Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=2)=[NH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:22](Cl)([O:27][CH2:28][CH3:29])([O:24][CH2:25][CH3:26])=[O:23]>C(Cl)Cl>[C:1]1([NH:7][C:8](=[N:9][P:22](=[O:23])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOP(=O)(Cl)OCC
Reactant: N=C(Nc1ccccc1)Nc1nc(-c2ccccc2)cs1
Solvent: ClCCl
Product: CCOP(=O)(N=C(Nc1ccccc1)Nc1nc(-c2ccccc2)cs1)OCC

Procedure:
A stirred suspension of 2.94 g (10 mmol) of 1-phenyl-3-(4-phenyl-2-thiazolyl) guanidine (dried at 110° C./0.1 mm) in 150 ml of methylene chloride was allowed to react with 2.03 g (10 mmol) of N,O-bis-(trimethylsilyl) acetamide and 1.73 g (10 mmol) of diethyl chlorophosphate for 3 months by the procedure of Example 4. The reaction mixture was evaporated to dryness then was subjected to "dry column" chromatography (method of B. Loev and M. M. Goodman, Chem. and Industry, 2026 (1967) on 500 g of silica gel, and developed with 700 ml of methylene chloride-ethyl acetate, 9/1 (v/v). A band in the Nylon® column at Rf 0.25-0.4, visualized as a dark band under ultraviolet light at 254 nm, was cut out, and extracted with chloroform-methanol, 3/1 (v/v). Evaporation of the extracts left 1.35 g of product as a pale yellow, thick syrup; NMR (CDCl3, 80 MHz) δ 1.37 (t, 6H, CH3), δ 4.11(5 peaks, 4H, OCH2), 6.98 (s, 1H, =CH--S), 7.35(m, 10H, aromatic); IR (neat) 1653 (C=N) and 1032 cm-1 (P=O); TLC (SiO2, CHCl3 --MEOH, 19/1 (v/v)) showed only one spot under UV light.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][N:8]([CH2:10][CH2:11][OH:12])[CH3:9].[C:13]1([CH:23]2[CH2:25][O:24]2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.[ClH:26]>CC(C)=O.C(OCC)(=O)C>[ClH:26].[CH3:7][N:8]([CH2:10][CH2:11][O:12][CH2:25][CH:23]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[OH:24])[CH3:9]
Reactant: c1ccc2c(C3CO3)cccc2c1
Reactant: CN(C)CCO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CN(C)CCOCC(O)c1cccc2ccccc12
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
A mixture of 13 g of potassium tert-butoxide and 47.2 ml of 2-(N,N-dimethylamino)ethanol was heated to 80° C. Thereto was dropwise added 40.0 g of 2-(1-naphthyl)oxirane in 3.5 hours. The resulting mixture was stirred for 1.5 hours at 80°-85° C. The reaction mixture was cooled and added to a mixture of 100 ml of ethyl acetate and 100 ml of ice water. The resulting mixture was adjusted to pH 11.5 with 6N hydrochloric acid. The organic layer was separated. The aqueous layer was extracted with 50 ml of ethyl acetate. The extract was combined with the previously separated organic layer. The combined organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate The solvent was removed by distillation under reduced pressure. The residue thus obtained was subjected to distillation to obtain a fraction having a boiling point of 152°-163° C./0.6-0.8 mmHg. The oily product obtained was dissolved in 200 ml of acetone. Into the solution was blown hydrogen chloride gas with ice cooling. The resulting crystals were collected by filtration, washed with acetone, and dried to obtain 22.7 g of 2-[2-(N,N-dimethylamino)ethoxy]-1-(1-naphthyl)ethanol hydrochloride (compound No. 228).
Reaction SMILES: CI.[C:3](=O)([O-])[O-].[K+].[K+].[CH3:9][CH:10]([CH3:42])[C@H:11]([NH:19][CH2:20][C@H:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]([O:27][CH2:28][C:29]2[N:30]=[C:31]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)[O:32][C:33]=2[CH3:34])[CH2:22]1)[C:12]([O:14]C(C)(C)C)=[O:13].[C:43]([OH:49])([C:45]([F:48])([F:47])[F:46])=[O:44]>CN(C=O)C>[F:46][C:45]([F:48])([F:47])[C:43]([OH:49])=[O:44].[CH3:3][N:19]([CH2:20][C@H:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]([O:27][CH2:28][C:29]2[N:30]=[C:31]([C:35]3[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=3)[O:32][C:33]=2[CH3:34])[CH2:22]1)[C@@H:11]([CH:10]([CH3:9])[CH3:42])[C:12]([OH:14])=[O:13]
Reactant: Cc1ccc(-c2nc(CO[C@@H]3CCC[C@H](CN[C@H](C(=O)OC(C)(C)C)C(C)C)C3)c(C)o2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2nc(CO[C@@H]3CCC[C@H](CN(C)[C@H](C(=O)O)C(C)C)C3)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
60 mg of methyl iodide and 12 mg of potassium carbonate are added to 40 mg of tert-butyl (S)-3-methyl-2-{[cis-3-(5-methyl-2-p-tolyloxazol-4-yl-methoxy)cyclohexylmethyl]amino}butyrate (see Example 42) in 0.5 ml of DMF, and the mixture is stirred at RT overnight. 1 ml of TFA is added to the reaction solution, and the mixture is stirred for a further 1 h. The solution is purified by preparative HPLC, yielding 6.4 mg of (S)-2-{methyl-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]amino}-3-methyl-butyric acid trifluoroacetic acid salt. C25H36N2O4 (542.60); MS (ESI): 543 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][CH:21]=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:10][C:9]1([CH3:29])[CH3:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:30]1([CH:37]=CC(O)=[CH:33][CH:32]=1)O.C=CC=C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][CH:21]2[CH:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:33][CH:32]=[CH:30][CH2:37]2)[O:10][C:9]1([CH3:28])[CH3:29])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Oc1ccc(O)cc1
Reactant: CCOC(=O)C=CCC1OC(C)(C)N(C(=O)OC(C)(C)C)C1Cc1ccccc1
Agent: C=CC=C
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC=CCC1CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1Cc1ccccc1
Temperature: -78 °C
Yield: 174.6 %

Procedure:
A solution of 4-benzyl-5-(3-ethoxycarbonyl-allyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (6.55 g) in toluene (50 ml) was placed in a stainless steel bomb equipped with a PTFE liner. Hydroquinone (350 mg) was added, and the vessel cooled to −78° C. 1,3-butadiene (100 g) was condensed into the vessel, which was then sealed and heated to 150° C. for 16 hours. After cooling, the vessel was opened and the contents removed and evaporated to dryness. The residue was subjected to flash chromatography on silica gel eluting with hexane/ethyl acetate (95:5) to afford 4-benzyl-5-(6-ethoxycarbonyl-cyclohex-3-enylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (2.54 g, 34%) as a mixture of trans isomers (mass spectrum 458 [M+H]+) together with recovered starting material (2.17 g, 33%).
Reaction SMILES: C(OC(C)COC)(=O)C.[CH:10]#[C:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:30]([N:32]1[CH2:36][CH2:35][CH2:34][C:33]1=[O:37])=[CH2:31]>C(C(C)=O)C(C)C>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([CH:11]=[CH2:10])=[CH:13][CH:14]=1.[O:37]=[C:33]1[CH2:34][CH2:35][CH2:36][N:32]1[CH:30]([O:18][C:15]1[CH:16]=[CH:17][C:12]([CH:11]=[CH2:10])=[CH:13][CH:14]=1)[CH3:31]
Reactant: C#Cc1ccc(O)cc1
Reactant: C=CN1CCCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COCC(C)OC(C)=O
Solvent: CC(=O)CC(C)C
Product: C=Cc1ccc(O)cc1
Product: C=Cc1ccc(OC(C)N2CCCC2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into 200 parts of propylene glycol monomethyl ether acetate was dissolved 50.0 parts of poly(p-vinylphenol) [“VP-2500”, manufactured by Nippon Soda, having a weight average molecular weight of 4,000 and a distribution of 1.15]. The solution was cooled to room temperature and a catalytic amount of p-toluenesulfonic acid was added thereto and dissolved. To this solution was added dropwise 4.63 parts of N-vinyl-2-pyrrolidone over 30 minutes. Then the solution was kept at room temperature for 2 hours. After adding methyl isobutyl ketone, the solution was washed with ion-exchanged water. The organic layer after washing was concentrated to 250 parts, combined with 250 parts of propylene glycol monomethyl ether acetate and further concentrated to 124 parts. The solid content of the concentrate measured by weight-loss on heating was 39.65% by weight. A broad peak at 6.0 ppm was confirmed by 1H-NMR [270 MHz, in (dimethylsulfoxide)-d6] and assigned to the methine proton in —O—CH(CH3)—N<. From the ratio of integrated area for this methine proton and that for the aromatic protons, it was confirmed that the resin was a copolymer constituted by p-hydroxystyrene unit and p-[1-(2-oxo-1-pyrrolidinyl)ethoxy]styrene in a ratio of 91:9. The resin was referred to as Resin R1.
Reaction SMILES: [C:1]1(C#CC2(O)CCCC2)[CH:6]=CC=C[CH:2]=1.[CH2:15]1[C:20](=[O:21])N(I)[C:17](=O)[CH2:16]1.CC1C=CC(S(O[I:34](O)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)(=O)=O)=CC=1>CO.C(OCC)C>[C:40]1(=[C:35]([I:34])[C:20]([C:15]2[CH:6]=[CH:1][CH:2]=[CH:17][CH:16]=2)=[O:21])[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: OC1(C#Cc2ccccc2)CCCC1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1ccc(S(=O)(=O)OI(O)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CO
Product: O=C(C(I)=C1CCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-Phenylethynyl-l-cyclopentanol (352 mg, 1.89 mmol) was dissolved in 20 mL of methanol. NIS (514 mg, 2.29 mmol) and HTIB (96 mg, 0.24 mmol) were added in one portion to the stirring solution. The reaction was protected from light and stirred at room temperature for 18 hours. The reaction mixture was diluted with 75 mL of diethyl ether and washed with 25 mL of 5% Na2S2O3 solution and followed by 3×25 mL of water. The organic solution was dried with MgSO4 and following filtration it was evaporated under vacuum to give a light green oil. The residue was subjected to a silica gel (40-40 mesh) column chromatography. Iodobenzene was eluted first with hexanes. The product was eluted next with 1:1 mixture Et2O/ hexanes to yield a light green oil after solvent evaporation (329 mg, 56%). The product was characterized by spectroscopy: 1H-NMR (CDCl3) δ1.75-1.84 (m, 4H), 2126 (t,7 Hz, 2H), 2154 (t, 7 Hz, 2H), 7.47 (t, 6 Hz, 2H), 7.67 (d, 6 Hz, 1H), 7.91(d, 6 Hz, 2H); 13C-NMR (CDCl3) δ25.22, 28.53, 34.02, 40.85, 85.60, 128.57, 128.61, 129.70, 133.23, 133.30, 134.50, 158.84, 1.92.83; IR (CHCl3) 1655 (s), 1590 (w), 1400 (w), 1300 (m), 1250 (s),1220 (m), 1170 (m), 1050 (w), 1025 (w), 820 (w), 750 (s) cm-1 ; MS m/z(rel. int.) 312 (M+, 2), 185 (M-I, 20), 184 (M-I-H, 11), 157 (13), 129 (11), 127 (I, 18), 115 (18), 105 (C6H5CO, 35), 80 (16), 77 (C6H5, 100); Anal. calcd for C13 H13IO: C, 49.98; H, 4.21. Found: C, 50.54: H, 4.21.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:12](=[O:50])[N:13]([CH2:21][C:22]3[C:30]4[C:25](=[N:26][C:27]([NH:31]CC5C=CC(OC)=CC=5)=[CH:28][CH:29]=4)[N:24](CC4C=CC(OC)=CC=4)[N:23]=3)[CH:14]=[CH:15][C:16]=2[C:17]([F:20])([F:19])[F:18])[CH:9]=1)[C:5]#[N:6].[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52]>>[F:54][C:53]([F:56])([F:55])[C:51]([O-:57])=[O:52].[Cl:1][C:2]1[CH:9]=[C:8]([CH:7]=[C:4]([C:5]#[N:6])[CH:3]=1)[O:10][C:11]1[C:12](=[O:50])[N:13]([CH2:21][C:22]2[C:30]3[C:25](=[N:26][C:27]([NH3+:31])=[CH:28][CH:29]=3)[NH:24][N:23]=2)[CH:14]=[CH:15][C:16]=1[C:17]([F:18])([F:19])[F:20]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(CNc2ccc3c(Cn4ccc(C(F)(F)F)c(Oc5cc(Cl)cc(C#N)c5)c4=O)nn(Cc4ccc(OC)cc4)c3n2)cc1
Product: N#Cc1cc(Cl)cc(Oc2c(C(F)(F)F)ccn(Cc3n[nH]c4nc([NH3+])ccc34)c2=O)c1
Product: O=C([O-])C(F)(F)F
Reaction time: 2 h

Procedure:
3-chloro-5-{[1-({1-(4-methoxybenzyl)-6-[(4-methoxybenzyl)amino]-1H-pyrazolo[3,4-b]pyridin-3-yl}methyl)-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl]oxy}benzonitrile (0.185 g, 0.264 mmol) was dissolved in TFA (5 mL) and placed in an oil bath at 75° C. After 2 hours, the reaction mixture was concentrated under reduced pressure and purified by preparative HPLC eluting with 30-95% MeCN/H2O+0.1% TFA to afford the title compound as a solid. 1H NMR (DMSO-d6, with NH4OH) δ 7.94 (d, J=7.3 Hz, 1H), 7.77-7.74 (m, 1H), 7.62-7.56 (m, 2H), 7.50-7.46 (m, 1H), 6.60 (d, J=7.3 Hz, 1H), 6.38-6.33 (m, 2H), 6.30 (d, J=8.8 Hz, 1H), 5.32 (s, 2H). HRMS (M+1)=461.0729.
Reaction SMILES: C(OCC1[CH2:7][S:8][C@@H]2C(N)C(=O)N2C=1C(OC(C)(C)C)=O)(=O)C.[C:23]([O:26][CH2:27][C:28]1[CH2:29][S:30][C@@H:31]2[CH:42]([NH:43][C:44]3[NH:45][CH:46]=[C:47]([CH2:49]OC)[N:48]=3)[C:41](=[O:52])[N:32]2[C:33]=1[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])(=[O:25])[CH3:24]>>[C:23]([O:26][CH2:27][C:28]1[CH2:29][S:30][C@@H:31]2[CH:42]([NH:43][C:44]3[NH:45][CH:46]=[C:47]([CH2:49][S:8][CH3:7])[N:48]=3)[C:41](=[O:52])[N:32]2[C:33]=1[C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])(=[O:25])[CH3:24]
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(N)[C@H]2SC1
Reactant: COCc1c[nH]c(NC2C(=O)N3C(C(=O)OC(C)(C)C)=C(COC(C)=O)CS[C@H]23)n1
Product: CSCc1c[nH]c(NC2C(=O)N3C(C(=O)OC(C)(C)C)=C(COC(C)=O)CS[C@H]23)n1

Procedure:
4-Chloromethyl-2-fluoro-1-triphenylmethylimidazole was treated with methanethiol and triethylamine in THF solution to give 2-fluoro-4-methylthiomethyl-1-triphenylmethylimidazole. This was condensed with t-butyl 3-acetoxymethyl-7-aminoceph-3-em-4-carboxylate as for the starting material of Example 42 to give t-butyl 3-acetoxymethyl-7-(4-methylthiomethylimidazol-2-yl)aminoceph-3-em-4-carboxylate, having the following n.m.r. spectrum in d6DMSO: 1.5 (s, 9H); 2.0 (s, 6H); 3.5 (d, 2H); 3.8 (d, 2H); 4.7 (d, 1H); 5.0 (d, 1H); 5.25 (d, 1H); 5.65 (d, 1H); 7.0 (s, 1H).
Reaction SMILES: [CH2:1]([C:8]1[C:9]([NH:21][C:22](=[S:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>N1C=CC=CC=1>[C:31]([O:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[N:13]=[C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9]([NH:21][C:22](=[S:30])[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:10][CH:11]=2)=[CH:15][CH:16]=1)(=[O:33])[CH3:32]
Reactant: Oc1ccc(-c2cnc(NC(=S)Cc3ccccc3)c(Cc3ccccc3)n2)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(-c2cnc(NC(=S)Cc3ccccc3)c(Cc3ccccc3)n2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 47.8 %

Procedure:
Under an argon atmosphere, 3-benzyl-5-(4-hydroxyphenyl)-2-(phenylthioacetyl amino)pyrazine (h-coelenterathioamide) (c-14) (183 mg, 444 μmol) was dissolved in pyridine (2 mL) and cooled to 0° C. To this was added acetic anhydride (55 μL, 0.58 mmol) and stirred for 2 h after warming to room temperature. To this was further added acetic anhydride (25 μL, 0.26 mmol) and stirred at room temperature for 2.5 h. To this was added saturated aqueous solution of sodium bicarbonate and ethyl acetate to stop the reaction, and after separating the aqueous layer and organic layer, the organic layer was washed 3 times with water and once with brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated under reduced pressure with a rotary evaporator. After purifying the residue by silica gel column chromatography (22 g, n-hexane/ethyl acetate=2/1), the obtained solid was further purified by silica gel column chromatography (7 g, n-hexane/ethyl acetate=2/1) to give 5-(4-acetoxyphenyl)-3-benzyl-2-(phenylthioacetylamino)pyrazine (c-31) as a pale yellow solid (96.3 mg, 47.8%). Rf=0.36 (n-hexane/ethyl acetate=2/1). Mp. 143-145° C. UV (MeOH) λmax (log ε) 320 (4.30), 258 (4.41). UV (pH 7.4 PB) λmax (log ε) 346 (4.36), 274 (4.35). 1H NMR (400 MHz, DMSO-d6) δ 2.29 (s, 3H), 3.95 (s, 2H), 4.14 (s, 2H), 7.00 (d, J=6.6 Hz, 2H), 7.12-7.24 (m, 3H), 7.26-7.32 (AA′BB′, 3H), 7.36 (t, J=7.3 Hz, 2H), 7.51 (d, J=7.5 Hz, 2H), 8.12-8.18 (AA′BB′, 2H), 9.04 (s, 1H), 12.23 (s, 1H). 13C NMR (75.5 MHz, DMSO-d6) δ 20.9, 39.4, 51.6, 122.6 (2C), 126.4, 127.0, 128.0 (2C), 128.3 (2C), 128.4 (2C), 128.9 (2C), 129.0 (2C), 132.8, 136.8, 137.9, 138.6, 145.9, 149.0, 151.9, 152.4, 169.1, 204.7. IR (KBr, cm−1) 700, 1128, 1165, 1179, 1200, 1238, 1368, 1389, 1416, 1441, 1493, 1508, 1730, 3265. HRMS (FAB+) m/z 454.1583 (M+H, C27H24N3O2S requires 454.1589).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][SH:5].[Na].Cl.[Cl:8][CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][N:11]=1>C(O)C.CO>[ClH:8].[ClH:1].[NH2:2][CH2:3][CH2:4][S:5][CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][N:11]=1
Reactant: NCCS
Reactant: COc1ccnc(CCl)c1
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: CCO
Product: COc1ccnc(CSCCN)c1
Reaction time: 8 h
Yield: 77.2 %

Procedure:
Cysteamine hydrochloride (7.62 g) was added to a solution of sodium (4.70 g) in ethanol (170 cc) and the mixture was stirred and cooled to 10° and 2-chloromethyl-4-methoxypyridine hydrochloride (11.5 g) in methanol (50 cc) was added over 35 minutes, and the mixture was left overnight at room temperature. The mixture was filtered and the filtrate was evaporated to a residue which was partitioned between chloroform and water. The chloroform extract was evaporated to an oil which was crystallised from 2.1M ethanolic hydrogen chloride to give 2-(2-aminoethylthiomethyl)-4-methoxypyridine dihydrochloride (12.4 g) m.p. 172.5° (decomp).
Reaction SMILES: [NH2:1][C@H:2]([C@@H:6]([OH:9])[CH2:7][CH3:8])[C:3]([OH:5])=[O:4].C([O-])(O)=O.[Na+].[C:15](=O)([O-:36])[O:16][C:17]1C(C)=C(C2C=CC(C3C=CC=CC=3)=CC=2)C=CN=1.[C:38]1([C:44]2[CH:49]=[CH:48][C:47](C3C=CN(C([O-])=O)C(=O)C=3C)=[CH:46][CH:45]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>O.C1COCC1>[OH:9][C@@H:6]([CH2:7][CH3:8])[C@@H:2]([N:1]([C:47]1[CH:46]=[CH:45][C:44]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[CH:49][CH:48]=1)[C:15]([O:16][CH3:17])=[O:36])[C:3]([OH:5])=[O:4]
Reactant: Cc1c(-c2ccc(-c3ccccc3)cc2)ccn(C(=O)[O-])c1=O
Reactant: CC[C@H](O)[C@@H](N)C(=O)O
Reactant: Cc1c(-c2ccc(-c3ccccc3)cc2)ccnc1OC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC[C@H](O)[C@H](C(=O)O)N(C(=O)OC)c1ccc(-c2ccccc2)cc1
Reaction time: 15 h
Yield: 74 %

Procedure:
To a stirred diastereomeric mixture containing (2R*,3R*) and (2R*,3S*)-2-amino-3-hydroxy-pentanoic acid (0.108 g, 0.81 mmol) and NaHCO3 (0.204 g, 2.43 mmol) in H2O (2.0 mL), at rt, the isomeric mixture containing (4-phenylphenyl)-methyl-2-pyridyl carbonate and (4-phenylphenyl)-methyl-2-oxopyridine-1-carboxylate (0.37 g, 1.22 mmol) [prepared as for example 17, step 1] in THF (2.0 mL) was added. After 15 h at rt, the crude mixture was rotary evaporated to remove the organics and subsequently extracted with Et2O (3×10 mL). The aqueous phase was acidified with 2.0 M HCl solution to pH 2-3 and subsequently extracted with AcOEt (3×20 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford the title compound (0.206 g, 74% over 2 steps), as a diastereoisomeric mixture (anti:syn=8:2), as an off-white solid, which was used in the next step without further purification. MS (ESI) m/z: 361 [M−NH4]+; (ESI) m/z: 342 [M−H]−. 1H NMR (DMSO-d6) δ 0.87 (t, J=7.38 Hz, 3H), 1.36-1.55 (m, 2H), 3.55-3.69 (m, 1H), 3.94-4.05 (m, 1H), 4.73-4.99 (m, 1H), 5.08 (s, 2H), 7.29-7.54 (m, 6H), 7.57-7.77 (m, 4H), 11.38-13.49 (m, 1H) (reported data refer to the major anti diastereoisomer).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=O.[CH3:14][N:15]([CH3:17])[NH2:16]>[Cl-].[Na+]>[CH3:14][N:15]([CH3:17])[N:16]=[C:8]1[C:9]2[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1
Reactant: CN(C)N
Reactant: COc1cccc2c1CCCC2=O
Agent: [Cl-]
Agent: [Na+]
Product: COc1cccc2c1CCCC2=NN(C)C
Yield: 83 %

Procedure:
35.25 g of 5-methoxy-1-tetralone and 61 ml of N,N-dimethylhydrazine were heated to about 80° under argon for 5 hours. The mixture was left to cool, 200 ml of 10% sodium chloride solution were added and the mixture was extracted several times with diethyl ether. The mixture was dried over sodium sulfate, filtered and evaporated. The oily residue was distilled over a 10 cm Vigreux column. At 85°-95°/0.1 mbar there were obtained 36.4 g (83%) of 5-methoxy-1-tetralone N,N-dimethylhydrazone as a yellow oil.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:19][CH:18]([CH2:20][NH:21][C:22]4[CH:26]=[CH:25][O:24][N:23]=4)[O:17][N:16]=3)=[CH:11][CH:10]=2)=[CH:5][CH2:4]1.C(N(CC)CC)C.CC1(C)[O:39][C@H:38]([C:40](Cl)=[O:41])[CH2:37][O:36]1>C(#N)C>[OH:39][C@@H:38]([CH2:40][OH:41])[C:37]([N:3]1[CH2:8][CH2:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:19][CH:18]([CH2:20][NH:21][C:22]4[CH:26]=[CH:25][O:24][N:23]=4)[O:17][N:16]=3)=[CH:11][CH:10]=2)=[CH:5][CH2:4]1)=[O:36]
Reactant: CC1(C)OC[C@@H](C(=O)Cl)O1
Reactant: C1=C(c2ccc(C3=NOC(CNc4ccon4)C3)cc2)CCNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C([C@@H](O)CO)N1CC=C(c2ccc(C3=NOC(CNc4ccon4)C3)cc2)CC1
Reaction time: 0.5 h
Yield: 30.3 %

Procedure:
(5RS)-3-(4-(1,2,5,6-Tetrahydropyrid-4-yl)phenyl)-5-(3-isoxazolylaminomethyl)-4,5-dihydro-isoxazole dihydrochloride (397 mg, 1 mM) was suspended by stirring in acetonitrile (15 ml) under nitrogen, triethylamine (404 mg, 4 mM) added, and the mixture cooled to 0° C. (4S)-2,2-Dimethyl-1,3-dioxolan-4-ylcarbonyl chloride (328 mg, 2 mM) was added dropwise, stirring continued for 30 minutes at 0° C., then for 18 hours allowing the temperature to rise to ambient. Solvent was evaporated, the residue treated with water (25 ml) and extracted into dichloromethane (4×20 ml). The extracts were washed with brine (25 ml), dried (magnesium sulfate), and evaporated. The residue was dissolved in tetrahydrofuran (40 ml), treated with hydrochloric acid (2N, 2 ml), and stirred 48 hours at ambient temperature. Potassium carbonate (2 g) was added, the mixture stirred 30 minutes and filtered. After removal of solvent, the residue was chromatographed on a 10 g silica Mega Bond Elut® column, eluting with a gradient from 5 to 10% methanol in dichloromethane. Relevant fractions were combined to give the desired product (125 mg). MS (ESP): 413 (MH+) for C21H24N4O5 NMR (CDCl3) δ: 2.54 (br, 2H); 3.18 (dd, 1H); 3.26 (m overlapped by H2O, 2H); 3.47 (dd, 2H); 3.55 (m, 1H); 3.74 (m, 2H); 4.13 (br, 1H); 4.26 (m, 1H); 4.38 (m, 1H); 4.67 (d, 1H); 4.89 (overlapping m, 2H); 5.96 (d, 1H); 6.26 (br, 1H); 6.37 (t, 1H); 7.50 (d, 2H); 7.62 (d, 2H); 8.34 (d, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[N:10][N:9]2[C:12]([C:30]([N:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)=[O:31])=[C:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=3[CH3:29])[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:8]2[C:7]=1Cl)=[O:5])[CH3:2].C(N(CC)CC)C>C(O)C.C1COCC1.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[N:10][N:9]2[C:12]([C:30]([N:32]3[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[CH2:36][CH2:37]3)=[O:31])=[C:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=3[CH3:29])[C:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[C:8]2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn2c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c(Cc3cccc(F)c3C)c(-c3ccccc3)c2c1Cl
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cnn2c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c(Cc3cccc(F)c3C)c(-c3ccccc3)c2c1
Yield: 93.9 %

Procedure:
The compound of step 9 (1.880 g, 2.96 mmol) in 29.6 ml of ethanol/THF (1:1) was hydrogenated under a hydrogen pressure of 2 bar for 3.5 h at room temperature in the presence of 0.315 g of 10% palladium on charcoal and triethylamine (0.62 ml, 4.44 mmol). The catalyst was filtered off and the filtrate was washed with brine (50 ml), dried with magnesium sulfate, filtered and concentrated to dryness under reduced pressure. 1.67 g of the title compound were obtained as a yellow solid.