and the resulting reaction mixture was stirred at room temperature for 1 h. Then, 1-[2-(4-aminomethyl-phenyl)-5-tert-butyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)phenyl]urea (450 mg, 0.99 mmol) was added to the solution and the reaction mixture was stirred at 50° C. for 18 h. The reaction mixture was cooled to room temperature, concentrated at reduced pressure, and the residue was dissolved in EtOAc (20 mL). The solution was washed with water and brine, dried over Na2SO4, and concentrated at reduced pressure. The residue was purified by preparative TLC (50:50 hexanes/EtOAc) to give 65 mg (11%) of the desired product. 1H-NMR (DMSO-d6) δ 8.68 (s, 1H), 8.42 (d, J=6.3 Hz, 2H), 7.98 (s, 1H), 7.82 (b, 1H), 7.61 (d, J=6.9 Hz, 2H), 7.50 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.08 (d, J=6.6 Hz, 2H), 6.80 (d, J=6.3 Hz, 2H), 6.46 (s, 1H), 4.48 (d, J=6.0 Hz, 2H), 3.78 (d, J=5.7 Hz, 2H), 1.35 (s, 9H), 1.30 (s, 9H); MS LC-MS [M+H]+=614, RT=2.89 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>>[Cl:1][C:2]1[C:7]([C:8]([Cl:13])=[O:10])=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnccc1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cnccc1Cl

Procedure:
o-Halogeno-(hetero-)aryl-carboxylic acid halides which can be employed in the process according to the invention, and processes for their preparation, are known. Thus, for example, J. Am. Chem. Soc. 40,233 (1908) describes the preparation of 2-ethylmercapto-6-chloropyrimidine-5-carboxylic acid chloride by reacting 2-ethylmercapto-4-oxo-3,4-dihydropyrimidine-5-carboxylic acid with phosphorus oxychloride. The reaction of 2-hydroxy-quinoxaline-3-carboxylic acid with thionyl chloride in the presence of a catalytic amount of dimethylformamide to give 2-chloroquinoxaline-3-carboxylic acid chloride is described in Arch. Pharm. 306, 401 (1973). The reaction of 4-chloronicotinic acid with thionyl chloride under reflux to give 4-chloronicotinic acid chloride is described in J. Chem. Soc. (C), 1966, 1816.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[N+:11]([O-])([O-:13])=[O:12].[K+].O.[OH-].[Na+]>C(O)(C(F)(F)F)=O>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: NC(=O)c1ccc(N)nc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cnc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 23 %

Procedure:
To a solution of 6-aminonicotinamide (524 mg, 3.82 mmol) in TFA (10 mL) was added KNO3 (524 mg, 5.18 mmol) at room temperature with stirring. The resulting solution was stirred at 80° C. for 18 h, cooled to room temperature, then cooled water (100 mL) was added (no precipitate was formed). The resulting acidic aqueous solution was basified to pH 9 with 40% aq NaOH. The precipitate was filtered, washed with cooled water (2×5 mL), and dried to give 160 mg (23%) of 65 as a yellow powder, mp 289°-90° C. 1H NMR (DMSO-d6), 7.430 (s, 1H), 8.078 (s, 1H), 8.285 (bs, 2H, easily exchanged with D2O), 8.840 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[N:7]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][O:17]C2CCCCO2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.O.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>O1CCCC1>[C:1]([O:5][C:6](=[O:32])[N:7]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][OH:17])[CH:10]=1)[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCc1ccccn1)Cc1cccc(CCOC2CCCCO2)c1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N(CCc1ccccn1)Cc1cccc(CCO)c1

Procedure:
(2-Pyridin-2-yl-ethyl)-{3-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-benzyl}-carbamic acid tert-butyl ester (8 g) in tetrahydrofuran (100 mL) was treated with acetic acid (10 mL) and water (10 mL). The reaction was refluxed for 8 hour. Another 10 mL acetic and 10 mL water were added and the reaction heated at reflux for a further 2 hours. The reaction was cooled and the volatiles removed under vacuum. The reaction mixture was partitioned between aqueous sodium bicarbonate and ethyl acetate. The organic layers were dried over sodium sulfate and concentrated in vacuo. The yellow residue was passed through a plug of silica, eluting with ether then ethyl acetate to elute the desired product (4.1 g).
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([NH2:18])[CH2:14][CH2:15][CH2:16][CH3:17]>>[CH2:13]([NH:18][C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCN
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)NCCCCC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and amylamine as starting materials to give the aimed compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:16]([C:18]12[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2)#[CH:17].C(N(CC)CC)C.N1C=CC=CC=1>[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[CH3:10][O:9][C:7]([C:6]1[CH:11]=[C:2]([C:17]#[C:16][C:18]23[CH2:27][CH:22]4[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]4)[CH2:19]2)[CH2:25]3)[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=1)=[O:8]
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Reactant: C#CC12CC3CC(CC(C3)C1)C2
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1cc(C#CC23CC4CC(CC(C4)C2)C3)cc(C(=O)OC)c1
Reaction time: 1 h
Yield: 86 %

Procedure:
In a 1 L four-neck flask provided with a thermometer, a Dimroth condenser, a nitrogen inlet pipe and an agitator, 125 g of dimethyl 5-bromoisophthalate (0.458 mol), 1.1 g of triphenyl phosphine (0.00419 mol), 0.275 g of copper iodide (0.00144 mol) and 64.26 g of the obtained 1-ethynyladamantane (0.401 mol) were charged and nitrogen was passed into the flask. Then, 375 mL of dehydrated triethylamine and 200 mL of dehydrated pyridine were added therein and the mixture was agitated and dissolved. After nitrogen was passed into the flask for one hour, 0.3 g of dichlorobis (triphenyl phosphine) palladium (0.000427 mol) was quickly added and the mixture was heated and refluxed in an oil bath. Then, triethylamine and pyridine was removed under reduced pressure to obtain a brown viscous solution. The solution was added to 500 mL of water and filtered to separate a solid. The solid was washed with 500 mL of water, 500 mL of 5 mol/L hydrochloric acid and 500 mL of water each two times and dried under pressure at 50° C., thus obtaining 121.5 g of 1-(3,5-bis(methoxycarbonyl)phenyl)-2-(1-adamantyl)ethyne (the yield was 86%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B2OC(C)(C)C(C)(C)O2)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[Cl:22][C:23]1[CH:24]=[C:25]([CH2:29][N:30]2[CH:34]=[CH:33][N:32]=[C:31]2[CH3:35])[N:26]=[N:27][CH:28]=1>>[ClH:22].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:23]2[CH:24]=[C:25]([CH2:29][N:30]3[CH:34]=[CH:33][N:32]=[C:31]3[CH3:35])[N:26]=[N:27][CH:28]=2)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)c2ccccc2c1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Product: COc1cc(-c2cnnc(Cn3ccnc3C)c2)c2ccccc2c1
Product: Cl

Procedure:
The title compound, MS: m/e 331.3 (M+H+), was prepared from 2-(3-methoxy-naphthalen-1-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([OH:10])=[O:9])[C:3]1=[O:11].[C:12](Cl)(=[O:14])[CH3:13]>O1CCCC1>[C:12]([O:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([OH:10])=[O:9])[C:3]1=[O:11])(=[O:14])[CH3:13]
Reactant: CC(=O)Cl
Reactant: O=C(O)CN1CCC(O)C1=O
Solvent: C1CCOC1
Product: CC(=O)OC1CCN(CC(=O)O)C1=O

Procedure:
4.0 g of (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetic acid, 80 ml of absolute tetrahydrofuran and 5 ml of acetyl chloride are boiled at reflux for 4 hours while stirring. Thereafter, the mixture is evaporated. The residue is filtered through silica gel (granular size 0.2-0.5 mm). The evaporation residue of the fractions which are eluted with ethyl acetate is stirred in diethyl ether. By filtration there is isolated (R/S)-2-(3-acetoxy-2-oxo-1-pyrrolidinyl)acetic acid of melting point 95°-96°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH:14]3[CH2:16][CH2:15]3)=[N:10][NH:11][C:12]=2[NH2:13])=[CH:4][CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=O)[CH2:25][C:26](OCC)=[O:27])=[CH:20][CH:19]=1>N1C=CC=CC=1>[CH:14]1([C:9]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[C:12]3[NH:13][C:26](=[O:27])[CH:25]=[C:24]([C:21]4[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=4)[N:11]3[N:10]=2)[CH2:16][CH2:15]1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Reactant: Nc1[nH]nc(C2CC2)c1-c1ccc(Cl)cc1
Solvent: c1ccncc1
Product: O=c1cc(-c2ccc(F)cc2)n2nc(C3CC3)c(-c3ccc(Cl)cc3)c2[nH]1
Temperature: 25 °C

Procedure:
4-(4-Chlorophenyl)-3-cyclopropyl-1H-pyrazol-5-amine (121 mg) and ethyl 3-(4-fluorophenyl)-3-oxopropanoate (0.095 mL) are stirred overnight in a pyridine (7 mL) solvent at 95° C. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and purified by column chromatography to yield 75 mg of the target compound. 1H NMR (CDCl3, 300 MHz): δ 10.15 (br, 1H), 8.02 (m, 2H), 7.42 (m, 4H), 7.18 (m, 2H), 4.08 (br, 1H), 1.80 (m, 1H) 0.89 (m, 4H).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][Cl:15])=[C:7]([O:16][CH3:17])[CH:6]=1)=O.[NH2:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][N:20]=1>C(O)C>[BrH:1].[Cl:15][CH2:14][CH2:13][CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:18]=[C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][N:20]3[CH:2]=2)=[CH:6][C:7]=1[O:16][CH3:17]
Reactant: Cc1ccnc(N)c1
Reactant: COc1cc(C(=O)CBr)ccc1OCCCCl
Solvent: CCO
Product: Br
Product: COc1cc(-c2cn3ccc(C)cc3n2)ccc1OCCCCl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.5 %

Procedure:
A solution of the product of Step B (1.44 g) and 2-amino-4-picoline (0.486 g) in ethanol (6 mL) was heated at 730 C for 1 hour. The reaction mixture was cooled to ambient temperature and evaporated to a yellow solid. The solid was stirred with 25 mL of dichloromethane for approximately 10 minutes. The mixture was filtered and the solid product collected to yield the title compound (1.3 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1N)[CH3:2].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.Cl.[N:24]1C=CC=CC=1>>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[C:13]1[CH:14]=[C:15]([S:18]([NH2:24])(=[O:20])=[O:19])[CH:16]=[CH:17][C:12]=1[CH3:22])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCc1cccc(CC)c1N
Reactant: c1ccncc1
Agent: Cl
Product: CCc1cccc(CC)c1-c1cc(S(N)(=O)=O)ccc1C
Reaction time: 8 h

Procedure:
To 29.85 g (0.200 mol) of 2,6-diethylaniline in 100 ml of pyridine was added 41.94 g (0.220 mol) of p-toluenesulfonyl chloride in portions at 10° to 4° C. The reaction mixture was stirred overnight, poured into 1 l of 10% hydrochloric acid, filtered, washed three times with water, dissolved in CHCl3, dried over MgSO4, and evaporated to dryness to yield 61.48 g (101.3%) of crude product. A portion (46.3 g) was recrystallized from cyclohexane to yield 33.1 g of 2,6-diethylphenyl-p-toluenesulfonamide, mp. 133.4°. NMR (CDCl3): δ 1.05 (t, 6H), 2.45 (m, 7H), 6.10 (s, 1H), 6.9-7.3 (m, 5H), 7.5-7.7 (d, 2H).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([Cl:28])[CH:27]=1)[NH2:24]>C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[C:23]([NH:24][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:25]=[C:26]([Cl:28])[CH:27]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(Nc1cc(Cl)cc(Cl)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Benzenesulfonyl chloride (1.74 mL, 13.57 mmol) and DIEA (0.34 mL, 2.49 mmol) were added to a solution of 3,5-dichloroaniline (2.0 g, 12.34 mmol) in DCM (50 mL). The resulting solution was stirred at room temperature for 48 h, during which a precipitate was formed. The reaction mixture was then evaporated to dryness and purified by flash column chromatography (ethyl acetate/hexanes=1/9) to give TC-IV-145 (1.90 g, 51%) as a yellow solid.
Reaction SMILES: [SH:1][CH2:2][CH2:3][S:4][CH2:5][CH2:6][SH:7].[OH-].[Na+].Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[C:17]([O:20][CH2:21][CH3:22])(=[O:19])[CH3:18]>C(C(C)=O)C>[CH2:15]([O:14][C:12]([CH2:11][S:1][CH2:2][CH2:3][S:4][CH2:5][CH2:6][S:7][CH2:18][C:17]([O:20][CH2:21][CH3:22])=[O:19])=[O:13])[CH3:16]
Reactant: SCCSCCS
Reactant: CCOC(=O)CBr
Reactant: CCOC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCC(C)=O
Product: CCOC(=O)CSCCSCCSCC(=O)OCC
Temperature: 5 °C
Reaction time: 1 h

Procedure:
In 360 ml of methyl ethyl ketone was dissolved 27.8 g of bis(2-mercaptoethyl)sulfide, and the solution was then cooled to 5° C. Next, 32 g of a 45% aqueous sodium hydroxide solution was added dropwise thereto, followed by vigorous stirring. To this solution, 60 g of ethyl bromoacetate was added dropwise, and reaction was then carried out at room temperature for 1 hour. Afterward, 200 ml of ethyl acetate was added thereto, and the solution was washed with 50 ml of an aqueous saturated ammonium chloride solution twice, and then dried over anhydrous sodium sulfate. Afterward, the solvent was distilled off under reduced pressure to obtain 44 g of light yellow oily bis(2-ethyloxycarbonylmethylthioethyl) sulfide. This sulfide was dissolved in 70 ml of isopropanol, and 18 g of hydrazine monohydrate was added dropwise thereto, while a solution temperature of 5° C. was maintained. After 2 hours, the produced white crystalline bis(2-hydrazinocarbonylmethylthioethyl) sulfide was collected by filtration. Next, the collected crystals were washed with 20 ml of cold isopropanol twice and further washed with 10 ml of hexane. After drying, the dried material was dissolved in 150 ml of water and then cooled to 5° C., and 25 g of concentrated hydrochloric acid was then added dropwise thereto. Furthermore, a solution obtained by dissolving 16 g of sodium nitrite in 50 ml of water was added dropwise thereto. After 30 minutes, 150 ml of benzene was added thereto, and the solution was then heated up to room temperature, while vigorously stirred. Next, the resulting organic layer was separated, and then dried over anhydrous magnesium sulfate. Afterward, toluene was added thereto for dilution so as to bring the total volume to 500 ml, and the solution was then slowly heated up to 55° C. to gently carry out reaction so that nitrogen might be continuously generated. After the reaction at 70° C. for 3 hours, the solution was cooled to room temperature and then allowed to stand overnight, and the resulting white precipitate was removed by filtration. Afterward, the solvent was distilled off under reduced pressure. The obtained colorless oily product was distilled at 80° C. under a reduced pressure of 0.3 mmHg for 2 hours to remove impurities, thereby obtaining the desired bis[2-(isocyanatomethylthio)ethyl] sulfide.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].[N-:11]=[N+]=[N-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+].[C:22]([O:29]C(OC(C)(C)C)=O)(=O)[O:23][C:24]([CH3:27])([CH3:26])[CH3:25]>CN(C=O)C>[C:24]([O:23][C:22](=[O:29])[NH:11][CH2:2][CH2:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C(CCCl)C1CCCC1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCC(=O)C1CCCC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
To a solution of 3-chloro-1-cyclopentyl-propan-1-one (2.913 g, 18.1 mmol) from Step 1 above in DMF (40 mL) was added sodium azide (1.77 er sodium sulfate, filtered, and concentrated to an oil. The oil was then dissolved in g, 27.2 mmol). The reaction was heated to 70° C. for 3 hours. The reaction was cooled to room temperature, and then diluted with 100 mL of ethyl acetate and 100 mL of water. The layers were separated, and the aqueous was extracted with 2×50 mL of ethyl acetate. The organic layer was then washed with 2×50 mL of water. The organic layer was dried ovethanol (75 mL) and TFA was added (3 mL). To this solution was added 10% Pd/C (300 mg). The slurry was stirred under a hydrogen atmosphere for 2 hours. The solids were removed by filtration, and the organic was concentrated by rotary evaporation to a black oil. The black oil was dissolved in THF (100 mL) and TEA (7.5 mL) and di-tert-butyl pyrocarbonate (1 M in THF, 40 mL, 40 mmol) were added. The reaction was stirred at room temperature for 18 hours, and then concentrated by rotary evaporation. The crude oil was purified by flash chromatography to yield the product (1.677 g, 38%). 1H NMR (CDCl3) δ: 1.43 (s, 9H), 1.56-1.84 (m, 8H), 2.68 (t, J=5.65 Hz, 2H), 2.85 (p, J=5.65 Hz, 1H), 3.36 (q, J=6.03, 2H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([NH:10][NH2:11])[CH:7]=[CH:8][CH:9]=1.[CH2:12]([O:14][C:15](=[O:23])[CH:16]([C:20](=O)[CH3:21])[C:17](=O)[CH3:18])[CH3:13].N1C=CC=CC=1>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[C:17]([CH3:18])=[N:11][N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH3:2])[CH:5]=2)[C:20]=1[CH3:21])=[O:23])[CH3:13]
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Reactant: COc1cccc(NN)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)c1c(C)nn(-c2cccc(OC)c2)c1C

Procedure:
Similar to Example 1, equimolar amounts of 3-methoxyphenylhydrazine hydrochloride and 2-acetyl-3-oxo-butyric acid ethyl ester were combined in a solution of 50% pyridine in ethanol. The resulting solid was determined to be the named product by 1H-NMR (CDCl3, ppm): 1.38 t (3H); 2.50 s (3H); 2.52 s (3H); 3.84 s (3H); 4.32 q (2H); 6.96 m (3H); 7.3 st (1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([S:15][CH3:16])[CH:9]=[C:8]([CH3:17])[N:7]=1.ClC1C=CC=C(C(OO)=[O:26])C=1.S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([S:15]([CH3:16])=[O:26])[CH:9]=[C:8]([CH3:17])[N:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COCCOc1nc(C)cc(SC)c1[N+](=O)[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COCCOc1nc(C)cc(S(C)=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2-[(2-methoxyethyl)oxy]-6-methyl-4-methylthio-3-nitropyridine (2.00 g, 7.74 mmol) was dissolved in dichloromethane (25 mL). m-Chloroperbenzoic acid (60%, 5.0 g, 17.38 mmol) was added to the solution, followed by stirring at room temperature for 12 hours. Saturated aqueous sodium sulfite was added to the reaction mixture, followed by stirring for 1.5 hours so that excessive m-chloroperbenzoic acid was deactivated. The organic layer was washed with saturated brine, followed by drying over sodium sulfate anhydrate and concentration under reduced pressure. The obtained residue was recrystallized from ether, to thereby yield 2-[(2-methoxyethyl)oxy]-6-methyl-4-methylsulfinyl-3-nitropyridine as colorless crystals (1.93 g, 91%).