Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CC1C=CC2C(=CC=CC=2)C=1.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[OH:32]>>[CH2:23]([O:32][C:7]1[CH:8]=[CH:9][C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=1)[CH3:22].[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[OH:32]
Reactant: c1ccc2ccccc2c1
Agent: Cc1ccc2ccccc2c1
Agent: Oc1ccc2ccccc2c1
Product: CCOc1ccc2ccccc2c1

Procedure:
Silylations of aryl alkyl ethers at elevated temperatures were conducted under the conditions applied to diaryl ethers to probe the cleavage selectivity of sp2 versus sp3 C—O bond. At the elevated temperatures of these experiments, the reaction of 2-methoxynaphthalene gave 2-naphthol as the major product in moderate yield (Scheme 1). GC-MS analysis of the crude reaction mixture indicated the presence of trace amounts of naphthalene along with 2-methylnaphthalene and further reduced species, including products of partial aromatic reduction. Compounds presumably derived from 2-naphthol silylation were also detected. Likewise, cleavage of 2-ethoxynaphthalene under the same conditions gave 2-naphthol in slightly higher yield, but with the same or analogous side products. Sterically bulkier ethers were investigated to probe the versatility and possible mechanism of the C—O bond cleavage. Despite the large alkyl substituent adjacent to the ether oxygen, reaction of 2-neopentyloxynaphthalene provided 2-naphthol in approximately the same yield as with the less bulky substrates. Even 2-tert-butyloxynapthalene was cleaved to give the expected naphthol in 55% yield (Scheme 1). Control experiments performed at identical conditions but without triethylsilane provided 2-naphthol in cases of 2-ethoxy- and 2-tert-butyloxynapthalene albeit with substantially diminished yields. Since 2-methoxy- and 2-neopentyloxy-substrates remained intact in such silane-free cleavages, a b elimination mechanism is likely to be operative. When attempting to reduce 4-tert-butyl and 4-methyl anisoles under the standard conditions, the yields of the corresponding phenols were high, likely because of more challenging silylation of the substituted phenyl ring for the steric reasons (Scheme 2).
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:10])[CH2:4]/[CH:5]=[CH:6]/[C:7](O)=[O:8].C(Cl)(=O)C([Cl:14])=O>C1COCC1.CN(C=O)C>[ClH:14].[CH3:2][N:3]([CH3:10])[CH2:4]/[CH:5]=[CH:6]/[C:7]([Cl:1])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C)C/C=C/C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(C)C/C=C/C(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
A well stirred suspension of 4-dimethylaminocrotonic acid hydrochloride (5.0 g, 30 mmol) in cold (0° C.) THF (40 mL) and DMF (2 pipet drops) is treated with oxalyl chloride (3.15 mL, 36 mmol). Stirring at 20–25° C. for 3 hours is followed by cooling to 0° C. and holding for 30 minutes. Solids are collected on a Buchner funnel (under a blanket of nitrogen) and the cake is washed with cold (0° C.) THF (3×5 mL). The solid is dried under vacuum (˜1 torr) at 40–50° C. for 3 hours to give 4.0 g of 4-dimethylaminocrotonoyl chloride hydrochloride. This material is characterized as its methyl ester by treatment of the solid with methanol.
Reaction SMILES: C(OC(=O)[NH:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][N:12]=[C:13]2[C:16]2([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH2:19][CH2:18][CH2:17]2)=[CH:8][CH:7]=1)C.[OH-].[K+]>C(O)C.O>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([C:16]2([C:13]3[C:14]4[C:9](=[CH:8][CH:7]=[C:6]([NH2:5])[CH:15]=4)[CH2:10][CH2:11][N:12]=3)[CH2:19][CH2:18][CH2:17]2)=[CH:25][CH:24]=1
Reactant: CCOC(=O)Nc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2
Yield: 100 %

Procedure:
{1-[1-(4-Chloro-phenyl)-cyclobutyl]-3,4-dihydro-isoquinolin-7-yl}-carbamic acid ethyl ester (400 mg, 1.04 mmol) in a solution of potassium hydroxid in ethanol (20 ml, 10%) are stirred for 5 h under reflux. The solvent was reduced, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution and dried with sodium sulphate to give the final product (0.32 mg, 1.04 mmol, 99%) as an orange solid that was used without further purification.
Reaction SMILES: [NH2:1][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl[C:16]([S:18]Cl)=[O:17]>ClC1C=CC=CC=1>[O:17]=[C:16]1[NH:1][C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[S:18]1
Reactant: CCOC(=O)C=C(N)c1ccccc1
Reactant: O=C(Cl)SCl
Solvent: Clc1ccccc1
Product: CCOC(=O)c1sc(=O)[nH]c1-c1ccccc1
Temperature: 110 °C
Yield: 55 %

Procedure:
To a solution of 20.0 g (0.105 mole) of ethyl β-amino-cinnamate in 40 ml. of chlorobenzene under ice cooling was added a solution of 11.6 g (0.112 mole) of chorocarbonylsulfenyl chloride in 10 ml. of chlorobenzene. The reaction mixture was heated at 110° C. for 2 hours, cooled to triturated with petroleum ether. The precipitate was heated with hot benzene, cooled and filtered to give 14.4 g (55%) of ethyl 2,3-dihydro-2-oxo-4-phenyl-5-thiazolecarboxylate as yellow needles. A mixture of 3.0 g (0.012 mole) of ethyl 2,3-dihydro-2-oxo-4-phenyl-5-thiazolecarboxylate and 14 ml. of phosphorus oxychloride was held at reflux for 24 hours and cooled. The reaction mixture was poured into ice water. The solid precipitate was extracted into ether. The ether solution was dried and concentrated under reduced pressure. The residue was recrystallized from hexane to give 2.2 g (68%) of ethyl 2-chloro-4-phenyl-5-thiazolecarboxylate, m.p. 56°-57° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25](O[C@@H]1[C@@H](OC(=O)C)[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1[N-]C(NC(OC(C)(C)C)=O)CCCCCCCCCCC)(=O)[CH3:26]>C(Cl)(Cl)Cl.CO>[OH:12][CH2:10][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCC([N-][C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O)NC(=O)OC(C)(C)C
Reactant: CCCCCCCCCCCCC(NC(=O)OC(C)(C)C)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCCCCCCCCCCCC(CO)NC(=O)OC(C)(C)C
Yield: 82 %

Procedure:
Procedure as for 44, Method C (using 42 in place of 41). RF=0.72 chloroform:methanol 10:0.7 (v/v); yield 82%; 1H NMR δ 3.69-3.45 (m, 2H, αCH, CH2a), 2.97 (m, 1H, CH2b), 1.41 (s, 9H, 3×Boc CH3), 1.25 (m, 18H, 13CH2), 0.88 (t, 3H, CH3); FAB MS C21H43NO3 (357.32) m/z (%) 380 [M+Na]+ (15), 258 [M−Boc+H]+ (100).
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([OH:13])[CH3:12].O.NN.[CH3:17][N:18](C)C=O>>[CH2:3]([O:13][CH2:11][CH2:12][CH2:17][NH2:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCO
Reactant: CN(C)C=O
Reactant: BrCc1ccccc1
Agent: NN
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: NCCCOCc1ccccc1
Yield: 50 %

Procedure:
To 20.5 g(0.1 mol) of the compound prepared in Preparation 5-1) in 40 ml of dimethylformamide was added 4.4 g(0.11 mol) of sodium hydride(60%). 18.9 g(0.11 mol) of benzyl bromide was added and the resulting mixture was reacted for 12 hours. After removal of solvent the reaction, solvent was removed and the residue was dissolved in ethylacetate and the organic layer was washed with saturated sodium bicarbonate solution. After removal of solvent, 200 ml of ethanol and 12.5 g(0.25 mol) of hydrazine hydrate was added thereto, and the resulting mixture was refluxed for 3 hours. After the reaction, solvent was removed under reduced pressure. The residue was dissolved in 200 ml of dichloromethane and the organic layer was washed with saturated sodium bicarbonate solution. 200 ml of 1N aqueous hydrochloric acid solution was added and the organic layer was removed. To the aqueous layer was added 200 ml of dichloromethane, and the resulting solution was basified with 6N sodium hydroxide solution. The organic layer was separated and the solvent was removed under reduced pressure to give 8.3 g(Yield 50%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([OH:15])=O)[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:7]=1)=[O:5])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH2:42]([O:49][C:50](=[O:56])[C@@H:51]1[CH2:55][CH2:54][CH2:53][NH:52]1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C=O)C.C(Cl)CCl>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([N:52]2[CH2:53][CH2:54][CH2:55][C@H:51]2[C:50]([O:49][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:56])=[O:15])[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(OCC(=O)O)n(-c2ccccc2)n1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)n(-c2ccccc2)n1
Reaction time: 16 h

Procedure:
To a solution of 9.5 g 5-carboxymethoxy-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester in 100 ml DMF were added 5.0 g HOBt, 6.3 g EDC and 10.9 ml DIPEA. After 5 minutes 7.9 g L-proline benzyl ester hydrochloride were added and the resulting solution stirred for 16 h. The reaction mixture was concentrated, dissolved in dichloromethane and extracted with aqueous LiCl (4%) and saturated NaHCO3. The crude product obtained after evaporation of the solvent was purified by flash chromatography on silica using ethyl acetate/heptane 1:1 as eluent. Yield: 13.2 g colorless foam.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([O:20][C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:25])[CH2:4][CH2:3]1.[O:26]=[C:27]1[CH2:32][O:31][C:30]2[CH:33]=[CH:34][C:35]([CH:37]=O)=[N:36][C:29]=2[NH:28]1.C([BH3-])#N.[Na+]>>[O:25]=[C:11]1[N:10]([CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][CH:2]([NH:1][CH2:37][C:35]3[CH:34]=[CH:33][C:30]4[O:31][CH2:32][C:27](=[O:26])[NH:28][C:29]=4[N:36]=3)[CH2:7][CH2:6]2)[C:15]2[CH:16]=[C:17]([O:20][C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:19][C:14]=2[O:13][CH2:12]1
Reactant: NC1CCN(CCN2C(=O)COc3ccc(OC(F)(F)F)cc32)CC1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Product: O=C1COc2ccc(CNC3CCN(CCN4C(=O)COc5ccc(OC(F)(F)F)cc54)CC3)nc2N1
Yield: 15.3 %

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-(trifluoromethoxy)-2H-1,4-benzoxazin-3(4H)-one (Intermediate 61) (0.55 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (120 mg, 0.66 mmol) and sodium cyanoborohydride (69 mg, 1.1 mmol) were reacted as described under Example 21 to give 44 mg (15%) product as a solid.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1([CH3:23])[O:11][CH:10]([CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]3[CH:18]=[CH:19][S:20][C:16]=3[CH:15]=2)[CH2:9][O:8]1.[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C.O>CCCCCC.O1CCCC1>[CH3:6][C:7]1([CH3:23])[O:11][CH:10]([CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]3[CH:18]=[C:19]([B:24]([OH:29])[OH:25])[S:20][C:16]=3[CH:15]=2)[CH2:9][O:8]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC1(C)OCC(COc2ccc3ccsc3c2)O1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C)OCC(COc2ccc3cc(B(O)O)sc3c2)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.5 M n-butyllithium (1.75 mL, 4.37 mmol) in hexane was slowly added to 6-[(R/S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyloxy]benzothiophene ((R/S)-25, 1.05 g, 3.97 mmol) obtained in step 1 dissolved in anhydrous tetrahydrofuran (150 mL) at −78° C. under nitrogen atmosphere. 15 Minutes later, the resulting mixture was agitated at room temperature for 1 hour. After cooling again to −78° C., triisopropyl borate ((i-PrO)3B; 1.10 mL, 4.77 mmol) was slowly added. After slowly heating to room temperature and agitating for 3 hours, water was added to quench the reaction. After extracting the organic compound with ethyl acetate and drying with sodium sulfate, column chromatography yielded the target compound 6-[(R/S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyloxy]benzothiophene-2-boronic acid ((R/S)-26, 880 mg, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:26])[C:16]#[C:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=3)=[CH:10][CH:9]=2)=[C:4]([F:27])[CH:3]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].ClCCl.CO.N>>[CH3:28][S:29]([O:25][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]#[C:16][C:15](=[O:26])[NH:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[F:27])=[CH:9][CH:10]=2)=[CH:19][CH:20]=1)(=[O:31])=[O:30]
Reactant: O=C(C#Cc1ccc(CO)cc1)Nc1ccc(-c2ccc(Cl)cc2F)cc1
Reactant: CS(=O)(=O)Cl
Agent: N
Solvent: ClCCl
Solvent: CO
Product: CS(=O)(=O)OCc1ccc(C#CC(=O)Nc2ccc(-c3ccc(Cl)cc3F)cc2)cc1

Procedure:
Prepared analogously to Example 1.2.b. from 3-(4-hydroxymethylphenyl)propynoic acid-(4′-chloro-2′-fluorobiphenyl-4-yl)amide and methanesulfonic acid chloride. Yield: 0.23 g (50% of theory); C23H17ClFN2O2S (M=457.91); calc.: molecular ion peak (M+H)+: 456/458; found: molecular ion peak (M+H)+: 456/458; Rf value: 0.5 (silica gel, dichloromethane/methanol/ammonia (20:1:0.1)).
Reaction SMILES: Cl.CN.CC(C)(C)C[CH2:7][NH2:8].[O:11]=[C:12]1[C:20]2([C:24]3=[CH:25][C:26]4[O:30][CH2:29][O:28][C:27]=4[CH:31]=[C:23]3[O:22][CH2:21]2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]1[CH2:32][C:33]1[O:37][C:36]([C:38]([F:41])([F:40])[F:39])=[C:35]([C:42]([OH:44])=O)[CH:34]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC(O)=O>>[CH3:7][NH:8][C:42]([C:35]1[CH:34]=[C:33]([CH2:32][N:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]3([C:24]4=[CH:25][C:26]5[O:30][CH2:29][O:28][C:27]=5[CH:31]=[C:23]4[O:22][CH2:21]3)[C:12]2=[O:11])[O:37][C:36]=1[C:38]([F:40])([F:41])[F:39])=[O:44]
Reactant: CC(C)(C)CCN
Reactant: O=C(O)c1cc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)oc1C(F)(F)F
Agent: CN
Agent: Cl
Agent: O=C(O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Product: CNC(=O)c1cc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)oc1C(F)(F)F

Procedure:
Following the procedure as described in EXAMPLE 12.49 and making non-critical variations using methylamine hydrochloride to replace 3,3-dimethylbutylamine, 5-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-2-(trifluoromethyl)furan-3-carboxylic acid to replace (2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetic acid, N-methyl-5-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-2-(trifluoromethyl)furan-3-carboxamide was obtained (96%) as a colorless solid: mp 202-203° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.31-7.27 (m, 2H), 7.19-7.17 (m, 1H), 7.10-7.05 (m, 1H), 6.95-6.92 (m, 1H), 6.62 (s, 1H), 6.49 (s, 1H), 6.09 (s, 1H), 5.94 (br s, 1H), 5.85-5.84 (m, 2H), 5.03-4.85 (m, 3H), 4.67-4.64 (m, 1H), 2.92 (d, J=3.0 Hz, 3H); MS (ES+) m/z 487.3 (M+1).
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:19][CH2:20][CH2:21][NH2:22].[C@H:23]1([NH:32][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[C:38]([NH2:43])[CH:39]=3)[N:34]=2)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1>>[C@H:23]1([NH:32][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[C:38]([NH:43][C:1]([NH:22][CH2:21][CH2:20][O:19][CH:14]4[CH2:15][CH2:16][CH2:17][CH2:18][O:13]4)=[O:12])[CH:39]=3)[N:34]=2)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1
Reactant: NCCOC1CCCCO1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Product: O=C(NCCOC1CCCCO1)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, 2-(tetrahydro-pyran-2-yloxy)-ethylamine and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=446.6 (M+H+).
Reaction SMILES: Cl.[O:2]=[C:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][NH2:5].[CH2:12]([O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28]([C:33](Cl)=[O:34])[CH:27]=[CH:26]2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].O1CCOCC1.N1C=CC=CC=1>O>[O:2]=[C:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][NH:5][C:33]([C:28]1[CH:27]=[CH:26][C:25]2[C:30](=[CH:31][CH:32]=[C:23]([O:22][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:24]=2)[CH:29]=1)=[O:34]
Reactant: CCCCCCCCCCOc1ccc2cc(C(=O)Cl)ccc2c1
Reactant: CCCCCCC(=O)CN
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CCCCCCCCCCOc1ccc2cc(C(=O)NCC(=O)CCCCCC)ccc2c1
Yield: 81.2 %

Procedure:
In a 50 ml-three-necked flask, 0.20 g (1.11 mM) of 2-oxooctylamine hydrochloride, 0.46 g (1.33 mM) of 6-decyloxy-2-naphthoyl chloride and 5 ml of dioxane were placed. To the mixture, 1.6 ml of pyridine was added at about 85° C. under heat-stirring, followed by heat-stirring for 30 minutes at 92°-94° C. After the reaction, the reaction mixture was poured into water to precipitate a crystal. The crystal was recovered by filtration and washed with water, followed by recrystallization from a mixture solvent of acetonemethanol to provide 0.41 g of 2-oxooctyl-(6-decyloxy-2-naphthoyl)amine (Yield: 81.2%).
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>C(OCC)(=O)C>[C:26]1([CH3:29])[CH:25]=[CH:24][C:23]([S:20]([O-:22])(=[O:19])=[O:21])=[CH:28][CH:27]=1.[C:1]1([C@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[N+:13]2([CH3:18])[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc([C@H]2CCCC[C@H]2N2CCCC2)cc1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Solvent: CCOC(C)=O
Product: C[N+]1([C@@H]2CCCC[C@@H]2c2ccccc2)CCCC1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Yield: 72 %

Procedure:
cis- 2Phenyl-1-pyrrolidinocyclohexane (2.3g) and methyl-p-toluenesulphonate (1.9g) were heated in boiling ethyl acetate under reflux for 18 hours. An oil slowly formed which quickly crystallised on cooling. Recrystallisation from ethyl alcohol/ethyl acetate afforded the quaternary salt (3.0g), m.p. 146° to 148° C
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[C:12]3[CH2:20][NH:19][CH2:18][CH2:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:5][CH:4]=1.F[C:24]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:25]=1[C:26]#[N:27].C(#N)C.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[F:32][C:29]1[CH:30]=[CH:31][C:24]([N:19]2[CH2:18][CH2:17][C:13]3[N:14]=[CH:15][N:16]=[C:11]([NH:10][CH2:9][C:6]4[CH:7]=[N:8][C:3]([C:2]([F:21])([F:1])[F:22])=[CH:4][CH:5]=4)[C:12]=3[CH2:20]2)=[C:25]([CH:28]=1)[C:26]#[N:27]
Reactant: FC(F)(F)c1ccc(CNc2ncnc3c2CNCC3)cn1
Reactant: N#Cc1cc(F)ccc1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: N#Cc1cc(F)ccc1N1CCc2ncnc(NCc3ccc(C(F)(F)F)nc3)c2C1
Yield: 11.7 %

Procedure:
A 2 mL microwave vial was charged with N-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (50 mg, 0.16 mmol), 2,5-difluorobenzonitrile (130 mg, 0.97 mmol), acetonitrile (0.4 mL) and N,N-diisopropylethylamine (84 μL, 0.48 mmol). The mixture was subjected to microwave irradiation at 200° C. for 4 h. After cooling the mixture was diluted with chloroform (7 mL), and washed with 0.1 M NaH2PO4 (10 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by semi-preparative HPLC (100×20.2 mm, C18 column; 20-90% MeCN/H2O [10 mM diethylamine]) to yield an off-white solid (8 mg).
Reaction SMILES: C([O-])=O.[C:4]([O:7][CH2:8][C:9]1[CH2:10][S:11][C@@H:12]2[CH:19]([NH:20][C:21](=[O:32])[C:22]([C:26]3[N:27]=[C:28]([NH2:31])[S:29][CH:30]=3)=[N:23][O:24][CH3:25])[C:18](=[O:33])[N:13]2[C:14]=1[C:15]([OH:17])=[O:16])(=[O:6])[CH3:5].C([O-])(=O)C.[Na+:38]>O.C(O)C>[C:4]([O:7][CH2:8][C:9]1[CH2:10][S:11][C@@H:12]2[CH:19]([NH:20][C:21](=[O:32])[C:22]([C:26]3[N:27]=[C:28]([NH2:31])[S:29][CH:30]=3)=[N:23][O:24][CH3:25])[C:18](=[O:33])[N:13]2[C:14]=1[C:15]([O-:17])=[O:16])(=[O:6])[CH3:5].[Na+:38]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Agent: CC(=O)[O-]
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Yield: 0.95 %

Procedure:
10 g of the formate solvate of the syn isomer of 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylic acid (described in Belgium Pat. No. 850,662) were added at room temperature to a solution of 3.5 g of sodium acetate in 5 ml of water and 300 ml of ethanol and when dissolution was complete, the mixture was filtered. The filtrate was added dropwise over one hour with stirring at room temperature to 160 ml of absolute ethanol and the resulting mixture was stirred at room temperature for 3 hours and at 0° C. for 16 hours. The mixture was vacuum filtered and the crystals were washed with ethanol and dried under reduced pressure to obtain 7.75 g of the crystalline D form of the syn isomer of sodium 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylate containing 0.95% of water.
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:8][O:7][CH2:6][CH2:5][NH:4]1.[Cl:9][CH2:10][C:11]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[N:14]=[N:13][N:12]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[ClH:9].[CH3:2][C@@H:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[CH2:10][C:11]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[CH:17]=2)[N:14]=[N:13][N:12]=1
Reactant: FC(F)(F)c1cccc(-n2nnnc2CCl)c1
Reactant: C[C@@H]1COCCN1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1COCCN1Cc1nnnn1-c1cccc(C(F)(F)F)c1

Procedure:
A solution of (3R)-3-methylmorpholine hydrochloride (52.4 mg, 0.381 mmol), 5-(chloromethyl)-1-[3-(trifluoromethyl)phenyl]-1H-tetrazole (50 mg, 0.190 mmol, commercially available from Otava, Kiev, Ukraine) and di-isopropylethylamine (0.067 mL, 0.381 mmol) in acetonitrile (1.5 mL) was heated to 120° C. for 15 minutes in a microwave reactor. The reaction mixture was allowed to cool and the solvent removed under vacuum. The residue was purified by MDAP and fractions containing the desired product were combined and the solvent removed. The residue was dissolved in a minimum of diethyl ether before the dropwise addition of 1N HCl in diethyl ether (3 mL) leading to precipitation. The solvent was removed under a stream of argon and the residue triturated with diethyl ether then dried under vacuum to yield the title compound as a white solid (46 mg).
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8](Cl)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CCN(C(C)C)C(C)C.[CH3:20][NH:21][C@@H:22]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23]1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[N:9]=[C:8]([N:21]([CH3:20])[C@@H:22]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[CH2:23]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(Cl)nc1Cl
Reactant: CN[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(c1ccc(C#N)c(Cl)n1)[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C

Procedure:
To a solution of 2,6-dichloronicotinonitrile (2.2 mmol) and DIPEA (10 mmol) in DMF (10 mL) was added (R)-tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate with stirring at room temperature. The reaction mixture was stirred at 100° C. overnight. Then the mixture was diluted with EtOAc, washed 3 times with water, dried, filtered and concentrated. The crude product was purified by flash chromatography to give the title compound.