Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[Br:14]N1C(C)(C)C(=O)N(Br)C1=O>ClCCl.CCCCCCC>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([F:13])([F:9])([F:10])([F:11])[F:12])=[CH:4][C:3]=1[Br:14]
Reactant: Nc1ccc(S(F)(F)(F)(F)F)cc1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: ClCCl
Solvent: CCCCCCC
Product: Nc1ccc(S(F)(F)(F)(F)F)cc1Br
Temperature: 5 °C
Yield: 173.6 %

Procedure:
4-Aminophenylsulfur pentafluoride (510 g, 2.327 mol) was dissolved in dichloromethane (7 l), the solution was cooled to 5° C. and, while stirring, 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (326 g, 1.14 mol) was introduced in several portions with ice cooling such that the internal temperature was kept at 3-8° C. (about 1 h). Subsequently, the mixture was stirred without external cooling for 1 h and allowed to warm to room temperature. The mixture was filtered through a bed of silica gel (volume about 1 l) and washed with dichloromethane (5.5 l), and the filtrate was concentrated under reduced pressure. About 700 g of a red-brown crystalline mass were obtained and were dissolved in n-heptane (600 ml) at 60° C. and then crystallized in a refrigerator at 4° C. Filtration with suction gave 590 g (85%) of 4-amino-3-bromophenylsulfur pentafluoride as brownish crystals, m.p. 59-59.5° C.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([O:7][C:8](Cl)=[S:9])=[CH:3][CH:2]=1.[N-:11]=[N+:12]=[N-:13].[Na+]>CC(C)=O.O>[O:7]([C:8]1[S:9][N:13]=[N:12][N:11]=1)[C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: S=C(Cl)Oc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: c1ccc(Oc2nnns2)cc1
Reaction time: 0.75 h

Procedure:
Phenyl chlorothionoformate (3.44 grams, 0.02 mole) was dissolved in 5 ml of dry acetone. Sodium azide (1.4 grams, 0.22 mole) was dissolved in 12 ml of deionized water with 8 ml of acetone and slowly added to the phenyl chlorothionoformate solution over a 5 minute period. The reaction was kept at 5° C. in an ice bath and stirred an additional 45 minutes before adding 12 ml of water. The solution was filtered to collect the product; m.p. 35°-36° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=O.[NH2:7][NH:8][C:9]([NH2:11])=[S:10]>N1C=CC=CC=1>[CH3:1][O:2][CH2:3][C:4]1[NH:7][N:8]=[C:9]([SH:10])[N:11]=1
Reactant: COCC(=O)Cl
Reactant: NNC(N)=S
Solvent: c1ccncc1
Product: COCc1nc(S)n[nH]1
Temperature: 25 °C
Yield: 29.9 %

Procedure:
Methoxyacetyl chloride (2.82 g; 0.023 mol) was added to a solution (15 ml) of 2.09 g (0.0230 mol) of thiosemicarbazide in pyridine followed by stirring for a whole day and night at room temperature. The reaction solution was concentrated and 10 ml of methanol and 8 ml of a 25 wt % methanolic solution of sodium methoxide ere added thereto followed by heating to reflux for a whole day and night. After cooling to room temperature, the solvent was evaporated and concentrated hydrochloric acid was added thereto to acidify. The solid separated out therefrom was filtered, washed with distilled water and dried to give 1.0 g (yield: 33%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:19]>C(O)C.O>[F:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[NH:19][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: Nc1cccc(F)c1F
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cnccc1Nc1cccc(F)c1F
Yield: 77.9 %

Procedure:
To a solution of 4-chloro-3-nitropyridine (3.0 g, 18.9 mmol) in dry ethanol as added 2,3-difluorobenzenamine (3.66 g, 28.3 mmol). The reaction mixture was refluxed for 30 min. After cooling and concentration in vacuo to give a brown solid, the crude product was taken up in water and the aqueous solution adjusted to a pH of 8-9 and the solution extracted with EtOAc (3×100 mL). The combined organics were washed with water (3×100 mL) and brine solution (1×100 mL), respectively, dried over Na2SO4, and evaporated in vacuo to give a light brown solid. The crude product was triturated with petroleum ether (3×30 mL) to afford N-(2,3-difluorophenyl)-3-nitropyridin-4-amine (3.7 g, 79% yield) as light yellow solid.
Reaction SMILES: [C:1]1([CH:7]=[C:8]([C:13](=[O:26])[C:14](=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([O:17][CH3:18])=[O:16])[C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H].C(Cl)Cl>CO.[Pd]>[CH3:18][O:17][C:15](=[O:16])[CH:14]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:13](=[O:26])[CH:8]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: [H][H]
Reactant: COC(=O)C(=Cc1ccccc1)C(=O)C(=Cc1ccccc1)C(=O)OC
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C(Cc1ccccc1)C(=O)C(Cc1ccccc1)C(=O)OC
Yield: 58.6 %

Procedure:
Dimethyl 2,4-bis(phenylmethylene)-3-oxo-glutarate (630 mg, 1.8 mmol) (C. H. Chen, et al, J. Org. Chem., 1981, 46, 2752-2757) was dissolved in about 100 mL of methanol and 250 mg of 10% palladium on carbon was added. The reaction mixture was shaken at ambient temperature under 4 atmospheres of hydrogen for about 12 h. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue (750 mg) was taken up in ~15 mL of methylene chloride and applied to a 1.0×45 cm column of silica gel. The column was eluted @5 p.s.i. with 150 mL of methylene chloride to give 374 mg (58% yield) of the title compound. The 300 MHz 1H NMR was consistent with the assigned structure.
Reaction SMILES: [CH3:1][C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:27]2[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]2)[CH2:17][CH2:18]CCC2C=CC=CC=2)=[O:15])=[N:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=[O:4].[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39](CCO)=[CH:38][CH:37]=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:18][CH2:17][N:16]([C@H:27]2[CH2:28][CH2:29][C@H:30]([CH3:33])[CH2:31][CH2:32]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][C:2]([CH3:6])([CH3:1])[C:3]([OH:5])=[O:4])=[CH:9][N:10]=2)=[CH:38][CH:37]=1
Reactant: COc1ccc(CCO)cc1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCCCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: COc1ccc(CCN(C(=O)Nc2ncc(SC(C)(C)C(=O)O)s2)[C@H]2CC[C@H](C)CC2)cc1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-(4-phenyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-propionic acid using 2-(4-methoxy-phenyl)-ethanol and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>O1CCOCC1.C(OCC)(=O)C>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:36]=[CH:37][C:38]([NH:41][C:5]3[N:4]=[C:3]([N:9]([CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:2]([Br:1])=[CH:7][N:6]=3)=[CH:39][CH:40]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: Clc1ncc(Br)c(N(c2ccccc2)C2CCCCC2)n1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(Br)c(N(c4ccccc4)C4CCCCC4)n3)cc2)CC1
Temperature: 100 °C
Yield: 32.9 %

Procedure:
Compound 37 (0.42 g, 1.15 mmol) and 4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.64 g, 2.30 mmol) were dissolved in dioxane (2 mL), and this mixture was heated at 100° C. for 24 hours. The reaction was cooled to room temperature and diluted with ethyl acetate. This mixture was washed with water and brine. The organic layer was dried with sodium sulfate and purified by flash chromatography (ethyl acetate/hexane) to give compound 38 as a yellow solid (0.23 g, 33%). 1H NMR (500 MHz, DMSO-d6) δ ppm 9.18 (1 H, s), 7.97 (1 H, s), 7.55 (2 H, d, J=10 Hz), 7.37 (2 H, m), 7.31 (1 H, m), 7.12 (2 H, m), 6.89 (2 H, d, J=10 Hz), 4.68 (1 H, m), 3.44 (4 H, m), 3.00 (4 H, m), 1.91 (2 H, d, J=10 Hz), 1.72 (2 H, d, J=10 Hz), 1.57 (1 H, d, J=10 Hz), 1.41 (9 H, s), 1.35 (2 H, m), 1.14 (2 H, m), 0.92 (1 H, m); LCMS-ESI (POS), M/Z, M+1: Found 609.2, Calculated 607.2/609.2.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@@H:9](O)[CH2:8][N:7]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:6]1)=[N+:2]=[N-:3].C(N(S(F)(F)[F:27])CC)C.C(=O)([O-])O.[Na+]>ClCCl>[N:1]([CH2:4][C@@H:5]1[C@H:9]([F:27])[CH2:8][N:7]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:6]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: [N-]=[N+]=NC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Process (A): (3R,4R)-3-Azidomethyl-1-benzyloxycarbonyl-4-hydroxypyrrolidine (1.20 g) was dissolved in dichloromethane (40 mL). While this solution was cooled on a sodium chloride/ice bath, diethylaminosulfur trifluoride (1.20 mL) was added dropwise and the mixture was stirred at room temperature for 3 hours. The reaction vessel was again cooled on a sodium chloride/ice bath and diethylaminosulfur trifluoride (0.57 mL) was again added dropwise. The mixture was then stirred at room temperature for 2 hours. While the reaction mixture was cooled on an ice bath, a saturated aqueous solution of sodium hydrogen carbonate (40 mL) was added dropwise and the dichloromethane layer was separated. The dichloromethane layer was sequentially washed with a saturated aqueous solution of sodium hydrogen carbonate (2×20 mL) and water (20 mL), followed by drying over anhydrous sodium sulfate and concentration under reduced pressure. The resulting residue was purified on a silica gel column (eluant=hexane:ethyl acetate=2:1) to give 726 mg of (3R,4S)-3-azidomethyl-1-benzyloxycarbonyl-4-fluoropyrrolidine as a pale brown oil.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:9]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[C@@H:11]([O:17][C:18](=[O:26])[C:19](=[O:25])[C:20]1[O:21][CH:22]=[CH:23][CH:24]=1)[CH2:10]2.[Cl-].[NH4+].CCOCC>C1COCC1.N#N>[N:9]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[C@@H:11]([O:17][C:18](=[O:26])[C:19]([C:20]1[O:21][CH:22]=[CH:23][CH:24]=1)([OH:25])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:10]2
Reactant: Br[Mg]c1ccccc1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(=O)c1ccco1
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(O)(c1ccccc1)c1ccco1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40 %

Procedure:
Phenylmagnesium bromide, 0.0057 mol (5.7 ml of a solution 1M in THF), was added to a solution of 1.3 g (0.0052 mol) of oxofuran-2-ylacetic acid 1-azabicyclo[2.2.2]oct-3(R)-yl ester (intermediate I-4e-) dissolved in 15 ml of THF, at −701C in N2 atmosphere. The mixture was stirred at this temperature for 10 minutes, and then warmed to room temperature. After 1 hour, the reaction mixture was treated with a saturated solution of ammonium chloride and extracted three times with ethyl acetate The organic phases were combined, washed with water and dried over Na2SO4. After removal of the solvent, the solid obtained was treated with ether and filtered to yield 0.67 g (40%) of a product whose structure was confirmed by 1H-NMR. This compound was also prepared as is described in Example I-1a (Method c). The diastereomers were separated by crystallization from acetonitrile and distinguished by 1H-NMR.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([I:17])=[C:11]3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:18]N1C(=O)CCC1=O>CN(C=O)C.C(OCC)(=O)C>[Cl:18][C:10]1[C:11]2[C:12](=[N:13][CH:14]=[CH:15][C:16]=2[I:17])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Fc1ccc(-n2ncc3c(I)ccnc32)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1ccc(-n2nc(Cl)c3c(I)ccnc32)cc1
Reaction time: 8 h

Procedure:
To a solution of Intermediate 2A (33.9 mg, 0.1 mmol) in DMF (Volume: 1 mL) under argon at room temp was added N-chlorosuccinimide (107 mg, 0.800 mmol). The reaction mixture was allowed to stir overnight. The reaction mixture was diluted with ethyl acetate and washed (2×15 mL) with 10% LiCl, once with brine, dried over Na2SO4, filtered and concentrated. The crude product was dissolved in a small amount of dichloromethane and charged to a 4 g silica gel cartridge which was eluted with a 20 min gradient from 0% to 100% of ethyl acetate in dichloromethane. The resulting brown solid (23 mg, 61.6%) was determined to be the desired material by 1HNMR and LCMS. MS (ES): m/z=274.0 [M+H]+. 1H NMR (400 MHz, CCl3D) δ ppm 8.58-8.60 (1 H, m), 8.24 (1 H, s), 8.14-8.20 (2 H, m), 7.18-7.26 (2 H, m).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH2:4][CH2:3]1.[C:6]([O:10][C:11]([N:13]1[CH2:16][CH:15]([C:17]([OH:19])=O)[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:6]([O:10][C:11]([N:13]1[CH2:14][CH:15]([C:17]([N:2]2[CH2:5][CH2:4][CH2:3]2)=[O:19])[CH2:16]1)=[O:12])([CH3:7])([CH3:8])[CH3:9]
Reactant: C1CNC1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(C(=O)N2CCC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Azetidine hydrochloride salt (515 mg, 5.50 mmol) was added to a solution of azetidine-1,3-dicarboxylic acid mono-tert-butyl ester (1.0 g, 4.97 mmol), HATU (2.09 g, 5.50 mmol) and DIPEA (2.18 mL, 12.52 mmol) in DMF (100 mL) and the resulting mixture stirred at ambient temperature for 1 h, then concentrated in vacuo. The resulting oil was partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, then dried (MgSO4) and concentrated in vacuo to give 3-(azetidine-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester as a colourless oil. TFA (3 mL) was added to a solution of 3-(azetidine-1-carbonyl)-azetidine-1-carboxylic acid tert-butyl ester in DCM (15 mL) and the mixture stirred at ambient temperature for 1 h, then loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to afford the title compound as a colourless oil (260 mg, 37%). 1H NMR (CD3OD, 400 MHz) δ 4.19-4.08 (m, 2H); 4.07-3.92 (m, 2H); 3.91-3.78 (m, 2H); 3.72-3.52 (m, 3H) and 2.36-2.21 (m, 2H).
Reaction SMILES: [F:1][CH2:2][CH2:3][OH:4].[Cl:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8](Cl)[N:7]=1>O1CCOCC1.ClCCl>[Cl:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([O:4][CH2:3][CH2:2][F:1])[N:7]=1
Reactant: OCCF
Reactant: Clc1cncc(Cl)n1
Solvent: C1COCCO1
Solvent: ClCCl
Product: FCCOc1cncc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
K-t-BuO (1.32 g, 11.8 mmol) was added portionwise to a stirred mixture of 2-fluoroethanol (2.16 g, 33.7 mmol) and 2,6-dichloropyrazine (1.61 g, 10.8 mmol) in dioxane (2 mL) at 0° C. (ice-bath). The reaction mixture was then stirred at room temperature for 1 hour, diluted with dichloromethane, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (19×4 cm) using n-hexane/ethyl acetate (85:15) as eluent. This furnished 1.49 g (78%) of the title compound as a beige liquid. Anal. (C6H6FClN2O) C, H, N.
Reaction SMILES: [CH3:1][C:2]([S:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[CH3:8][C:9]([CH3:15])([CH3:14])/[CH:10]=[CH:11]/[CH:12]=O>ClCCl.[O-]S([O-])(=O)=O.[Cu+2]>[CH3:8][C:9]([CH3:15])([CH3:14])/[CH:10]=[CH:11]/[CH:12]=[N:7]/[S:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6]
Reactant: CC(C)(C)S(N)=O
Reactant: CC(C)(C)/C=C/C=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)/C=C/C=N/S(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
To a solution of 2-methylpropane-2-sulfinamide (3.08 g, 0.025 mol) in dichloromethane (10 ml) was added CuSO4 (5.42 g, 0.034 mol) followed by (2E)-4,4-dimethylpent-2-enal (Journal of Organic Chemistry 1993, 58(9), 2517-22, 1.9 g, 0.017 mol) in dichloromethane (60 ml). The reaction mixture was stirred at RT overnight under nitrogen and then filtered through a pad of celite. The filtrate was evaporated under reduced pressure and purified by chromatography on silica gel eluting with 10% AcOEt/Hexane to give 2.1 g (58%) of the title compound; 1H NMR δ (ppm)(CDCl3, 400 MHz): 8.19 (1 H, d, J=9.2 Hz), 6.53 (1 H, d, J=15.7 Hz), 6.36 (1 H, dd, J=9.2, 15.7 Hz), 1.21 (9 H, s), 1.12 (9 H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1.O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[O:7])=[CH:4][N:3]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: COc1ccc(N)cc1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(NC(=O)c2ccc(Cl)nc2)cc1
Temperature: 120 °C
Yield: 60.9 %

Procedure:
6-Chloronicotinoyl chloride (35, 17.6 g, 100.0 mmol) was added to p-anisidine (33, 12.3 g, 100.0 mmol) dissolved in pyridine (150 mL) solution and the resulting reaction mixture was heated for 3 hours at 120° C. After cooling to room temperature and adding water, the produced gray precipitate was filtered and washed with 5% sodium bicarbonate aqueous solution. Then, the solvent was removed under reduced pressure to obtain the target compound 6-chloro-N-(4-methoxyphenyl)nicotinamide (37, 16.0 g, 60%).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[S:4][C:3]=1/[CH:8]=[CH:9]/[C:10](N(C)C)=O.[N+]([O-])(O)=O.[N+:19]([C:22]1[CH:23]=[C:24]([NH:28][C:29]([NH2:31])=[NH:30])[CH:25]=[CH:26][CH:27]=1)([O-:21])=[O:20].[OH-].[Na+]>COCCO>[CH3:7][C:5]1[S:4][C:3]([C:8]2[CH:9]=[CH:10][N:31]=[C:29]([NH:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=3)[N:30]=2)=[C:2]([CH3:1])[N:6]=1
Reactant: Cc1nc(C)c(/C=C/C(=O)N(C)C)s1
Reactant: N=C(N)Nc1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: COCCO
Product: Cc1nc(C)c(-c2ccnc(Nc3cccc([N+](=O)[O-])c3)n2)s1
Yield: 46.1 %

Procedure:
A mixture of 3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone (1.0 mmol, 0.21 g) and N-(3-nitro-phenyl)-guanidine nitrate (1.0 mmol, 0.24 g) in 2-methoxyethanol (5 mL) was treated with NaOH (40 mg). The reaction mixture was refluxed under N2 for 20 h. The solvent was evaporated and the residue was purified by flash chromatography (EtOAc/PE, 5:1) and recrystallisation from EtOAc/MeOH to afford the title compound as a yellow solid (151 mg, 46%). M.p. 176-178° C. LC−MS: m/z=328 (M+1). C15H13N5O2S requires: C, 55.03; H, 4.00; N, 21.39; found: C, 54.67; H, 3.88; N, 21.77. 1H-NMR (300 MHz, CDCl3) δ2.72 (s, 3H, CH3), 2.74 (s, 3H, CH3), 7.06 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 7.74-7.92 (m, 3H, Ph-H), 8.46 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 8.91 (t, 1H, J=4.3, 2.1 Hz, Ph-H).
Reaction SMILES: C1(=O)[NH:5][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].NN>C(O)(C)C>[CH2:16]([O:15][C:13]([NH:12][C@H:9]1[CH2:10][CH2:2][C@H:3]([CH2:4][NH2:5])[CH2:7][CH2:8]1)=[O:14])[C:17]1[CH:4]=[CH:3][CH:2]=[CH:10][CH:9]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCOC(N)=O
Agent: NN
Solvent: CC(C)O
Product: NC[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Reaction time: 4 h

Procedure:
The above urethane phthalimide was treated with 1 equiv anhydrous hydrazine in isopropanol for 18 h at room temperature followed by 4 h reflux. The mixture was concentrated, diluted with cold aqueous acetic acid and filtered to remove phthalazinedione. The aqueous layer was basified with NaOH followed by extraction with ethyl acetate, drying, and evaporation to afford the desired product as a solid. mp 118-121.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([CH2:32][C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[C:8](=[O:9])[N:7]([CH2:10][CH:11]2[CH2:16][CH:15]3[CH2:17][CH:13]([C:14]3([CH3:19])[CH3:18])[CH:12]2[CH3:20])[C:6](=[CH:21][C:22]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=2)=[O:23])[NH:5]1.C(NC(C)C)(C)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>C(Cl)Cl>[C:28]([C:27]1[CH:26]=[CH:25][C:24]([C:22](=[O:23])[CH:21]=[C:6]2[NH:5][C:4]([CH2:3][CH2:2][O:1][S:47]([CH3:46])(=[O:49])=[O:48])([CH2:32][C:33]3[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=3)[C:8](=[O:9])[N:7]2[CH2:10][CH:11]2[CH2:16][CH:15]3[CH2:17][CH:13]([C:14]3([CH3:18])[CH3:19])[CH:12]2[CH3:20])=[CH:31][CH:30]=1)#[N:29]
Reactant: CS(=O)(=O)Cl
Reactant: CC1C(CN2C(=O)C(CCO)(Cc3ccncc3)NC2=CC(=O)c2ccc(C#N)cc2)CC2CC1C2(C)C
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: CC1C(CN2C(=O)C(CCOS(C)(=O)=O)(Cc3ccncc3)NC2=CC(=O)c2ccc(C#N)cc2)CC2CC1C2(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
4-{[4-(2-Hydroxy-ethyl)-5-oxo-4-pyridin-4-ylmethyl-1-((+)-(2,6,6-trimethyl-bicyclo[3.1.1]hept-3-ylmethyl))-imidazolidin-2-ylidene]-acetyl}-benzonitrile (1.76 g, 3.44 mMol) and diisopropylamine (0.90 mL, 5.16 mMol) were dissolved in CH2Cl2 (20 mL) under an atmosphere of dry N2. To this solution was added methanesulfonyl chloride (0.41 mL, 5.16 mMol) and the mixture was stirred at ambient temperature for 20 minutes. The mixture was concentrated under vacuum and was partitioned between Et2O-EtOAc (50:50) and water. The organic layer was washed succesively with saturated aquoeus NaHCO3 solution, brine and then dried over MgSO4, filtered and concentrated under vacuum to give the titled compound as an oil as a 1:1 mixture of diastereomers.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][C:7](=[O:10])[N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].O.[F:19][C:20]1[CH:21]=[C:22]([Mg]Br)[CH:23]=[CH:24][C:25]=1[F:26]>O1CCCC1>[C:14]([O:13][C:11]([NH:6][C@@H:5]([CH2:9][CH2:8][C:7]([C:23]1[CH:22]=[CH:21][C:20]([F:19])=[C:25]([F:26])[CH:24]=1)=[O:10])[C:3]([O:2][CH3:1])=[O:4])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: Fc1ccc([Mg]Br)cc1F
Reactant: COC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@H](CCC(=O)c1ccc(F)c(F)c1)NC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of (S)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (5.5 g) in tetrahydrofuran (100 mL), 3,4-difluorophenylmagnesium bromide (0.5 M solution in tetrahydrofuran; 50 mL) was added dropwise at −40° C. over 10 minutes, and the reaction solution was stirred at −40° C. to 0° C. for two hours. Water was added to the solution in small portions, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 8.0 g of the title compound. The property values of the compound are as follows.