Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:11]1[N:12]=[C:13]([C:16]([N:18]2[CH2:23][C@@H:22]([CH3:24])[O:21][C@@H:20]([CH3:25])[CH2:19]2)=[O:17])[S:14][CH:15]=1.BrC1N=C(C(N2C[C@@H](C)O[C@@H](C)C2)=O)SC=1.Br[C:43]1[CH:48]=[CH:47][C:46]([S:49]([NH2:52])(=[O:51])=[O:50])=[CH:45][CH:44]=1.C([O-])(=O)C.[K+]>CC(N(C)C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:11]1[N:12]=[C:13]([C:16]([N:18]2[CH2:23][C@H:22]([CH3:24])[O:21][C@H:20]([CH3:25])[CH2:19]2)=[O:17])[S:14][C:15]=1[C:43]1[CH:48]=[CH:47][C:46]([S:49]([NH2:52])(=[O:51])=[O:50])=[CH:45][CH:44]=1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Reactant: C[C@@H]1CN(C(=O)c2nc(N3CCc4c(Cl)cccc43)cs2)C[C@H](C)O1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: C[C@@H]1CN(C(=O)c2nc(Br)cs2)C[C@H](C)O1
Solvent: CC(=O)N(C)C
Product: C[C@@H]1CN(C(=O)c2nc(N3CCc4c(Cl)cccc43)c(-c3ccc(S(N)(=O)=O)cc3)s2)C[C@H](C)O1
Temperature: 150 °C
Yield: 26 %

Procedure:
To a solution of (cis) (4-(4-chloroindolin-1-yl)thiazol-2-yl) (2,6-dimethylmorpholino) methanone (Step-2, of compound 45, 0.6 g, 1.59 mmol in dimethyl acetamide (10 ml) were added 4-bromobenzenesulfonamide (0.41 g, 1.75 mmol) and potassium acetate (0.31 g, 3.18 mmol) at 25° C. in a tube, the nitrogen gas was bubbled through reaction mixture for 15 minutes. To this was added palladium (II) acetate (0.03 g, 0.16 mmol) under nitrogen and the tube was sealed. The reaction mixture was heated at 150° C. for 18 hr under stirring. The progress of reaction was monitored by TLC. The reaction mixture was cooled to 25° C. and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (30 ml), reaction mixture was washed with water (2×10 ml), dried over sodium sulphate and concentrated under reduced pressure to obtain a crude product; which was purified by preparative HPLC to obtain the title compound (0.22 g, 26.0%). MS: m/z 533 (M+1).
Reaction SMILES: [CH2:1]([C:3]1([CH2:12][CH3:13])[CH:8]([NH2:9])[CH2:7][CH2:6][CH2:5][C:4]1([CH3:11])[NH2:10])[CH3:2]>[Pt].CC(C)=O>[CH:1]([NH:10][C:4]1([CH3:11])[CH2:5][CH2:6][CH2:7][CH:8]([NH:9][CH:4]([CH3:11])[CH3:5])[C:3]1([CH2:1][CH3:2])[CH2:12][CH3:13])([CH3:3])[CH3:2]
Reactant: CCC1(CC)C(N)CCCC1(C)N
Agent: [Pt]
Solvent: CC(C)=O
Product: CCC1(CC)C(NC(C)C)CCCC1(C)NC(C)C
Temperature: 120 °C
Yield: 95 %

Procedure:
Diethyl(methyl)-1,3-cyclohexanediamine, as a mixture of its 2,4-diethyl-6-methyl- and 4,6-diethyl-2-methyl-isomers was made as described in Example 4. Diethyl(methyl)-1,3-cyclohexanediamine, as a mixture of its 2,4-diethyl-6-methyl- and 4,6-diethyl-2-methyl-isomers (10 g), Pt(S)/C (0.5 g), Amberlyst-15 (0.5 g), and acetone (50 g) were charged into a 100 mL metal autoclave at 22° C. The closed autoclave was purged 3 times with 125 psig (9.63×105 Pa) of H2 at 22° C. to remove traces of air. The reaction mixture was then heated at 110-130° C. under 125 psig (9.63×105 Pa) of H2 for 8 hrs (until no further H2 uptake was observed). The product mixture was cooled to 22° C. and degassed. A diluted product sample was analyzed by GC (100° C. for 5 minutes at 110° C. per minute rate; final temperature, 270° C.). The GC data (normalization method) showed 100% conversion of diethyl(methyl)-1,3-cyclohexanediamine, and a 95-97% yield of N,N′-diisopropyl-[diethyl(methyl)-1,3-cyclohexanediamine].
Reaction SMILES: Cl[C:2]([C:4]1[CH:47]=[CH:46][C:7]([CH2:8][O:9][CH:10]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH3:35])=[CH:18][CH:17]=3)[CH2:14][CH2:13][N:12]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])[CH2:11]2)=[CH:6][C:5]=1[O:48][CH2:49][CH2:50][CH2:51][O:52][CH3:53])=[O:3].[CH3:54][NH:55][CH3:56]>C1(C)C=CC=CC=1>[CH3:54][N:55]([CH3:56])[C:2]([C:4]1[CH:47]=[CH:46][C:7]([CH2:8][O:9][CH:10]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH3:35])=[CH:18][CH:17]=3)[CH2:14][CH2:13][N:12]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])[CH2:11]2)=[CH:6][C:5]=1[O:48][CH2:49][CH2:50][CH2:51][O:52][CH3:53])=[O:3]
Reactant: COCCCOc1cc(COC2CN(C(=O)OCc3ccccc3)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1C(=O)Cl
Reactant: CNC
Solvent: Cc1ccccc1
Product: COCCCOc1cc(COC2CN(C(=O)OCc3ccccc3)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1C(=O)N(C)C
Reaction time: 0.25 h

Procedure:
The solution of 0.290 g of benzyl 3-[4-chlorocarbonyl-3-(3-methoxypropoxy)benzyloxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 69b) in 1.0 ml of toluene is slowly added dropwise to 2.4 ml of dimethylamine solution (5.6M in ethanol, precooled to 0° C.). After 15 minutes, the reaction solution is poured onto water (20 ml) and extracted with tert-butyl methyl ether (2×20 ml). The organic phases are washed with brine (1×30 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.06 (2:1 EtOAc-heptane); Rt=5.67.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)=O.[NH2:15][C:16]([NH2:18])=[S:17]>CO>[NH2:18][C:16]1[S:17][CH:2]=[C:3]([C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)[N:15]=1
Reactant: NC(N)=S
Reactant: COC(=O)c1ccc(C(=O)CBr)cc1
Solvent: CO
Product: COC(=O)c1ccc(-c2csc(N)n2)cc1

Procedure:
Methyl 4-(bromoacetyl)benzoate (300 mg, 1.17 mmol) and thiourea 110 mg, 1.40 mmol) were taken in MeOH (5 ml) and refluxed for 2 hours. The precipitated product was collected by filtration, washed with MeOH and dried (260 g). MS (ESP): 235 (M+H+) for C11H10N2O2S; NMR: 3.87 (s, 3H), 7.38 (s, 1H), 7.90 (d, 2H), 8.01 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][C:16](OC)=[O:17])[CH:5]=[CH:6][C:7]=1[F:8].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][CH2:16][OH:17])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)CCc1cnoc1-c1ccc(F)c(Cl)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCc1cnoc1-c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
To a solution of methyl 3-[5-(3-chloro-4-fluorophenyl)-4-isoxazolyl]propionate (3.00 g) in tetrahydrofuran (25 ml) was gently added diisobutylaluminum hydride (1.0 M hexane solution, 25 ml) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 3-[5-(3-chloro-4-fluorophenyl)-4-isoxazolyl]propan-1-ol (2.59 g, yield 95%) was obtained as a pale yellow oil from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). NMR (CDCl3) δ: 1.40 (1H, br s), 1.82–2.00 (2H, m), 2.70–2.84 (2H, m), 3.66–3.78 (2H, m), 7.20–7.32 (1H, m), 7.55–7.67 (1H, m), 7.76–7.84 (1H, m), 8.22 (1H, s).
Reaction SMILES: Cl.[F:2][C:3]1[CH:24]=[C:23]([NH:25][C:26]([NH:28][C:29](=[O:37])[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[S:27])[CH:22]=[CH:21][C:4]=1[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([C:16](O)=[O:17])[CH:14]=2)[N:9]=[CH:8][CH:7]=1.[CH:38]([O:41][CH2:42][CH2:43][CH2:44][NH2:45])([CH3:40])[CH3:39]>O1CCCC1>[F:2][C:3]1[CH:24]=[C:23]([NH:25][C:26]([NH:28][C:29](=[O:37])[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[S:27])[CH:22]=[CH:21][C:4]=1[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([C:16]([NH:45][CH2:44][CH2:43][CH2:42][O:41][CH:38]([CH3:40])[CH3:39])=[O:17])[CH:14]=2)[N:9]=[CH:8][CH:7]=1
Reactant: CC(C)OCCCN
Reactant: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2cc1C(=O)O
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2cc1C(=O)NCCCOC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
Compound 1e (13.2 mg), 3-isopropoxypropylamine (9.11 μL), and 4-(5,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholine hydrochloride n-hydrate (hereinafter referred to as DMTMM•n-hydrate) (8.67 mg) were dissolved in tetrahydrofuran (1 mL), followed by stirring at room temperature for 2 hours. The reaction mixture was distilled under reduced pressure, and water was added to the residue. The precipitate was filtrated, to thereby yield the titled compound 1 (11.6 mg, yield: 79%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:20]([CH3:21])=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[C:17]3[C:13]=2[CH2:14][CH2:15][CH2:16]3)=[CH:7][C:4]=1[CH:5]=O.[Br-].[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:51]=[CH:52][CH:53]=1)[CH2:31][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:20]([CH3:21])=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[C:17]3[C:13]=2[CH2:14][CH2:15][CH2:16]3)=[CH:7][C:4]=1[CH:5]=[CH:31][C:30]1[CH:51]=[CH:52][CH:53]=[C:28]([O:27][CH3:26])[CH:29]=1
Reactant: COc1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)cc1C=O
Agent: [Br-]
Product: COc1cccc(C=Cc2cc(Oc3c(C)cc([N+](=O)[O-])c4c3CCC4)ccc2OC)c1

Procedure:
4-{4-Methoxy-3-[2-(3-methoxyphenyl)vinyl]phenoxy}-5-methyl-7-nitroindane was prepared in a similar manner to those described in Reference Example 15 using 2-methoxy-5-(5-methyl-7-nitroindan-4-yloxy)benzaldehyde instead of 2-benzyloxy-5-(5-methyl-7-nitroindan-4-yloxy)benzaldehyde and using (3-methoxybenzyl) triphenylphosphonium bromide instead of furfuryltriphenylphosphonium bromide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])[CH:5]=[N:4][C:3]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[F:20].[F:21][C:22]1[C:23]([Sn](CCCC)(CCCC)CCCC)=[N:24][CH:25]=[C:26]([F:32])[C:27]=1[Si](C)(C)C.[Cl-].[Li+]>[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[F:21][C:22]1[C:23]([C:2]2[N:7]=[C:6]([NH:8][C:9]([CH:11]3[CH2:13][CH2:12]3)=[O:10])[CH:5]=[N:4][C:3]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[F:20])=[N:24][CH:25]=[C:26]([F:32])[CH:27]=1
Reactant: O=C(Nc1cnc(-c2ccncc2F)c(Cl)n1)C1CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncc(F)c([Si](C)(C)C)c1F
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Product: O=C(Nc1cnc(-c2ccncc2F)c(-c2ncc(F)cc2F)n1)C1CC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
In a Schienk tube were charged N-[6-chloro-5-(3-fluoropyridin-4-yl)pyrazin-2-yl]cyclopropanecarboxamide (Preparation 10, 70 mg, 0.24 mmol), 3,5-difluoro-2-tributylstannanyl-4-trimethylsilylpyridine (prepared according to the procedure described in J. Med. Chem. 2006, 49(1), 35-38) (177.6 mg, 0.48 mmol), copper(I) iodide (2.28 mg, 12 μmol), lithium chloride (previously dried) (10.14 mg, 0.24 mmol) and dioxane (1.5 mL). The mixture was submitted to three vacuum-argon cycles, then tetrakis(triphenylphosphine)palladium(0) (27.64 mg, 24 μmol) was added and the mixture purged in the same way and the mixture was heated at 100° C. for 18 h. The reaction was concentrated, ethyl acetate (1 ml) and HCl 2N (5 ml) were added and the reaction was stirred at room temperature for 1 h. Ethyl acetate was added, the organic layer was separated, and the aqueous phase was extracted with ethyl acetate. The combined extracts were washed with water and the organic layer was dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica flash, using dichloromethane/methanol (100:1) to yield the title compound (23 mg, 26%) as a yellowish solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.C([Sn](CCCC)(CCCC)[C:24]1[CH:29]=[CH:28][N:27]=[N:26][CH:25]=1)CCC>O1CCOCC1>[CH:11]([N:8]1[C:9]2[CH:10]=[C:2]([C:24]3[CH:29]=[CH:28][N:27]=[N:26][CH:25]=3)[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]=2[C:6]([CH3:14])=[CH:7]1)([CH3:13])[CH3:12]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Reactant: COC(=O)c1cc(Br)cc2c1c(C)cn2C(C)C
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnnc2)cc2c1c(C)cn2C(C)C
Temperature: 105 °C

Procedure:
To a 50 ml round bottom flask was added; methyl 6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxylate (150 mg, 0.484 mmol), PdCl2(dppf)-CH2C12 adduct (39.5 mg, 0.048 mmol) and 1,4-Dioxane (4836 μl) followed with 4-(tributylstannyl)pyridazine (179 mg, 0.484 mmol) and a magnetic stir bar. The flask was equipped with a reflux condenser and an exhaust bubbler and heated to 105° C. The reaction solution changed to a dark brown at 30 minutes. LCMS (105C-3 h) showed the reaction to be complete. The reaction solvent was removed in-vacuo and the remaining residue taken up with DMSO. (1.5 ml). The DMSO solution was purified by reverse phase HPLC using a Phenomenex Gemini 100×30 mm column, neutral acetonitrile and 0.1% formic acid in water, 40-70%, 10 min gradient. The desired fractions were dried in a Genovac EZ-2 evaporator and the solid residues combined. The product, methyl 1-isopropyl-3-methyl-6-(pyridazin-4-yl)-1H-indole-4-carboxylate, was obtained as a white solid. 1H NMR (400 MHz, METHANOL-δ4) 9.68 (δ, J=1.26 Hz, 1H), 9.19 (d, J=5.56 Hz, 1H), 8.20 (d, J=1.52 Hz, 1H), 8.13 (dd, J=2.53, 5.56 Hz, 1H), 7.98 (d, J=1.52 Hz, 1H), 7.48 (s, 1H), 4.96 (dt, J=6.60, 13.33 Hz, 1H), 4.00 (s, 3H), 2.39 (s, 3H), 1.56 (d, 6H). MS(ES) [M+H]+ 310.2.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10]([NH:13][C:14]2[S:15][C@@H:16]([F:20])[C@H:17](O)[N:18]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].C(N(CC)CC)C.C(OC(=O)C)(=O)C>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([S:10]([NH:13][C:14]2[S:15][C:16]([F:20])=[CH:17][N:18]=2)(=[O:11])=[O:12])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: N#Cc1cc(S(=O)(=O)NC2=N[C@@H](O)[C@H](F)S2)ccc1F
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cc(S(=O)(=O)Nc2ncc(F)s2)ccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.5 %

Procedure:
To a suspension of 3-cyano-4-fluoro-N-[(4S,5R)-5-fluoro-4-hydroxy-4,5-dihydro-1,3-thiazol-2-yl]benzenesulfonamide (Preparation 33, 1.42 g, 4.45 mmol) in dichloromethane (150 mL) was added triethylamine (6.20 mL, 44.5 mmol) and acetic anhydride (1.30 mL, 13.8 mL). The reaction mixture was stirred at room temperature under an atmosphere of nitrogen for 18 hours. The mixture was washed with a 2M aqueous solution of hydrogen chloride. The organics were separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting residue was triturated with dichloromethane to afford the title compound as a pale yellow solid (825 mg, 62%).
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:14]([CH3:16])[CH3:15])=[S:13])=[CH:7][CH:6]=1)=[O:2].[C:17](NNC1C=CC(N)=CC=1)(=O)C.CN(C)C(Cl)=S.C(N(CC)C(C)C)(C)C>>[C:1]([NH:3][NH:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([N:14]([CH3:16])[CH3:15])=[S:13])=[CH:9][CH:10]=1)(=[O:2])[CH3:17]
Reactant: CC(=O)NNc1ccc(N)cc1
Reactant: CN(C)C(=S)Nc1ccc(NNC=O)cc1
Agent: CN(C)C(=S)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NNc1ccc(NC(=S)N(C)C)cc1

Procedure:
The procedure for the preparation of NA-1 in Example 1 was followed with 1-acetyl-2-(4-aminophenyl)hydrazine (0.82 g, 0.005 mole), dimethylthiocarbamoyl chloride (0.62 g, 0.005 mole) and N,N-diisopropylethylamine (0.65 g, 0.005 mole). Yield 0.30 g (24 percent), m.p. 187°-189° C.
Reaction SMILES: [N:1](=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:10])([CH3:9])[S:4]1)[OH:2].[CH3:11][N:12]=[C:13]=[O:14]>C(N(CC)CC)C.ClCCl>[CH3:11][NH:12][C:13]([O:2][N:1]=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:10])([CH3:9])[S:4]1)=[O:14]
Reactant: CC1=NC(=NO)SC1(C)C
Reactant: CN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)ON=C1N=C(C)C(C)(C)S1

Procedure:
15.8 g (0.1 mol) of 2-oxo-4,5,5-trimethyl-3-thiazoline-oxime and 8.5 g. (0.15 mol) of methyl isocyanate were dissolved in 100 ml. of anhydrous dichloromethane. After a few drops of triethylamine were added to this solution, the mixture warmed to 40°-45° C. The mixture was warmed to 50°-60° C. for a short time and then the solvent was distilled off under vacuum. The residue was dissolved in 50 ml. of hot ethyl acetate, treated with carbon and filtered. The hot filtrate was concentrated to 20-30 ml. and treated with 20-30 ml. of hexane. The precipitated crystals were filtered off under vacuum, washed with ether and dried to yield 2-oxo-4,5,5-trimethyl-3-thiazoline-O-(methylcarbamoyl)-oxime, m.p. 123°-125° C.
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH2:23][CH3:24])[CH2:3][C:4](=O)[CH2:5][NH:6][C:7](=O)[CH2:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[N:11]=1.C([O-])(=O)C.[NH4+:30].C(OCC)(=O)C.[OH-].[NH4+]>C(O)(=O)C.O>[CH3:1][C:2]([CH3:25])([CH2:23][CH3:24])[CH2:3][C:4]1[NH:30][C:7]([CH2:8][CH2:9][C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[N:11]=2)=[N:6][CH:5]=1
Reactant: CCC(C)(C)CC(=O)CNC(=O)CCc1nc(-c2ccccn2)no1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CCC(C)(C)Cc1cnc(CCc2nc(-c3ccccn3)no2)[nH]1
Temperature: 180 °C

Procedure:
To N-(4,4-dimethyl-2-oxohexyl)-3-(3-pyridin-2-yl-[1,2,4]oxadiazol-5-yl)propionamide (413 mg, 1.2 mmol) in acetic acid (3 mL) was added ammonium acetate (924 mg, 12 mmol), and the mixture was heated at 180° C. for 20 minutes in a microwave reactor (maximum 150 W). The reaction mixture was poured into ethyl acetate and water, and pH of the aqueous layer was adjusted to 9 with concentrated ammonium hydroxide. The organic layer was separated and concentrated to give a residue. The residue was purified by flash column chromatography (silica gel, eluting with 0-15% 9:1 methanol/ammonium hydroxide mixture in methylene chloride) to afford the title compound, which was converted to the HCl salt with 1M HCl in diethyl ether. 1H NMR (500 MHz, CD3OD) δ 8.83-8.85 (m, 1H), 8.32-8.35 (m, 2H), 7.84-7.89 (m, 1H), 7.22 (s, 1H), 3.59-3.61 (m, 4H), 2.21 (s, 2H), 1.26 (q, J=7.7 Hz, 2H), 0.85 (m, 9H); LC-MS: m/e 326 (M+H).
Reaction SMILES: [C:1]([C:4]1[N:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)(=[O:3])[CH3:2].[C:13]1([NH:19][C:20](=[O:23])[NH:21][NH2:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[C:13]1([NH:19][C:20](=[O:23])[NH:21][N:22]=[C:6]([OH:8])[C:5]2[CH:9]=[CH:10][CH:11]=[N:12][C:4]=2[C:1](=[O:3])[CH3:2])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NNC(=O)Nc1ccccc1
Reactant: CC(=O)c1ncccc1C(=O)O
Solvent: CO
Product: CC(=O)c1ncccc1C(O)=NNC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-acetylnicotinic acid (0.40 g, 2.4 mmol) in 7 ml of methanol is added a solution of 4-phenylsemicarbazide (0.37 g, 2.4 mmol) in 5 ml of methanol. The mixture is stirred at RT overnight, after which the solid precipitate is collected by filtration, washed with ethanol and dried to give 2-acetylnicotinic acid 4-phenylsemicarbazone, m.p. 174° (dec.) (compound 1, Table A).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[H-].[Na+].[CH2:11]([O:13][C:14]([C@@H:16]1[CH2:20][CH:19](OS(C)(=O)=O)[CH2:18][C@H:17]1[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)=[O:15])[CH3:12].Cl>O1CCCC1>[CH2:11]([O:13][C:14]([C@@H:16]1[CH2:20][CH:19]([S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:18][C@H:17]1[CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)=[O:15])[CH3:12]
Reactant: CCOC(=O)[C@@H]1CC(OS(C)(=O)=O)C[C@H]1COc1ccc(Cl)cc1
Reactant: Sc1ccccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1CC(Sc2ccccc2Cl)C[C@H]1COc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 96 h
Yield: 52.9 %

Procedure:
To a solution of 2-chlorobenzenthiol (306 mg) in tetrahydrofuran (4 mL) was added a suspension of sodium hydride in oil (55% w/w, 107 mg). The white suspension was cooled down to 0° C. then a solution of (1R,2R)-2-(4-Chloro-phenoxymethyl)-4-methanesulfonyloxy-cyclopentanecarboxylic acid ethyl ester (epimeric mixture, 343 mg) in tetrahydrofuran (5 mL) was slowly added. The reaction mixture was stirred at room temperature for 4 days. Hydrochloric acid (1N) was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with an aqueous saturated solution of sodiumcarbonate and brine then dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with a gradient of cyclohexane/ethylacetate (19:1 to 3:1 v/v) as eluant to afford the title compound (0.205 g, 53%) as light yellow oil. MS (EI): 424.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[CH2:9](O)[CH:10](O)[CH2:11]O.OS(O)(=O)=O.[OH-].[Na+]>O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[CH:9][CH:10]=[CH:11][N:8]=2)[N:7]=1
Reactant: OCC(O)CO
Reactant: Cc1ccc(N)cn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc2ncccc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45.3 %

Procedure:
A mixture of 6-methylpyridin-3-amine (8-1) (4.8 g, 44.4 mmol) and propane-1,2,3-triol (20 g, 222 mmol) in 5 mL of H2O was stirred at room temperature for 5 min, then concentrated H2SO4 (47 g, 488 mmol) was added dropwise within 20 min at room temperature. After addition, the reaction mixture was stirred at 150° C. for 30 min. After cooled to room temperature, the mixture was poured into water, adjusted with 6 N NaOH to pH 13, then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by chromatography on silica gel to afford the title compound (2.9 g). MS: 145 (M+1)+.
Reaction SMILES: C1(C2N=C([C:9]([NH2:11])=[NH:10])SC=2)CC1.Br[C:13]1[S:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=1.BrCC(C1CC1)=O>>[F:19][C:18]([F:21])([F:20])[C:16]1[N:17]=[C:13]([C:9]([NH2:11])=[NH:10])[S:14][CH:15]=1
Reactant: N=C(N)c1nc(C2CC2)cs1
Reactant: FC(F)(F)c1csc(Br)n1
Agent: O=C(CBr)C1CC1
Product: N=C(N)c1nc(C(F)(F)F)cs1

Procedure:
4-Trifluoromethyl-thiazole-2-carboxamidine (Compound U) was prepared in analogy to Compound M with procedure shown in Example 10 by using 2-bromo-4-trifluoromethyl-thiazole (CAS: 41731-39-9) instead of 2-bromo-4-cyclopropyl-thiazole which is made from 2-bromo-1-cyclopropyl-ethanone in Example 10. MS: calc'd (MH+) 196, measured (MH+) 196.