Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:16][N:17]1[CH:21]=[C:20]([CH:22]=O)[CH:19]=[N:18]1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH:15][CH2:22][C:20]3[CH:19]=[N:18][N:17]([CH3:16])[CH:21]=3)[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cn1cc(C=O)cn1
Reactant: Nc1nc(Nc2cc(Cl)cc(Cl)c2)n[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1cc(CNc2nc(Nc3cc(Cl)cc(Cl)c3)n[nH]2)cn1
Temperature: -20 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A solution of N3-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 2 (70 mg, 287 μmol) and 1-methyl-1H-pyrazole-4-carbaldehyde (108.9 mg, 982 μmol) in MeOH (3 ml) was stirred at 45° C. for 4 days to give a suspension, cooled to −20° C. and was filtered to collect the solid. The solid was re-suspended in MeOH (5 ml), NaBH4 (65.1 mg, 1.72 mmol) was added and the reaction was stirred for 1 hour. The solvent was removed, and the reaction mixture was redissolved in EtOAc (5 ml) and washed with water (2×4 ml), dried over MgSO4 and concentrated in vacuo. Crystallization from DCM/hexanes afforded a white solid as desired product (66.6 mg, 69% yield). MS +m/z: 338 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=O)=[CH:9][CH:10]=2)[C:5](=[O:15])[NH:4][N:3]=1.ClC1C2C(=CC=C(C(O)=O)C=2)C(=O)NN=1.S(Cl)(Cl)=O.[F:35][C:36]([F:46])([F:45])[C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH2:40][NH2:41].[H-].[Na+]>O.CN(C=O)C>[F:35][C:36]([F:45])([F:46])[C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH2:40][NH:41][C:12]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([Cl:1])=[N:3][NH:4][C:5]2=[O:15])=[O:14]
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1ccc2c(Cl)n[nH]c(=O)c2c1
Agent: O=C(O)c1ccc2c(=O)[nH]nc(Cl)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: O=S(Cl)Cl
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccc2c(Cl)n[nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-chloro-4-oxo-3,4-dihydro-phthalazine-6-carboxylic acid and 4-chloro-1-oxo-1,2-dihydro-phthalazine-6-carboxylic acid (311 mg, 1.385 mmol), catalytic DMF and thionyl chloride (7 mL) was refluxed for 3 hours. The solution was cooled, concentrated under vacuum and treated 3 times with toluene in order to remove the excess thionyl chloride. The crude residue was dissolved in DMF (3 mL) and added dropwise to a 0° C. solution of 3-(trifluoromethyl)benzylamine (0.22 mL, 1.524 mmol), DMF (5 mL) and 60% NaH (199 mg, 8.31 mmol). The reaction was stirred at room temperature overnight, diluted with water and extracted with EtOAc (×3). The combined organic layers were washed with water, brine and dried (Na2SO4). Column chromatography (Hex/EtOAc) afforded 1-chloro-4-oxo-3,4-dihydro-phthalazine-6-carboxylic acid 3-trifluoromethyl-benzylamide (30 mg) as a white solid. 1H NMR (400 MHz, d6-DMSO) δ: 4.62 (d, 2H), 7.65 (m, 4H), 8.10 (d, 1H), 8.47 (dd, 1H), 8.80 (d, 1H), 9.65 (t, 1H), 12.99 (s, 1H) ppm; m/z (M+1) 382.17; and 4-chloro-1-oxo-1,2-dihydro-phthalazine-6-carboxylic acid 3-trifluoromethyl-benzylamide (33 mg) as a white solid. 1H NMR (400 MHz, d6-DMSO) δ: 4.63 (d, 2H), 7.65 (m, 4H), 8.38 (m, 2H), 8.46 (s, 1H), 9.63 (t, 1H), 12.98 (s, 1H) ppm; m/z (M+1) 382.24.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:11].[Br:25][C:26]1[CH:27]=[N:28][C:29](Cl)=[N:30][CH:31]=1.CCN(C(C)C)C(C)C>C(O)(C)C>[Br:25][C:26]1[CH:27]=[N:28][C:29]([NH:1][CH2:2][C@H:3]2[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[N:13]=[C:14]([CH3:24])[S:15][C:16]=2[C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[O:11])=[N:30][CH:31]=1
Reactant: Clc1ncc(Br)cn1
Reactant: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2CN)c(-c2ccc(F)cc2)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2CNc2ncc(Br)cn2)c(-c2ccc(F)cc2)s1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A mixture of rac-cis-(2-(aminomethyl)-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone, 5-bromo-2-chloropyrimidine, and DIPEA in isopropanol was stirred at 120° C. for 1 h in a microwave reactor. The reaction was complete as judged by reverse-phase analytical HPLC. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 505.88 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9](S(C(F)(F)F)(=O)=O)=[CH:8][C:7]=1[CH3:20].[C:30]([O-])([O-:32])=[O:31].[K+].[K+]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:25]([O:24][C:22]([NH:21][C@H:4]([C:3]([O:2][CH3:1])=[O:29])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:30]([OH:32])=[O:31])=[CH:8][C:7]=1[CH3:20])=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)[C@H](Cc1c(C)cc(S(=O)(=O)C(F)(F)F)cc1C)NC(=O)OC(C)(C)C
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1c(C)cc(C(=O)O)cc1C)NC(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 94.2 %

Procedure:
To a suspension of (S)-2-tert-butoxycarbonylamino-3-(2,6-dimethyl-4-trifluoromethanesulfonylphenyl)-propionic acid methyl ester (9.68 g, 21.3 mmol), K2CO3 (14.1 g, 0.102 mol), Pd(OAc)2 (0.48 g, 2.13 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (2.56 g, 4.47 mmol) in DMF (48 mL) was bubbled in gaseous CO for 15 min. The mixture was heated to 60° C. for 8 h with a CO balloon. The cool mixture was partitioned between NaHCO3 and EtOAc, and filtered. The aqueous layer was separated, acidified with 10% citric acid aqueous solution, extracted with EtOAc, and finally dried over Na2SO4. Filtration and concentration of the filtrate resulted in a residue. The residue was recrystallized from EtOAc-hexanes to afford the desired product (7.05 g, 94%); 1H NMR (300 MHz, CDCl3): δ 1.36 (9H, s), 2.42 (6H, s), 3.14 (2H, J=7.4 Hz), 3.65 (3H, s), 4.57-4.59 (1H, m), 5.14 (1H, d, J=8.6 Hz), 7.75 (2H, s); MS (ES+) (relative intensity): 251.9 (100) (M-Boc)+.
Reaction SMILES: [Na].O=C1O[C@H]([C@H](CO)O)C(O)=C1O.[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH:15]1[NH:23][C:24]1[N:25]=[CH:26][C:27]2[CH2:32][N:31]([C:33]([NH:35][CH2:36][CH2:37][CH2:38][C:39]#[CH:40])=[O:34])[CH2:30][C:28]=2[N:29]=1.[N:41]([Si](C)(C)C)=[N+:42]=[N-:43]>CN(C)C=O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH:15]1[NH:23][C:24]1[N:25]=[CH:26][C:27]2[CH2:32][N:31]([C:33]([NH:35][CH2:36][CH2:37][CH2:38][C:39]3[N:41]=[N:42][NH:43][CH:40]=3)=[O:34])[CH2:30][C:28]=2[N:29]=1
Reactant: C#CCCCNC(=O)N1Cc2cnc(NC3Cc4ccccc4C3)nc2C1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCCCc1c[nH]nn1)N1Cc2cnc(NC3Cc4ccccc4C3)nc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.4 %

Procedure:
Add copper(II)sulfate pentahydrate (0.049 g; 0.2 equiv; 0.20 mmoles) and L-ascorbic acid sodium salt (0.388 g; 2.0 equiv; 1.96 mmoles) to a deoxygenated solution of 2-(2,3-dihydro-1H-inden-2-ylamino)-N-(pent-4-yn-1-yl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxamide (0.354 g; 1.0 equiv; 0.98 mmoles) in dimethylformamide (3.26 mL) and water (3.26 mL). Add azidotrimethylsilane (1.04 mL; 8 equiv; 7.84 mmoles) and heat the mixture to 90° C. for 1 hour, the cool to ambient temperature and stir for 16 hours. Concentrate the solution to dryness, and purify the resulting orange semisolid by column chromatography (0 to 10% methanol in ethyl acetate) to afford 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-(1H-1,2,3-triazol-4-yl)propyl]-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxamide (0.085 g; 21%) as a solid: MS (m/z): 405(M+1).
Reaction SMILES: [O:1]1[C:6]2=[CH:7][N:8]=[C:9]([CH2:11][OH:12])[CH:10]=[C:5]2[CH2:4][CH2:3][CH2:2]1.CS(C)=O.C(N(CC)CC)C.S(=O)(=O)=O.N1C=CC=CC=1>C(Cl)Cl>[O:1]1[C:6]2=[CH:7][N:8]=[C:9]([CH:11]=[O:12])[CH:10]=[C:5]2[CH2:4][CH2:3][CH2:2]1
Reactant: OCc1cc2c(cn1)OCCC2
Agent: O=S(=O)=O
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=Cc1cc2c(cn1)OCCC2
Temperature: 2.5 °C

Procedure:
(3,4-Dihydro-2H-pyrano[2,3-c]pyridin-6-yl)methanol (300 g, 1.0 eq), DCM (1.5 L) and dimethyl sulfoxide (216 mL, 2.05 eq) were added with stirring to a vessel maintained at ˜0 to 5° C. Triethylamine (858 mL, 4.1 eq) followed by solid pyridine sulphur trioxide (474 g, 2.0 eq) were slowly added to the mixture while maintaining the mixture temperature at ˜0 to 7° C. The mixture was stirred at ˜0 to 7° C. for ˜5 to 8 h then quenched with aqueous 5 wt % NaHCO3 solution (3 L) to form a biphasic mixture. The layers were separated and the aqueous layer was extracted with DCM (0.9 L). The combined organic layers were washed with aqueous 5 wt % citric acid (3.0 L) and brine (300 mL), dried over anhydrous sodium sulfate and filtered to provide the title compound in DCM solution. 1H NMR (300 MHz, CDCl3) δ ppm 9.94 (s, 1H), 8.21-8.32 (m, 1H), 7.72 (s, 1H), 4.25-4.40 (m, 2H), 2.85 (t, J=6.50 Hz, 2H), 1.97-2.19 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11](=[O:18])[CH2:12][C:13](OCC)=[O:14])[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20].[OH-].[Na+].Cl.[NH2:28]O.Cl>CO.CO.O.O>[CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][CH2:4][C@H:5]1[CH2:10][C@H:9]([C:11]2[O:18][NH:28][C:13](=[O:14])[CH:12]=2)[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20]
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](CCC(C)(C)C)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1CCC(C)(C)C
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 38.8 %

Procedure:
A solution of cis-methyl 2-(3,3-dimethylbutyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (549 mg, 1.61 mmol) (from example 95, step 1) in MeOH (1.2 mL) was added to a solution of NaOH (70 mg, 1.75 mmol) in MeOH/H2O (1.3 mL/0.08 mL) at −30° C. After 10 min was added hydroxylaminehydrochloride (223 mg, 3.22 mmol) and NaOH (129 mg, 3.22 mmol) in MeOH (1.6 mL) and H2O (1.6 mL). Stirring was continued at −30° C. for 30 min. The reaction solution was poured into 6 M HCl (2.4 mL) at 80° C. and heated at 80° C. for 1 h. Concentration of the organic solvent and extraction with DCM (×2), drying using a phase separator and evaporation gave an orange oil. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 30-60% Acetonitrile in H2O/MeCN/FA 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Trans-methyl 2-(3,3-dimethylbutyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (194 mg, 39%) was isolated as a white solid. 1H NMR (400 MHz, cdcl3) δ 0.89 (s, 9H), 1.02-1.78 (m, 6H), 1.89-2.03 (m, 2H), 2.83-3.09 (m, 2H), 3.71 (s, 3H), 3.99-4.51 (m, 2H), 5.65 (s, 1H). MS m/z 311 (M+H)+
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][OH:11])=[N:7][CH:8]=1)[CH3:2].F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1>CN(C)C=O>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCc1ccc(CCO)nc1
Solvent: CN(C)C=O
Product: CCc1ccc(CCOc2ccc([N+](=O)[O-])cc2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(5-ethyl-2-pyridyl)ethanol (12 g) and 4-fluoronitrobenzene (11.2 g) in dimethylformamide (80 ml) sodium hydride (3.9 g) is added portionwise under ice cooling. This mixture is agitated under ice cooling for one hour, at room temperature for thirty minutes, poured into ice water and extracted with ethyl acetate. Drying the organic layer and evaporating the solvent gives a yellow solid (4-(2-(5-ethyl-2-pyridyl)ethoxy)nitrobenzene, 21.4 g, 98.2%). Recrystallizing from a mixture of ether and hexane yields pale yellow crystals (m.p. 45–47° C.). NMR δ (ppm) in CDCl3: 1.25 (3H, t, J=7.6), 2.65 (2H, q, J=7.6), 3.28 (2H, t, J=6.7), 4.47 (2H, t, J=6.7), 6.95 (2H, m), 7.19 (1H, d, J=7.9), 7.49 (1H, dd, J=2.4; 8.0), 8.17 (2H, m), 8.41 (1H, d, J=2.2).
Reaction SMILES: [F:1][C:2]1([F:21])[CH2:6][N:5](C(OC(C)(C)C)=O)[C@@H:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH2:3]1.Cl.[OH-].[Na+]>>[F:21][C:2]1([F:1])[CH2:6][NH:5][C@@H:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@@H]1c1cccc(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Fc1cccc([C@H]2CC(F)(F)CN2)c1
Temperature: 60 °C

Procedure:
To (R)-Tert-butyl 4,4-difluoro-2-(3-fluorophenyl)pyrrolidine-1-carboxylate (180 mg, 0.6 mmol) in a pressure reaction tube was added a solution of HCl (2 mL, 4 N dioxane, 8 mmol), then the reaction was sealed and heated at 60° C. for 4 hours. For workup, the reaction was poured into a mixture of ice and 1 M NaOH, and extracted with several portions of EtOAc. The combined organic extracts were filtered through a Phase Separator filter paper and concentrated, yielding the final product as clear oil, which was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([S:10][C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][C:5]=1[OH:15])([O-])=O.C(OCC)(=O)C.C(O)(=O)C>[Fe].O>[NH2:1][C:4]1[CH:9]=[C:8]([S:10][C:11]([F:14])([F:12])[F:13])[CH:7]=[CH:6][C:5]=1[OH:15]
Reactant: O=[N+]([O-])c1cc(SC(F)(F)F)ccc1O
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cc(SC(F)(F)F)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.7 %

Procedure:
A mixture of 5.49 g of 2-nitro-4-(trifluoromethylthio)phenol and 10 ml of ethyl acetate was added dropwise to a mixture, which was heated to 80° C., of 6.4 g of electrolytic iron, 10 ml of acetic acid and 20 ml of water. The reaction mixture was stirred for 30 minutes. The mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and a saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2.0 g of 2-amino-4-(trifluoromethylthio)phenol.
Reaction SMILES: [CH3:1][C@H:2]1[C@H:5]([S:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:4][C:3]1=[O:14].[H-].[Na+].Br[CH2:18][C:19](=[O:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH3:1][C@H:2]1[C@H:5]([S:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]([CH2:18][C:19](=[O:28])[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:3]1=[O:14]
Reactant: C[C@@H]1C(=O)N[C@H]1SCc1ccccc1
Reactant: O=C(CBr)CCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H]1C(=O)N(CC(=O)CCc2ccccc2)[C@H]1SCc1ccccc1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 27.5 %

Procedure:
A solution of trans-3-methyl-4-(benzylthio)azetidin-2-one (0.73 g, 3.5 mmol) in dry THF (5 ml) was added dropwise over 5 minutes to a suspension of sodium hydride (60% dispersion in oil, 0.15 g, 3.8 mmol) in dry THF (10 ml) under a nitrogen atmosphere at -10° C. The mixture was stirred for 10 minutes at -10° C. and 1-bromo-4-phenylbutan-2-one (0.79 g, 3.5 mmol) in dry THF (10 ml) was added over 5 minutes at -10° C. The mixture was stirred at room temperature for 30 minutes and poured into ice/water. The layers were separated and the aqueous was extracted with ethyl acetate. The combined organics were washed with brine, dried (MgSO4) and evaporated to an oil. This was purified by flash chromatography on silica gel eluting with petroleum ether 40-60° C./ethyl acetate 3:1, 2:1 to give a colourless solid (0.34 g, 27%) mp 69-71° C.
Reaction SMILES: [SH2:1].[SH:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1>C(=S)=S>[CH:9]1[CH:8]=[C:6]2[N:7]=[C:3]([S:2][S:1][C:3]3[S:4][C:5]4[C:6](=[CH:8][CH:9]=[CH:10][CH:11]=4)[N:7]=3)[S:4][C:5]2=[CH:11][CH:10]=1
Reactant: Sc1nc2ccccc2s1
Reactant: S
Solvent: S=C=S
Product: c1ccc2sc(SSc3nc4ccccc4s3)nc2c1

Procedure:
2-Mercaptobenzothiazole can be produced from aniline by the following synthesis approach. Here, carbon disulfide can be generated and separated for example by reacting mustard oil, which is contained about 0.4% in leaf mustard, with hydrogen sulfide. The method allows to produce the vulcanization accelerator without petroleum resources. Dibenzothiazyl disulfide is synthesized by oxidizing thus produced 2-mercaptobenzothiazole.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)[CH3:2].[Li+].[CH3:14]C([N-]C(C)C)C.CN(P(N(C)C)(N(C)C)=O)C.CI.Cl>C1COCC1>[CH2:1]([O:3][C:4](=[O:12])[CH:5]([CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)[CH3:14])[CH3:2]
Reactant: CCOC(=O)CC1CCOCC1
Reactant: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CI
Product: CCOC(=O)C(C)C1CCOCC1
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
To a solution of (Tetrahydro-pyran-4-yl)-acetic acid ethyl ester (2.0 g, 11.6 mmol) in 50 mL of THF at −78° C. LDA (1.0 M, 17.4 mL, 34.8 mmol) is added dropwise. The solution is stirred for 0.5 h and treated with HMPA (3.2 mL, 9.3 mmol) and MeI (4.94 g, 34.8 mmol). The reaction mixture is stirred at the same temperature for 0.5 h and for 1.5 h at 0° C., acidified with aqueous 1 N aqueous HCl solution, and extracted twice with ether (2×40 mL). The organic phase is washed with saturated aqueous NaCl solution, dried (MgSO4), and concentrated in vacuo to give 1.8 g of 2-(Tetrahydro-pyran-4-yl)-propionic acid ethyl ester which is hydrolyzed without further purification. A solution of the crude ester (500 mg, 2.68 mmol) and 5 N aqueous NaOH solution (2.68 mL, 13.4 mmol) in dioxane-water (4 mL/2 mL) is heated at 60° C. for 2 h. The solution is cooled to room temperature, acidified with 1 N aqueous HCl solution, and extracted with ether. The ether layer is washed with saturated aqueous NaCl solution, dried over anhydrous MgSO4, and concentrated in vacuo to give 400 mg of the title compound. MS: 159 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 2 min then 100% CH3CN+0.1% TFA for 1 min, flow 0.5 ml/min): 1.27 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:18]=[C:17]([NH2:19])[CH:16]=[C:6]([C:7]([N:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.CCN(CC)CC.[Cl:28][CH2:29][CH2:30][CH2:31][C:32](Cl)=[O:33]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:18]=[C:17]([NH:19][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][Cl:28])[CH:16]=[C:6]([C:7]([N:9]([CH2:10][CH2:11][CH3:12])[CH2:13][CH2:14][CH3:15])=[O:8])[CH:5]=1
Reactant: CCCN(CCC)C(=O)c1cc(N)cc(C(=O)OC)c1
Reactant: O=C(Cl)CCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(CCC)C(=O)c1cc(NC(=O)CCCCl)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 103.3 %

Procedure:
A solution of 5-amino-N,N-dipropyl-isophthalamic acid methyl ester (D88) (1.2 g, 4.3 mmol, 1 equiv) in CH2Cl2 (10 ml) was treated with NEt3 (525 mg, 5.2 mmol, 1.2 equiv). The solution was cooled to 0° C. and 4-chlorobutyryl chloride (733 mg, 5.0 mmol, 1.2 equiv) was added dropwise. The reaction mixture was then allowed to warm to room temperature and stirred for 1 h. The solution was washed with 2N aqueous HCl solution (20 ml), dried over MgSO4 and concentrated in vacuo to give 5-(4-chloro-butanoylamino)-N,N-dipropyl-isophthalamic acid methyl ester (D89) (1.7 g, 104%) as a colourless oil.
Reaction SMILES: C[Sn](C)(C)[C:3]1[C:11]2[C:10]([Cl:12])=[N:9][CH:8]=[N:7][C:6]=2[NH:5][CH:4]=1.[F:15][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>CC#N>[F:15][C:3]1[C:11]2[C:10]([Cl:12])=[N:9][CH:8]=[N:7][C:6]=2[NH:5][CH:4]=1
Reactant: C[Sn](C)(C)c1c[nH]c2ncnc(Cl)c12
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: Fc1c[nH]c2ncnc(Cl)c12
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of the compound from Step B (1.97 g, 6.20 mmol) in CH3CN (60 mL) was added [1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)] (SELECTFLUOR® fluorinating reagent) (2.40 g, 6.5 mmol) in one portion and the reaction mixture was stirred at room temperature for 7 h. The white precipitate was filtered off, and the filtrate was evaporated to dryness. The residue was purified over silica gel using ethyl acetate/hexane (3:7) as the eluent. Fractions containing the product were pooled and eveporated in vacuo to give the title compound as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][C:16]([C:25]2[N:26]=[CH:27][NH:28][CH:29]=2)([C:21]([O:23][CH3:24])=[O:22])[C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].F[C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][C:16]([C:25]2[N:26]=[CH:27][N:28]([C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)[CH:29]=2)([C:21]([O:23][CH3:24])=[O:22])[C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)(C(=O)OC)c1c[nH]cn1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)(C(=O)OC)c1cn(-c2ccc([N+](=O)[O-])cc2)cn1
Yield: 75 %

Procedure:
A solution of 404 mg (1.00 mmol) of the compound from example 12d in 10 ml of DMF was cooled to 0° C. and, while stirring, 80 mg (2.00 mmol, 60%) of sodium hydride were added in portions. The mixture was stirred at 0° C. for 1 h and then 423 mg (3 mmol) of 4-fluoronitrobenzene were added and stirred at RT until conversion was complete. Saturated aqueous NaHCO3 solution was added to the mixture, which was extracted with EA. The organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography on silica gel. 394 mg of the title compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:13])[NH:4][C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH:14]1([C:19](O)=O)[CH2:18][CH2:17][CH2:16][CH2:15]1.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH:14]1([C:19]2[NH:1][C:2]3[C:3](=[O:13])[NH:4][C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=3[N:8]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C(O)C1CCCC1
Reactant: CCCn1c(N)c(N)c(=O)[nH]c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: CCCn1c(=O)[nH]c(=O)c2[nH]c(C3CCCC3)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 5,6-diamino-1-propyl-2,4(1H, 3H)pyrimidinedione (Japanese Published Unexamined Patent Application No. 57517/80) in 600 ml of dimethylformamide were sequentially added 17.7 ml (163 mmol) of cyclopentanecarboxylic acid, 30.0 g (196 mmol) of hydroxybenzotriazole and 50.5 g (245 mmol) of dicyclohexylcarbodiimide. The mixture was stirred at room temperature overnight. Insoluble materials were filtered off and the solvent was evaporated under reduced pressure After 600 ml of 4N aqueous sodium hydroxide solution was added to the residue, the mixture was refluxed for 10 minutes under heating. Under ice cooling, insoluble materials were filtered off and 50 ml of methanol was added to the filtrate. After neutralization with conc. hydrochloric acid, the precipitate was collected by filtration to afford 28.3 g (yield, 66%) of Compound c.