Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:17]([C:18]([OH:20])=[O:19])=[C:16](C)[C:15](C=C)=C[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[N+]1([O-])CC[O:28]CC1.C([O-])(O)=O.[Na+].[CH2:37]1[CH2:41][O:40][CH2:39][CH2:38]1>O.O=[Os](=O)(=O)=O>[OH:28][CH:37]([C:38]1[C:16]([CH3:15])=[C:17]([C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[CH:13][CH:39]=1)[C:18]([OH:20])=[O:19])[CH2:41][OH:40]
Reactant: C=Cc1ccc(NS(=O)(=O)c2ccc(F)cc2)c(C(=O)O)c1C
Reactant: C1CCOC1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1c(C(O)CO)ccc(NS(=O)(=O)c2ccc(F)cc2)c1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.5 %

Procedure:
A solution of Example 173C (0.21 g, 0.62 mmol) in THF (8 mL) and water (1 mL) was treated with N-methylmorpholine oxide (0.11 g, 0.95 mmol) in one portion and dropwise with OsO4 (2.5% wt solution in tert-butanol, 0.5 mL). The mixture was stirred at room temperature for 4 hours, treated with water (20 mL), followed by 5% aqueous NaHCO3 (10 mL), and extracted with diethyl ether (2×10 mL). The aqueous solution was adjusted to pH 2.0 with 1N HCl and extracted with ethyl acetate (3×10 mL). The combined extracts were dried (MgSO4) filtered, and concentrated to provide the desired product (101 mg, 43.5%). 1H NMR (DMSO-d6) δ 2.22 (s, 3H), 4.73 (m, 2H), 5.18 (m, 1H), 6.79 (d, 1H), 7.34 (d, 1H), 7.40 (m, 2H), 7.80 (m, 2H), 9.80 (br s, 1H), 12.90 (br s, 1H); MS (ESI(−)) m/e 368 (M−H)−.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]1([C:22]([NH:35][CH:36]2[C:56](=[O:57])[N:38]3[CH:39]([C:44](=[N:46][CH2:47][C:48]4[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=4)[NH2:45])[C:40]([CH3:43])([CH3:42])[S:41][C@H:37]23)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:58](O)(=[O:63])[CH2:59][C:60](O)=[O:61]>CN(C)C=O.C(Cl)Cl>[C:29]1([C:22]([NH:35][CH:36]2[C:56](=[O:57])[N:38]3[CH:39]([C:44]4[N:46]([CH2:47][C:48]5[CH:49]=[CH:50][C:51]([O:54][CH3:55])=[CH:52][CH:53]=5)[C:58](=[O:63])[CH2:59][C:60](=[O:61])[N:45]=4)[C:40]([CH3:43])([CH3:42])[S:41][C@H:37]23)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COc1ccc(CN=C(N)C2N3C(=O)C(NC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@H]3SC2(C)C)cc1
Reactant: O=C(O)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(CN2C(=O)CC(=O)N=C2C2N3C(=O)C(NC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@H]3SC2(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 21.44 g. (104 mmoles) of N,N'-dicyclohexylcarbodiimide in 122 ml. of methylene chloride and 15 ml. dimethylformamide at -5° C., a solution of 29.9 g. (52 mmoles) of 6-(triphenylmethylamino)-2,2-dimethyl-3-[N'-(4-methoxybenzyl)amidino]penam and 5.41 g. (52 mmoles) of malonic acid in 122 ml. methylene chloride and 15 ml. dimethylformamide is added dropwise over 2 hours. The mixture is then stirred for 24 hours at 25° C. The N,N'-dicyclohexylurea precipitate (18.6 g., 79.8% of theory) is filtered off, and the filtrate washed with six 150 ml. portions of water. It is dried over anhydrous sodium sulfate and then rotoevaporated to yield the title compound in crude form as an orange foam (32.6 g.). The crude product is divided into two equal portions for silica gel chromatography (ethyl acetate elution) affording a total of 10.61 g. (31.6%) of the purified title compound. 1H--NHR (CDCl3) ppm (δ) 1.01 (3H, s, 2--CH3); 1.44 (3H, s, 2--CH3); 3.80 (3H, s, --OCH3); 4.31-4.73 (3H, m; 3-, 5- and 6--H); 5.25 (2H, s, --CH2 --); 4H, AB, Ha within a 7.18-7.68 multiplet, Hb centered at 6.91, J= 8 Hz, CH3O--C6H4 --); 7.18-7.68 (15H, m, C6H5 --).
Reaction SMILES: O=[C:2]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:3]([N:5]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=1)[C:6]1[CH:7]=[N:8][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:11]=1)=[O:4].Cl.[NH2:35][OH:36].N1C(C)=CC=CC=1C>CCO>[OH:36][N:35]=[C:2]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:3]([N:5]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:20][CH:19]=1)[C:6]1[CH:7]=[N:8][C:9]([C:12]([F:15])([F:13])[F:14])=[CH:10][CH:11]=1)=[O:4]
Reactant: NO
Reactant: O=C(C(=O)N(CCc1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)nc1)c1ccccc1
Agent: Cl
Solvent: Cc1cccc(C)n1
Solvent: CCO
Product: O=C(C(=NO)c1ccccc1)N(CCc1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 45.7 %

Procedure:
To a solution of 2-oxo-2-phenyl-N-[2-(4-trifluoromethyl-phenyl)-ethyl]-N-(6-trifluoromethyl-pyridin-3-yl)-acetamide (46 mg, 0.1 mmol) in EtOH (2 mL) was added hydroxylamine hydrochloride (14 mg, 0.2 mmol) and 2,6-lutidine (32 mg, 0.3 mmol) and the mixture stirred at ambient temperature for 36 h then concentrated and redissolved in EtOAc (5 mL), washed with 10% aqueous citric acid (3×5 mL), dried over Na2SO4, filtered, then purified by chromatography (SiO2, heptane:ethyl acetate=95:5 to 50:50) to afford the title compound (22 mg, 46%) as a white solid. MS m/e: 480.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][N:30]2[CH:34]=[CH:33][C:32]([NH2:35])=[N:31]2)[CH:24]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([NH:35][C:32]2[CH:33]=[CH:34][N:30]([CH2:29][C:25]3[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=3)[N:31]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Nc1ccn(Cc2cccnc2)n1
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)O)cc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)Nc2ccn(Cc3cccnc3)n2)cc1Cl
Reaction time: 2 h
Yield: 45.9 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid (prepared as in Example 1, 115 mg, 0.33 mmol), 1-pyridin-3-ylmethyl-1H-pyrazol-3-ylamine (72 mg, 0.41 mmol) and N,N-diisopropylethylamine (232 μL, 1.33 mmol) were combined in methylene chloride (1.7 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (139 mg, 0.37 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 50% ethyl acetate/chloroform to 5% methanol/chloroform) to afford (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-N-(1-pyridin-3-ylmethyl-1H-pyrazol-3-yl)-acetamide (76 mg, 46%) as a white solid after lyophilization from aqueous dioxane: LC-MS (ESI) m/e calcd for C23H24ClN5O4S [M+] 501.12, found 502 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.64 (m, 4 H, 2×CH2), 1.85 (m, 4 H, 2×CH2), 3.28 (s, 3 H, SO2CH3), 4.87 (m, 1 H, OCH), 5.26 (s, 2 H, NCH3), 6.78 (d, J=2.3 Hz, 1 H, Ar), 7.30 (dd, J=7.9, J=4.9 Hz, 1 H, Ar), 7.40 (d, J=2.3 Hz, 1 H, Ar), 7.51 (m, 1 H, Ar), 7.55 (dd, Jo=8.2, Jm=1.6 Hz, 1 H, Ar), 7.65 (d, Jm=1.6 Hz, 1 H, Ar), 8.18 (d, Jo=8.2 Hz, 1 H, Ar), 8.56 (m, 2H, Ar), 9.17 (s, 1 H, NH).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O:24]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20]I)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[CH3:43][N:44]([CH3:46])[CH3:45]>C(OCC)(=O)C.CCOCC>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O-:24])=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20][N+:44]([CH3:46])([CH3:45])[CH3:43])[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CCI)CS[C@H]12)c1nsc(N)n1
Reactant: CN(C)C
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C=CC[N+](C)(C)C)CS[C@H]12)c1nsc(N)n1
Reaction time: 0.17 h
Yield: 9.2 %

Procedure:
To a solution of diphenylmethyl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(3-iodo-1-propen-1-yl)-3-cephem-4-carboxylate (IX-1) (Z/E=2/1, 490 mg, 0.68 mmole) in ethyl acetate (14 ml) was added a 0.1M trimethylamine solution in ether (13.6 ml) in one portion. The mixture was stirred for 10 minutes and evaporated to dryness, and the residue was triturated with ether (20 ml). The resulting solid (490 mg) was added to trifluoroacetic acid (0.2 ml) containing one drop of anisole. After 1.5 hours' stirring, the mixture was evaporated to dryness under reduced pressure and the residual oil was triturated with ether (20 ml). The resulting precipitate was collected by filtration and dissolved in H2O (20 ml). Some insolubles were removed, and the aqueous solution was eluted on a C18 reverse phase column (the packing of PrepPAK-500/C18 cartridge, Waters' 30 ml) using water as eluant. Fractions containing the desired compound were combined and concentrated to a small volume and lyophilized to afford 30 mg (9.2%) of the title compound (I-1D) (8/E=1/1) as a colorless amorphous powder, melting at >150° C. (dec.).
Reaction SMILES: Cl.[CH2:2]([C@@H:9]1[CH2:20][N:19]2[C:11]([C:12]3[NH:13][C:14]([CH:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[N:15][C:16]=3[N:17]([CH2:22][C:23]([OH:25])=O)[C:18]2=[O:21])=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:31](N)[CH2:32][CH3:33].Cl.C([N:38]=C=NCCCN(C)C)C>O.O1CCOCC1>[CH2:2]([C@@H:9]1[CH2:20][N:19]2[C:11]([C:12]3[NH:13][C:14]([CH:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[N:15][C:16]=3[N:17]([CH:22]([CH2:31][CH2:32][CH3:33])[C:23]([NH2:38])=[O:25])[C:18]2=[O:21])=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)CN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2[nH]c(C3CCCC3)nc21
Reactant: CCCN
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CCCC(C(N)=O)N1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2[nH]c(C3CCCC3)nc21
Temperature: 25 °C
Reaction time: 96 h
Yield: 45.3 %

Procedure:
Compound 77(50 mg, 0.127 mmol) obtained in Example 77 was dissolved in water (1 mL) and 1,4-dioxane (1 mL), to the solution were added n-propylamine (14 μL, 0.176 mmol, 1.4 equivalents) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (24 mg, 0.127 mmol, 1.0 equivalent), and the mixture was stirred at room temperature for 4 days. The reaction solution was extracted with chloroform, and the extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform:methanol=98:2 to 90:10) to obtain the title compound (25 mg, 45%).
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:16][C:17]([F:27])([F:26])[O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10](=[O:12])[NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[C:19]([O:18][C:17]([F:16])([F:26])[F:27])[CH:20]=1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: Nc1cccc(OC(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1cccc(OC(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a mixture of Boc-L-proline (5 g, 23.23 mmol), 3-(trifluoromethoxy)aniline (3.73 mL, 27.88 mmol) and HBTU (13.2 g, 34.8 mmol) in DMF (60 mL) was added DIPEA (7.95 mL, 46.5 mmol) and the resulting yellow solution was stirred at RT under nitrogen. The solvent was concentrated under vacuum and the residue dissolved in EtOAc and washed with HCl 1N. The combined organic layers were neutralized by addition of an aqueous saturated solution of NaHCO3. The layers were separated and the aqueous one back-extracted twice with CH2Cl2. The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 3:1 to 2:1) to give the desired compound. TLC, Rf (c-hexane/EtOAc 1:1)=0.57; MS (LC/MS): 397.1 [M+Na]+, 275.2 [MH−Boc]+, 373.3 [M−H]−; tR (HPLC conditions a) 3.81 min.
Reaction SMILES: Br[CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:14][CH3:15])=[C:7]([O:12][CH3:13])[CH:8]=2)[C:3]1=O.[NH2:17][NH:18][C:19]([NH2:21])=[S:20]>O1CCOCC1>[CH3:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[O:14][CH3:15])[C:3]1[N:21]=[C:19]([NH:18][NH2:17])[S:20][C:2]=1[CH2:11][CH2:10]2
Reactant: NNC(N)=S
Reactant: COc1cc2c(cc1OC)C(=O)C(Br)CC2
Solvent: C1COCCO1
Product: COc1cc2c(cc1OC)-c1nc(NN)sc1CC2

Procedure:
A solution of 400 mg (1.4 mmol) of 2-bromo-6,7-dimethoxy-3,4-dihydronaphthalen-1(2H)-one and thiosemicarbazide (127 mg, 1.4 mmol) in 20 ml of anhydrous dioxane was stirred at 80° C. for 24 h. The resulting yellow precipitate was filtered and washed with dioxane (10 ml). The dried precipitate was then basified with 2 M Sodium Carbonate (20 ml) solution. The formed pale brown product was filtered at the pump and washed with water. The LCMS analysis showed the formation of the required 1-(7,8-dimethoxy-4,5-dihydronaphtho[1,2-d]thiazol-2-yl)hydrazine along with 7,8-dimethoxy-4,5-dihydro-4aH-naphtho[1,2-e][1,3,4]thiadiazin-3-amine.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:21][CH3:22])[CH2:4][N:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([O:15][CH3:16])[C:8](=[O:17])[C:7]([C:18]([OH:20])=O)=[CH:6]1.C(N(CC)C(C)C)(C)C.Cl.[F:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[C@H:41]([NH2:43])[CH3:42].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[F:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[C@H:41]([NH:43][C:18]([C:7]1[C:8](=[O:17])[C:9]([O:15][CH3:16])=[C:10]([C:11]([O:13][CH3:14])=[O:12])[N:5]([CH2:4][CH:3]([O:2][CH3:1])[O:21][CH3:22])[CH:6]=1)=[O:20])[CH3:42]
Reactant: COC(=O)c1c(OC)c(=O)c(C(=O)O)cn1CC(OC)OC
Reactant: C[C@@H](N)c1ccc(F)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(OC)c(=O)c(C(=O)N[C@H](C)c2ccc(F)cc2F)cn1CC(OC)OC
Reaction time: 1 h

Procedure:
1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (1-A, 0.315 g, 1.00 mmol), was suspended in acetonitrile (4 ml) and treated with N,N-diisopropylethylamine (DIPEA) (0.348 mL, 2.00 mmol), (R)-1-(2,4-difluorophenyl)ethanamine HCl salt (0.213 mg, 1.10 mmol) and HATU (0.418 g, 1.10 mmol). The reaction mixture was stirred for 1 hour and partitioned between dichloromethane and HCl (10% aq). The organic layer was separated and washed sodium bicarbonate (1M aq), dried over sodium sulfate, filtered and concentrated to afford crude (R)-methyl 5-(1-(2,4-difluorophenyl)ethylcarbamoyl)-1-(2,2-dimethoxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate which was used without purification in the next step. LCMS-ESI+ (m/z): [M+H]+ calculated for C21H25F2N2O7: 455.16; found: 455.1.
Reaction SMILES: O[C:2]1([C:7]#[C:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3]1.C(NCC)C.C([OH:24])C>>[N:14]1[CH:15]=[CH:16][C:11]([C:9]2[O:10][C:2]3([CH2:6][CH2:5][CH2:4][CH2:3]3)[C:7](=[O:24])[CH:8]=2)=[CH:12][CH:13]=1
Reactant: CCO
Reactant: O=C(C#CC1(O)CCCC1)c1ccncc1
Solvent: CCNCC
Product: O=C1C=C(c2ccncc2)OC12CCCC2
Reaction time: 1 h

Procedure:
To a stirred solution of 3-(1-hydroxycyclopentyl)-1-(pyridin-4-yl)prop-2-yn-1-one (0.42 g, 1.95 mmol) in ethanol (10 mL) was added diethyl amine (0.21 g, 2.9 mmol) EtOH (1 mL) dropwise at RT and the reaction mixture was stirred for additional 1 h. Then the EtOH was removed, diluted with EtOAc (20 mL), washed with water (10 mL), brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford 2-(pyridin-4-yl)-1-oxaspiro[4.4]non-2-en-4-one (0.4 g) as an oil.
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=O)=[C:2]=[S:3].C[C:15]1[N:16]=[CH:17][N:18]([CH2:20][CH2:21][CH2:22][NH2:23])[CH:19]=1>>[N:18]1([CH2:20][CH2:21][CH2:22][N:23]2[C:6](=[O:8])[C:5]3[C:4](=[CH:13][CH:12]=[CH:11][CH:10]=3)[NH:1][C:2]2=[S:3])[CH:19]=[CH:15][N:16]=[CH:17]1
Reactant: COC(=O)c1ccccc1N=C=S
Reactant: Cc1cn(CCCN)cn1
Product: O=c1c2ccccc2[nH]c(=S)n1CCCn1ccnc1

Procedure:
The compound was synthesized starting from methyl 2-isothiocyanatobenzoate (0.773 g, 4.0 mmol) and 3-(1H-imidazol-1-yl)propan-1-amine (9) (0.5 g, 4.0 mmol) as described above.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([CH2:9]Cl)[CH:5]=[CH:4][N:3]=1.[C:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)(=[O:13])[CH3:12]>CS(C)=O>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([CH2:9][N:17]2[CH2:18][CH2:19][N:14]([C:11](=[O:13])[CH3:12])[CH2:15][CH2:16]2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)N1CCNCC1
Reactant: Cc1c(CCl)ccnc1Cl
Solvent: CS(C)=O
Product: CC(=O)N1CCN(Cc2ccnc(Cl)c2C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2-Chloro-3-methyl-pyridin-4-yl)-methanol (12-4, impure, 0.200 g) was dissolved in 5 mL anhydrous DCM under N2. Anhydrous DMF (0.098 mL, 1.3 mmol) and POCl3 (0.118 mL, 1.27 mmol) were added and the reaction was stirred at RT for 17 h. The reaction was quenched with sat NaHCO3 (aq) and extracted 3× with DCM. The organic phases were dried over Na2SO4, filtered and concentrated to provide 2-chloro-4-chloromethyl-3-methyl-pyridine still contaminated with a major by-product. 2-Chloro-4-chloromethyl-3-methyl-pyridine (impure, 0.215 g) was stirred in 3 mL DMSO. 1-Acetylpiperazine (0.626 g, 4.88 mmol was added and the reaction was stirred at RT overnight. The solution was purified by directly loading onto a preparative reverse phase column to afford an oil which slowly crystallizes. TFA salt: 1H NMR (CD3OD) δ8.30 (d, 1H, J=5.0 Hz), 7.53 (d, 1H, J=5.0 Hz), 4.48 (s, 2H), 3.84 (bs, 4H), 3.39-3.30 (m, 4H), 2.14 (s, 3H).
Reaction SMILES: Cl.C[O:3][C:4](=[O:14])[C@H:5]([CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:13])[NH2:12])[NH2:6].C(N(C(C)C)CC)(C)C.COC1C=CC(N=NC(N[C@H](C(O)=O)CC2C=CC=CC=2)=O)=CC=1>CN(C)C=O>[NH2:6][C@H:5]([C:4]([OH:14])=[O:3])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:12])[NH2:13]
Reactant: COC(=O)[C@@H](N)CCCNC(=N)N
Agent: COc1ccc(N=NC(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N=C(N)NCCC[C@H](N)C(=O)O
Reaction time: 0.08 h

Procedure:
Operating mode: 1 equivalent of arginine methyl ester hydrochloride was taken up in dimethylformamide (3 ml/mmol). 1.1 equivalent of DIAE (diisopropyl ethylamine), 1 equivalent of N-(4-methoxyphenylazoformyl)-L-phenylalanine then 1.1 equivalent of TBTU (O-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate) were added. The necessary quantity of DIAE was added to obtain a pH of 7-8. After 5 min, it was evaporated to dryness and purified by chromatography (orange crystals).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[Na+].C(C1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1)=C.S([CH2:29][N+:30]#[C-])(C1C=CC(C)=CC=1)(=O)=O.Cl>CS(C)=O.O>[NH:30]1[CH:29]=[CH:3][C:2]([C:5]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[CH:1]1
Reactant: CC(C)(C)[O-]
Reactant: C=Cc1ccc(C(=O)OC)cc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(-c2cc[nH]c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.7 %

Procedure:
Sodium tert-butoxide (3.681 g, 38.3 mmol, 2.0 eq.) is suspended in anhydrous DMSO under nitrogen. To this a solution of methyl 4-vinylbenzoate (3.11 g 19.15 mmol, 1.0 eq.) and tosylmethyl isocyanide (4.86 g, 24.89 mmol, 1.3 eq.) in anhydrous DMSO is transferred via cannula. The dark brown mixture is stirred at room temperature for 16 hrs. The mixture is adjusted to pH 6 by addition of 10% HCl solution, diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic extract is washed with water (2×50 mL) and brine, dried over sodium sulfate and concentrated. The crude residue is purified by silica gel chromatography (20-40% ethyl acetate/hexanes) to give 990 mg (4.92 mmol, 25.7%) of methyl 4-(1H-pyrrol-3-yl)-benzoate as a cream colored solid. MS (ES+): m/e 201.08. 1H NMR (300 MHz, CDCl3): δ 8.39 (1H, br s), 8.00 (2H, d, J−9 Hz), 7.58 (2H, d, J=9 Hz), 7.20 (1H, m), 6.85 (1H, m), 6.60 (1H, m), 3.91 (3H, s).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=[C:14]([C:22](=[O:24])[CH3:23])[CH:13]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.O1CCC[CH2:26]1.C[Mg]Br.CCOCC>>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[N:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[N:15]=[C:14]([C:22]([OH:24])([CH3:26])[CH3:23])[CH:13]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: CC(=O)c1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)n1
Reactant: C1CCOC1
Agent: C[Mg]Br
Solvent: CCOCC
Product: CC(C)(O)c1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)n1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
1-[6-(1,4-Dioxaspiro[4.5]dec-8-yloxy)-2-(trifluoromethyl)pyrimidin-4-yl]ethanone (0.21 g, 0.60 mmol) was dissolved in tetrahydrofuran (6.00 mL, 74.0 mmol) and was cooled to −78° C., then 3.0 M methylmagnesium bromide in ether (0.30 mL, 0.90 mmol) was added. The reaction was stirred at −78° C. for 1 hour at which time LCMS analysis showed that it was mostly done. The reaction was quenched with sat. NH4Cl and was transferred to a separatory funnel and partitioned between water and EtOAc, the phases were separated and the aqueous phase was washed with additional EtOAc. The combined organic phase was washed with water, then sat. NaCl, dried over MgSO4 and filtered and the solvent removed in vacuo to leave the crude product. MS: 363 (M+H). 1H NMR (500 MHz, CDCl3): δ 6.90 (s, 1H); 5.30 (m, 1H, OCH); 3.96 (s, 4H, OCH2); 1.98 (m, 4H); 1.82 (m, 2H); 1.63 (m, 2H); 1.50 (s, 311, CH3). 13C NMR (125 MHz, CDCl3): δ 176 (s, NC); 171 (s, OC); 156 (q, N2C); 119 (q, CF3); 108 (s, O2C); 105 (s, CH); 74 (s, OCH); 73 (s, HOC); 65 (s, OCH2); 32 (s, CH2); 30 (s, CH3); 28 (s, CH2).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[N:6][CH:7]=1.CN([CH:16]=[O:17])C.[CH2:18]=[O:19].C[O-].[Na+]>C(O)(=O)C>[OH:19][CH2:18][C:8]([CH2:16][OH:17])([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: CN(C)C=O
Reactant: C=O
Reactant: COC(=O)Cc1ccc(C)cn1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)C(CO)(CO)c1ccc(C)cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of 575 mg of methyl (5-methylpyridin-2-yl)acetate and 11.5 ml of DMF were added 314 mg of paraformaldehyde and 38 mg of sodium methoxide under ice-cooling, followed by stirring at room temperature for 24 hours. The reaction mixture was ice-cooled and 50 μl of acetic acid was added thereto, followed by concentrating under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 462 mg of methyl 3-hydroxy-2-(hydroxymethyl)-2-(5-methylpyridin-2-yl)propanoate.