Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3]P(=O)(OC)OC.[H-].[Na+].[CH:20]([C@@H:22]1[C@@H:29]2[C@@H:25]([O:26][C:27](=[O:30])[CH2:28]2)[CH2:24][C@H:23]1[O:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:35][CH:34]=1)=O>ClCCl.C(#N)C>[O:1]=[C:2]([CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)/[CH:3]=[CH:20]/[C@@H:22]1[C@@H:29]2[C@@H:25]([O:26][C:27](=[O:30])[CH2:28]2)[CH2:24][C@H:23]1[O:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:35][CH:34]=1
Reactant: COP(=O)(CC(=O)CCc1ccccc1)OC
Reactant: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccc(-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: O=C(/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccc(-c2ccccc2)cc1)CCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
A solution of dimethyl (2-oxo-4-phenylbutyl)phosphonate (69.1 g) in dichloromethane (200 mL) was added dropwise at 0° C. to a suspension of sodium hydride (11.9 g) in dichloromethane (700 mL). The mixture was stirred at 0° C. during 1 h. The cold (0-5° C.) solution of aldehyde [3a] in dichloromethane prepared in the previous stage was added dropwise to the stirred mixture at 0-5° C. The obtained mixture was stirred for 1 hour at the same temperature (TLC monitoring), filtered through Celite and acidified with acetic acid to pH 5 at 0-5° C. The organic layer was separated, washed with water until the pH of the water layer was not less than 6.8, dried over sodium sulfate, filtered and evaporated under reduced pressure. The oily residue was triturated with ether (500 mL). The precipitated crystals were filtered and dried under reduced pressure to a constant weight to give 93.4 g (85% yield) of crude crystalline product. A solution of the product in acetonitrile was passed through Celite and evaporated under reduced pressure The crystalline residue was recrystallizated from methanol (2 L) gave 83.6 g (76.2% yield) of compound [4a] with mp 134-135° C. and [α]D20−141.7° (c 1.26, MeCN). 1H NMR (CDCl3, δ) 2.32-2.63 (m, 3H); 2.84-2.97 (m, 7H); 5.00-5.10 (m, 1H); 5.20-5.35 (m, 1H); 6.20 (d, J=16 Hz, 1H); 6.65 (dd, J=16 and 8 Hz, 1H); 7.15-7.67 (m, 12H); 8.03 (d, J=8 Hz, 2H).
Reaction SMILES: C(NC1C=CC=C2C=1CCC(N)C2)(=[O:3])C.Cl.[C:17]([NH:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:22]=1[CH2:23][CH2:24][CH:25]([NH:31][CH2:32][C:33]1[CH:38]=CC=CC=1)[CH2:26]2)(=[O:19])[CH3:18]>>[C:17]([NH:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:22]=1[CH2:23][CH2:24][CH:25]([NH:31][C:32](=[O:3])[CH2:33][CH3:38])[CH2:26]2)(=[O:19])[CH3:18]
Reactant: CC(=O)Nc1cccc2c1CCC(N)C2
Reactant: CC(=O)Nc1cccc2c1CCC(NCc1ccccc1)C2
Agent: Cl
Product: CCC(=O)NC1CCc2c(cccc2NC(C)=O)C1

Procedure:
Starting from 12.3 g (0.06 mol) of 5-acetylamino-2-amino-tetraline (known substance prepared by debenzylation of 5-acetylamino-2-benzylamino-tetraline (Example 4.1.16) analogously to Example 4.4.1) the title compound is obtained by propionylation analogously to Example 4.5.1 a) in a yield of 13.5 g (86.3% of theory).
Reaction SMILES: [N:1]1([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.[CH3:22][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI.[Cl-].[NH4+]>C1COCC1>[CH3:22][C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][N:1]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:2]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.6 %

Procedure:
To 1-benzyl 3-ethyl piperidine-1,3-dicarboxylate (3.0 g, 10.3 mmol) in THF (20 mL) was added lithium bis(trimethylsilyl)amide (12.9 mL, 12.9 mmol) in THF at −78° C., and the reaction was stirred at this temperature for 20 minutes. MeI (0.867 mL, 13.9 mmol) was added, and the reaction was warmed to room temperature. After 2 hours at room temperature, the mixture was poured onto saturated ammonium chloride (20 mL) and extracted with ether, washed with brine and dried over sodium sulfate. After removal of the solvent, the residue was purified by chromatography on silica gel (hexane:ethyl acetate 5:1) to give 1-benzyl 3-ethyl 3-methylpiperidine-1,3-dicarboxylate (3.1 g, 98% yield) as an oil.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:10]([O:12][C:13]([C:15]1[C:16](=[O:38])[C:17]2[CH:22]=[N:21][C:20](S(C)(=O)=O)=[N:19][C:18]=2[N:27]([C:29]2[CH:30]=[C:31]3[C:35](=[CH:36][CH:37]=2)[CH2:34][CH2:33][CH2:32]3)[CH:28]=1)=[O:14])[CH3:11]>>[CH2:10]([O:12][C:13]([C:15]1[C:16](=[O:38])[C:17]2[CH:22]=[N:21][C:20]([NH:9][CH2:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:19][C:18]=2[N:27]([C:29]2[CH:30]=[C:31]3[C:35](=[CH:36][CH:37]=2)[CH2:34][CH2:33][CH2:32]3)[CH:28]=1)=[O:14])[CH3:11]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: NCCCN1CCCC1
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(NCCCN3CCCC3)ncc2c1=O

Procedure:
Using the procedure described in Example 1 Step F, the title compound was prepared from 3-pyrrolidin-1-yl-propylamine and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(Step E), 10 mg, 0.022 mmol). 7 mg of 8-Indan-5-yl-5-oxo-2-(3-pyrrolidin-1-yl-propylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.24 (s, 1H), 8.76 (s, 1H), 7.30 (d, J=7.7 Hz, 1H), 7.21 (s, 1H), 7.14 (d, J=7.7 Hz, 1H), 5.72 (br, 1H), 4.36 (q, J=7.1 Hz, 2H), 3.27 (m, 2H), 2.98 (m, 4H), 2.50 (m, 6H), 2.17 (m, 2H), 1.80 (m, 4H), 1.68 (m, 2H), 1.38 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[NH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:27])[CH3:26].CN1CCOCC1>CO>[NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17]([NH:21][CH2:22][CH2:23][NH:24][C:25](=[O:27])[CH3:26])(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Reactant: CC(=O)NCCN
Solvent: CO
Solvent: CN1CCOCC1
Product: CC(=O)NCCNS(=O)(=O)c1ccc2nc(-c3c(C)n[nH]c3N)sc2c1
Yield: 43.9 %

Procedure:
the title compound (52 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (100 mg, 0.30 mmol), N-(2-aminoethyl)-acetamide (58 μL, 0.60 mmol) and PS-NMM (0.320 g, 0.60 mmol) in 5 mL of methanol. MS (m/z, ES+): 395.6 (M+1, 100%). Yield=43%.
Reaction SMILES: [CH3:1][CH:2]1[CH:11]=[C:10]2[CH:5]([CH:6]([CH2:13][CH2:14][C:15]3[NH:16][C:17](=[O:21])[CH:18]=[CH:19][CH:20]=3)[CH:7]([CH3:12])[CH:8]=[CH:9]2)[CH:4]([O:22][C:23](=[O:28])[CH:24]([CH3:27])[CH2:25][CH3:26])[CH2:3]1.[C:29](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:1][CH:2]1[CH:11]=[C:10]2[CH:5]([CH:6]([CH2:13][CH2:14][C:15]3[N:16]([CH3:29])[C:17](=[O:21])[CH:18]=[CH:19][CH:20]=3)[CH:7]([CH3:12])[CH:8]=[CH:9]2)[CH:4]([O:22][C:23](=[O:28])[CH:24]([CH3:27])[CH2:25][CH3:26])[CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: CCC(C)C(=O)OC1CC(C)C=C2C=CC(C)C(CCc3cccc(=O)[nH]3)C21
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCC(C)C(=O)OC1CC(C)C=C2C=CC(C)C(CCc3cccc(=O)n3C)C21

Procedure:
To a stirred solution of 77 mg (0.2 mmol) 2-methyl-butyric acid 3,7-dimethyl-8-[2-(6-oxo-1,6-dihydro-pyridin-2-yl)-ethyl]-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl ester in 5 ml DMF are added 0.1 g (0.8 mmol) potassium carbonate and 0.1 g (0.8 mmol) methyl iodide. After 2 hours at room temperature the mixture is poured on water. The aqueous phase is separated and extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is evaporated in vacuo. The residue is chromatographed over silica gel eluting with hexane/acetone 1/1 to afford the title compound as white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11]([O:16][C@@H:17]3[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:39])[CH3:38])[C@@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]3[O:19][C:20](=[O:22])[CH3:21])=[N:12][NH:13][C:14]=2[CH3:15])=[CH:5][CH:4]=1.[C:40](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]2[C:11]([O:16][C@@H:17]3[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:39])[CH3:38])[C@@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]3[O:19][C:20](=[O:22])[CH3:21])=[N:12][N:13]([CH3:40])[C:14]=2[CH3:15])=[CH:7][CH:8]=1
Reactant: COc1ccc(Cc2c(O[C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)n[nH]c2C)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COc1ccc(Cc2c(O[C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)nn(C)c2C)cc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 21.7 %

Procedure:
A suspension of 4-[(4-methoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole (18 mg), potassium carbonate (14 mg) and iodomethane (4.7 mg) in acetonitrile (2 mL) was stirred at 75° C. overnight. The reaction mixture was filtered through celite®, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by preparative thin layer chromatography (developing solvent:benzene/acetone=2/1) to give 4-[(4-methoxyphenyl)methyl]-1,5-dimethyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)pyrazole (4 mg).
Reaction SMILES: [CH2:1]([O:8][N:9]([CH2:12][C:13]1([C:18]([OH:20])=O)[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]([C:23]1[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=1)[NH2:22].CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH2:1]([O:8][N:9]([CH2:12][C:13]1([C:18]([NH:22][NH:21][C:23]2[N:28]=[C:27]([C:29]([F:31])([F:30])[F:32])[CH:26]=[CH:25][N:24]=2)=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17]1)[CH:10]=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNc1nccc(C(F)(F)F)n1
Reactant: O=CN(CC1(C(=O)O)CCCC1)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=CN(CC1(C(=O)NNc2nccc(C(F)(F)F)n2)CCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54 %

Procedure:
To a mixture of 1-[(Benzyloxy-formyl-amino)-methyl]-cyclopentanecarboxylic acid (0.10 g, 0.36 mmol), 2-hydrazino-4-(trifluoromethyl)pyrimidine (0.10 g, 0.43 mmol), NMM (0.11 g, 1.08 mmol) and HOAt (0.059 g, 0.43 mmol) in DMF (2 mL) at room temperature was added 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (0.085 g, 0.43 mmol). After stirring at room temperature 18 h, the reaction mixture was then purified by preparative, reverse-phase HPLC to afford the title compound as a white solid (0.085 g, 57%). MH+438.
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:13]([NH2:37])[CH2:14][C@H:15]([OH:36])[C@@H:16]([NH:24][C:25](=[O:35])[C@H:26]([CH:32]([CH3:34])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.CN1CCOCC1.[CH3:45][O:46][C:47]([NH:49][C@H:50]([C:55](O)=[O:56])[C@H:51]([CH2:53][CH3:54])[CH3:52])=[O:48].[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C>CN(C=O)C>[S:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]([CH2:12][N:13]([NH:37][C:55](=[O:56])[C@H:50]([C@H:51]([CH2:53][CH3:54])[CH3:52])[NH:49][C:47]([O:46][CH3:45])=[O:48])[CH2:14][C@H:15]([OH:36])[C@@H:16]([NH:24][C:25](=[O:35])[C@H:26]([CH:32]([CH3:34])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:10][CH:11]=2)=[CH:4][N:3]=[CH:2]1
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2cncs2)cc1)C(C)C
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)NN(Cc1ccc(-c2cncs2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Under an argon atmosphere, 0.6 mmol of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-valyl)amino-6-phenyl-2-azahexane and 198 μl (1.8 mmol) of NMM in 5.8 ml of DMF are added to 136 mg (0.72 nmol) of N-methoxycarbonyl-(L)-iso-leucine and 179 mg (0.60 mmol) of TPTU in 3 ml of DMF and the mixture is stirred at room temperature for 14 hours and worked up analogously to Example 3, yielding the title compound: TLC: Rf=0.59 (methylene chloride/THF 3:1); HPLC20-100: tRet=14.0; FAB MS (M+H)+=697.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([N+:21]([O-:23])=[O:22])[CH:14]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:24].C(N(CC)CC)C.Cl.[CH2:33]([O:35][CH:36]1[O:41][CH2:40][CH2:39][NH:38][CH2:37]1)[CH3:34]>O1CCCC1>[CH2:33]([O:35][CH:36]1[CH2:37][N:38]([C:2]2[N:10]=[C:9]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([N+:21]([O-:23])=[O:22])[CH:14]=3)[N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH3:24])[CH2:39][CH2:40][O:41]1)[CH3:34]
Reactant: COc1ccc(CSc2nc(Cl)c3ncn(C)c3n2)cc1[N+](=O)[O-]
Reactant: CCOC1CNCCO1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC1CN(c2nc(SCc3ccc(OC)c([N+](=O)[O-])c3)nc3c2ncn3C)CCO1
Yield: 69.1 %

Procedure:
6-chloro-2-(4-methoxy-3-nitrobenzylsulfanyl)-9-methyl-9H-purine (850 mg, 2.32 mmol) was dissolved in tetrahydrofuran (100 ml), triethylamine (1.57 g, 15.51 mmol) and 2-ethoxymorpholine hydrochloride (520 mg, 3.10 mmol) were added and heated to reflux for 7 hours. After distilling away the solvent under reduced pressure, water was added to the residue and extracted twice with ethyl acetate, then the organic layers were washed with a saturated saline solution and dried with MgSO4. After distilling away the solvent under reduced pressure, purification was performed by silica gel column chromatography (ethyl acetate:hexane=1:3) to obtain 738 mg (69% yield) of 6-(2-ethoxymorpholino)-2-(4-methoxy-3-nitrobenzylsulfanyl)-9-methyl-9H-purine.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:25]/[O:26][CH3:27])/[C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH2:18]O)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.P(OCC)(OCC)OCC.C(O)(=O)C>C(#N)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:25]/[O:26][CH3:27])/[C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH2:18][N+:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: c1ccncc1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12)c1csc(N)n1
Agent: CCOP(OCC)OCC
Solvent: CC(=O)O
Solvent: CC#N
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1csc(N)n1
Temperature: 22.5 °C
Reaction time: 8 h

Procedure:
In 2 ml of acetonitrile was suspended 103 mg of 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-hydroxymethyl-3-cephem-4 -carboxylic acid. To the suspension were added in sequence 0.10 ml of pyridine, 0.21 ml of triethyl phosphite and 0.2 ml of acetic acid. The mixture was stirred at 20 to 25° C. for 8 hours, followed by concentration under reduced pressure. To the concentrated solution was added 10 ml of tetrahydrofuran, then precipitating powdery product was collected by filtration, followed by concentration under reduced pressure to give 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-(1 -pyridinio)methyl-3-cephem-4-carboxylate.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][C@@H:6]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=1)[CH2:7][CH3:8])[CH2:3][OH:4].C([O-])(=O)C.[Na+].[N:29]#[C:30]Br>CO.[OH-].[Na+]>[CH2:17]([O:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[O:9][C@@H:6]([CH2:7][CH3:8])[CH2:5][C@H:2]1[CH2:3][O:4][C:30]([NH2:29])=[N:1]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC[C@@H](C[C@H](N)CO)Oc1cccc(OCc2ccccc2)c1
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC[C@@H](C[C@H]1COC(N)=N1)Oc1cccc(OCc2ccccc2)c1
Reaction time: 18 h
Yield: 71 %

Procedure:
To a stirred mixture of (2S,4S)-2-amino-4-(3-benzyloxy-phenoxy)-hexan-1-ol (90 mg) and sodium acetate (46 mg) in methanol (2 ml) under an argon atmosphere was added a solution of cyanogen bromide (37 mg) in methanol (1 ml). The mixture was stirred for 18 hours then diluted with 1 N aqueous sodium hydroxide solution. The mixture was extracted twice with dichloromethane and the combined organic phases were dried over sodium sulphate and concentrated in vacuo. The crude product was purified by column chromatography (column: Isolute® Flash-NH2 from Separtis; gradient: dichloromethane/MeOH 100:0→95:5) to afford (S)-4-[(S)-2-(3-benzyloxy-phenoxy)-butyl]-4,5-dihydro-oxazol-2-ylamine (69 mg, 71%) as a light yellow gum. MS (ISP): 341.1 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][CH:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].O[NH:23][C:24](=[NH:32])[CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH:15]1([CH2:14][CH2:13][CH2:12][C@@H:8]([C:9]2[O:11][N:32]=[C:24]([CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[N:23]=2)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)CC(CCCC1CCCCC1)C(=O)O
Reactant: N=C(CN1CCOCC1)NO
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CN2CCOCC2)no1

Procedure:
Method as for preparations 2 and 3 combined using 2-[2-(tert-butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acid (preparation 168) (1.00 g, 3.36 mmol) and N-hydroxy-2-(4-morpholinyl)ethanimidamide (J. Org. Chem.; 1958, 23, 1112) (534 mg, 3.36 mmol) as starting material.
Reaction SMILES: Cl[C@H:2]([C@H:8]([OH:12])[CH2:9][CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(O)C.C(=O)([O-])[O-].[K+].[K+]>C(OC)(C)(C)C>[CH2:9]([C@H:8]1[O:12][C@@H:2]1[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:10][CH3:11]
Reactant: CCC[C@@H](O)[C@@H](Cl)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CCO
Product: CCC[C@H]1O[C@@H]1C(=O)OCC
Temperature: 15 °C
Reaction time: 14 h
Yield: 104.9 %

Procedure:
Ethyl (2R,3R)-2-chloro-3-hydroxyhexanoate (1.0 g, 5 mmol), ethanol (10 ml) and potassium carbonate (2.1 g, 15 mmol) were mixed, and the mixture was stirred at 15° C. for 14 hours. Methyl tert-butyl ether (20 ml) was added. The mixture was washed with water (10 ml) three times. The organic layer was concentrated under reduced pressure to obtain the title compound (0.83 g, yield: 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([OH:12])=[C:6]([I:13])[CH:5]=1.C(N(C(C)C)CC)(C)C.[CH3:24][O:25][CH2:26]Cl>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:24][O:25][CH3:26])=[C:6]([I:13])[CH:5]=1
Reactant: COCCl
Reactant: COC(=O)c1cc(I)c(O)c(OC)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COCOc1c(I)cc(C(=O)OC)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
To a solution of 4-hydroxy-3-iodo-5-methoxybenzoic acid methyl ester (4.6 g) in chloroform (30 mL) were successively added diisopropylethylamine (3.88 g) and chloromethyl methyl ether (1.88 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was washed successively with ethyl acetate, 1N hydrochloric acid, water, and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel with solvent (hexane:ethyl acetate=3:1, v/v) to give the title compound (2.70 g).
Reaction SMILES: [CH:1]1[NH:2][C:3](=[S:10])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Cl[CH2:12][C:13]#[N:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:1]1[N:2]=[C:3]([S:10][CH2:12][C:13]#[N:14])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: N#CCCl
Reactant: S=c1[nH]cc2ccccn12
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: N#CCSc1ncc2ccccn12
Temperature: 25 °C

Procedure:
51.0 g (0.315 m) imidazo[1,5-a]pyridine-3(2H)-thione, prepared according to Example 1, 27.6 g (0.365 m) chloroacetonitrile and 30.7 g triethylamine are dissolved in 600 ml of toluene and the solution is heated to reflux for 3 hr, then allowed to cool to room temperature. The toluene solution is washed with water, dried over anhydrous magnesium sulfate and treated with Darco. After the solvent is removed, the residual solid is recrystallized from cyclohexane. A total yield of 62 g is obtained. The recrystallized sample has a melting point of 120°-2° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7]O.P(Br)(Br)[Br:12].O>COCCOC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7][Br:12]
Reactant: BrP(Br)Br
Reactant: OCc1cc(Br)ccc1Cl
Solvent: COCCOC
Solvent: O
Product: Clc1ccc(Br)cc1CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 252.1 %

Procedure:
20.0 g of 5-bromo-2-chlorobenzyl alcohol was dissolved in 100 ml of ethylene glycol dimethyl ether. To this solution, 9.4 g of phosphorus tribromide was added at −20° C., followed by stirring at room temperature for 1 hour. To the reaction solution, water was added, followed by extraction with toluene, and washing with an aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 24.9 g of a crude product of 5-bromo-2-chlorobenzyl bromide as white crystals.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]#[N:20])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4].[CH2:21]([C:23]1([CH2:31][CH3:32])[CH2:29][CH2:28][C:27](=[O:30])[O:26][C:24]1=[O:25])[CH3:22]>O1CCOCC1>[CH2:1]([N:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]#[N:20])=[CH:9][CH:8]=1)[C:27](=[O:30])[CH2:28][CH2:29][C:23]([C:24]([OH:26])=[O:25])([CH2:31][CH3:32])[CH2:21][CH3:22])[CH2:2][CH2:3][CH3:4]
Reactant: CCC1(CC)CCC(=O)OC1=O
Reactant: CCCCNCc1ccc(-c2ccccc2C#N)cc1
Solvent: C1COCCO1
Product: CCCCN(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)CCC(CC)(CC)C(=O)O

Procedure:
The starting material can be prepared, for example, as follows: A solution of 3.2 g of N-butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-amine and 3.09 g of 2,2-diethylglutaric acid anhydride in 50 ml of dioxane is heated at 115° (bath temperature) for 6 hours. After concentration of the reaction mixture by evaporation, the residue is taken up in 100 ml of ethyl acetate, and the ethyl acetate phase is washed twice with 50 ml of water each time, dried over Na2SO4 and concentrated by evaporation in vacuo. Chromatography of the evaporation residue on silica gel 60 (40-63 μm) using CH2Cl2 /CH3OH (95:5) as eluant yields pure 4-carboxy-4-ethyl-hexanoic acid N-butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-amide that has an Rf value of 0.72 [CH2Cl2 /CH3OH (4:1)].
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([CH:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][NH2:11])[CH3:8].[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[O:26][CH2:27][CH2:28][CH2:29][CH2:30]Cl>CS(C)=O.O>[CH2:7]([CH:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][NH:11][CH2:30][CH2:29][CH2:28][CH2:27][O:26][C:17]1[CH:18]=[CH:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=1)[CH3:8]
Reactant: ClCCCCOc1ccc2ccccc2c1
Reactant: CCCCC(CC)CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCC(CC)CNCCCCOc1ccc2ccccc2c1
Temperature: 140 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and 2-ethyl-n-hexylamine (0.33 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 4-(2-naphthyloxy)-1-chlorobutane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 140° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(2-ethyl-n-hexyl)-(4-(naphthalen-2-yloxy)butyl)amine, solid, m.p. 94° C., (yield 0.61 gm, 87.3%).