Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:30]([CH3:31])=[CH:29][C:15]2[N:16]=[C:17]([C:19]3[CH:20]=[C:21]4C(=[CH:26][CH:27]=3)N[C:23](=O)[CH2:22]4)[S:18][C:14]=2[C:13]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:39]([O-])([O-])=O.[Cs+].[Cs+].IC.[CH3:47][N:48]([CH:50]=[O:51])[CH3:49]>CCOC(C)=O>[C:1]([O:5][C@@H:6]([C:12]1[C:30]([CH3:31])=[CH:29][C:15]2[N:16]=[C:17]([C:19]3[CH:20]=[C:21]4[C:47](=[CH:26][CH:27]=3)[N:48]([CH3:49])[C:50](=[O:51])[C:22]4([CH3:23])[CH3:39])[S:18][C:14]=2[C:13]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)CC(=O)N4)sc2c1-c1ccc(Cl)cc1
Reactant: CN(C)C=O
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)C(C)(C)C(=O)N4C)sc2c1-c1ccc(Cl)cc1
Temperature: 50 °C

Procedure:
A vial was charged with (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-oxoindolin-5-yl)benzo[d]thiazol-6-yl)acetate (45 mg, 82 μmol), Cs2CO3 (134 mg, 0.410 mmol), iodomethane (51 μL, 0.82 mmol), and DMF (500 μL). The reaction was warmed to 50° C. for 2 h. The reaction was diluted with EtOAc and washed with 5% w/v aq LiCl (3×). The organic phase was dried (Na2SO4), filtered, and concentrated, giving the product, which was immediately used in the next step. LCMS-ESI+: calc'd for C30H29ClN2O4S: 591.2, 593.2 (M+H+); Found: 591.3, 593.3 (M+H+). 1H NMR (400 MHz, CD3CN): δ 8.04-7.88 (m, 2H), 7.81 (s, 1H), 7.63-7.48 (m, 4H), 7.02 (d, J=8.1 Hz, 1H), 5.18 (s, 1H), 4.32-4.06 (m, 2H), 3.15 (s, 3H), 2.51 (s, 3H), 1.41 (s, 6H), 1.27-1.12 (m, 3H), 0.94 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.C1C(=O)N([I:18])C(=O)C1>C(Cl)Cl.CCOC(C)=O>[NH2:1][C:2]1[S:3][C:4]([I:18])=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1
Reactant: COC(=O)c1csc(N)n1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(N)sc1I
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.5 %

Procedure:
To a solution of methyl 2-aminothiazole-4-carboxylate (5.6 g, 35.4 mmol) in DCM (60 mL) was added NIS (9.56 g, 42.5 mmol). The mixture was stirred at rt for 24 hours and then diluted with EtOAc (200 mL) and washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure to provide 9.5 g (94%) of the desired product methyl 2-amino-5-iodothiazole-4-carboxylate (8A): LC/MS(APCI): m/z 284.9 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][CH:8]([CH3:15])[CH2:7][C:6]2=[O:16].N1C=CC=CC=1.Cl[C:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]([C:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25])[CH:8]([CH3:15])[CH2:7][C:6]2=[O:16]
Reactant: CCCCOC(=O)Cl
Reactant: COc1cc2c(cc1OC)C(=O)CC(C)N2
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)CC1C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a cooled mixture of 1.15 g. (5.17 mmol) of the quinoline product of Example 4, 751 mg. (10.15 mmol) of dry pyridine and 5.5 ml. of methylene chloride stirred under a nitrogen atmosphere was added dropwise 1.03 g. (7.60 mmol) of butyl chloroformate in 1 ml. methylene chloride over 10 min. at a rate to maintain a 10°-15° temperature. After the addition was complete the bath was removed, the reaction stirred at room temperature for 45 min., and poured onto 25 ml. saturated sodium bicarbonate solution. The organic phase was collected and washed with 25 ml. of saturated sodium bicarbonate solution, 50 ml. saturated sodium chloride solution, dried over magnesium sulfate, then gravity filtered and evaporated to a viscous amber oil. Evaporative distillation at 110° C (0.05 mm) gave 1.4 g. of a very viscous amber oil.
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[NH:12]1[CH2:15][CH2:14][CH2:13]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[N:12]1([CH2:2][C:3]2[N:7]([CH3:8])[N:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: C1CNC1
Reactant: Cn1nc([N+](=O)[O-])cc1CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1nc([N+](=O)[O-])cc1CN1CCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Following Example 156e, 5-(bromomethyl)-1-methyl-3-nitro-1H-pyrazole 156d (1.76 g, 8 mmol), azetidine (550 mg, 9.6 mmol), di-isopropylethylamine (1.75 mL, 10 mmol) and methylene chloride (40 mL) were stirred at room temperature for 3-5 h. Work-up and concentrated under reduced pressure to afford 5-(azetidin-1-ylmethyl)-1-methyl-3-nitro-1H-pyrazole 200a (quant.) as yellow oil, which was used without further purification for the next step. MS (ESI+) m/z 197.1 (M+H).
Reaction SMILES: C[Si](N[Si](C)(C)C)(C)C.C(O)(=O)C.[C:14]1(=O)[CH2:18][CH2:17][CH2:16]C1.[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])#[N:21]>O>[C:20]([C:22](=[C:16]1[CH2:17][CH2:18][CH2:14]1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])#[N:21]
Reactant: CCOC(=O)CC#N
Reactant: O=C1CCCC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(C#N)=C1CCC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
HMDS (69.6 g, 0.43 mol) was added dropwise to 350 mL of acetic acid at ambient temp over 5 minutes. Cyclopentanone (20.3 g, 0.29 mol) and ethyl cyanoacetate (65.0 g, 0.57 mol) were added in single portions to the resulting solution. The mixture was stirred at 70° C. overnight after which it was cooled to ambient temperature and the reacting mixture was poured into 600 mL of water, and extracted with ethyl acetate (500 mL×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to afford the crude product, which was purified by flash chromatography (petroleum ether: ethyl acetate=10:1) to give the title compound as a yellow solid (37.0 g, 0.22 mol, 77.2%). LC-MS: m/e=166.2 (M+H+).
Reaction SMILES: [ClH:1].C[O:3][C:4]([C:6]1([NH:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH3:29])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5]>>[ClH:1].[CH2:27]([N:24]1[CH2:23][CH2:22][N:21]([C:18]2[CH:17]=[CH:16][C:15]([C:13]([NH:12][C:6]3([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]3)=[O:14])=[CH:20][CH:19]=2)[CH2:26][CH2:25]1)[CH2:28][CH3:29]
Reactant: CCCN1CCN(c2ccc(C(=O)NC3(C(=O)OC)CCCCC3)cc2)CC1
Agent: Cl
Product: CCCN1CCN(c2ccc(C(=O)NC3(C(=O)O)CCCCC3)cc2)CC1
Temperature: 25 °C
Yield: 41 %

Procedure:
3 ml of 4N hydrochloric acid was added to 600 mg (1.55 mmol) of 1-[[[4-(4-propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylic acid methyl ester, and the mixture was refluxed under heating for 6 hours. The precipitated crystal obtained by cooling it to room temperature was collected by filtration to obtain 258 mg (41%) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH2:4]1.[NH2:17][C:18]1[C:26]([Cl:27])=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([O:28][CH2:29][CH3:30])[CH:19]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[NH2:17][C:18]1[C:26]([Cl:27])=[CH:25][C:21]([C:22]([NH:1][CH2:2][CH:3]2[O:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[CH2:4]2)=[O:23])=[C:20]([O:28][CH2:29][CH3:30])[CH:19]=1
Reactant: CCOc1cc(N)c(Cl)cc1C(=O)O
Reactant: NCC1CN(Cc2ccc(F)cc2)CCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCOc1cc(N)c(Cl)cc1C(=O)NCC1CN(Cc2ccc(F)cc2)CCO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.8 %

Procedure:
To a solution of 2-aminomethyl-4-(4-fluorobenzyl)morpholine (2.5 g) in dichloromethane (50 ml), 4-amino-5-chloro-2-ethoxybenzoic acid (2.7 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.4 g) are added, and the mixture is stirred at 25° C. for 4 hours. The reaction mixture is washed successively with water, aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and evaporated under reduced pressure. The residue is recrystallized from ethanol to give the title compound (3.0 g), mp 151°-153° C.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:5]=1[NH2:6].[C:13]([O-])(=O)[CH3:14].[Na+].[C:18](=O)([O-])[O-].[Na+].[Na+]>O.C(O)(=O)C.CC(C)=O>[F:3][C:4]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:5]=1[NH:6][CH:13]([CH3:14])[CH3:18]
Reactant: Nc1ccc(F)c(F)c1F
Reactant: O=C([O-])[O-]
Reactant: CC(=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CC(C)=O
Product: CC(C)Nc1ccc(F)c(F)c1F
Reaction time: 2 h

Procedure:
7.70 g of sodium borohydride was added to a mixture of 3.70 g of 2,3,4-trifluoroaniline, 10.30 g of sodium acetate, 20 ml of acetone, 19.6 ml of acetic acid and 39 ml of water under stirring and ice-cooling. After 2 hours, the reaction mixture was made alkaline with sodium carbonate and extracted with benzene. The extract was washed with NaCl saturated water, dried and the solvent was evaporated to give 3.17 g of 2,3,4-trifluoro-N-isopropyl aniline as colorless oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[C:11]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=1>>[C:3]1([N:8]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:11]2[C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: O=C(Nc1ccccc1)c1cccnc1
Reactant: O=[N+]([O-])c1ccccc1I
Product: c1ccc(-n2c(-c3cccnc3)nc3ccccc32)cc1
Yield: 67.1 %

Procedure:
The title compound was prepared with the analogous procedure described in example 1 using 1-Iodo-2-nitrobenzene (125 mg, 0.5 mmol) and nicotinanilide (119 mg, 0.6 mmol) as starting materials to yield the title compound as brown solid (91 mg, 67%). mp 110-112° C. 1H NMR (DMSO) δ 7.26 (d, J=7.3 Hz, 1 H), 7.32-7.63 (m, 8 H), 7.86 (d, J=7.6 Hz, 1 H), 7.89 (d, J=7.8 Hz, 1 H), 8.62 (d, J=3.0 Hz, 1 H), 8.72 (br s, 1 H); 13C NMR δ 111.0, 118.7, 123.8, 124.0, 124.4, 125.4, 127.6, 129.5, 130.2, 135.2, 136.4, 137.7, 140.3, 148.6, 149.6, 158.3. HRMS (FAB): cal. for C18H14N3 [M+H+]: 272.1188; found: 272.1180.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:13][CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:32]=[C:31]([C:33](O)=[O:34])[NH:30][N:29]=2)=[CH:24][CH:23]=1>>[ClH:21].[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:32]=[C:31]([C:33]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C@H:8]4[O:13][CH2:12][CH2:11][NH:10][CH2:9]4)=[CH:6][CH:7]=3)=[O:34])[NH:30][N:29]=2)=[CH:26][CH:27]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)n[nH]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(N)cc2)C1
Product: Cl
Product: O=C(Nc1ccc([C@@H]2CNCCO2)cc1)c1cc(-c2ccc(Cl)cc2)n[nH]1

Procedure:
The title compound was prepared in analogy to Example 1 using (R)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate instead of (S)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate and 3-(4-chlorophenyl)-1H-pyrazole-5-carboxylic acid (CAS-54006-63-2) instead of 3-phenyl-1H-pyrazole-5-carboxylic acid. Off-white solid. MS (ISP): 383.1 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]=[C:5]([CH3:7])[N:6]=1.C(N(CC)CC)C.[Cl:15][CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>C1C=CC=CC=1>[Cl:15][CH2:16][CH2:17][CH2:18][C:19]([NH:1][C:2]1[O:3][CH:4]=[C:5]([CH3:7])[N:6]=1)=[O:20]
Reactant: O=C(Cl)CCCCl
Reactant: Cc1coc(N)n1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1coc(NC(=O)CCCCl)n1
Temperature: 25 °C
Yield: 23.92 %

Procedure:
2-Amino-4-methyloxazole (5.0 g., 0.0509 mol) was dissolved in dry benzene (100 mls.) and triethylamine (5.70 g., 0.0563 mol) was added. The mixture was stirred vigorously at room temperature and 4-chlorobutyrylchloride (7.88 g., 0.0558 mol) in dry benzene (50 mls.) was added rapidly. After the addition the mixture was heated under reflux for 2 hours. The mixture was then cooled and filtered. The filtrate was placed in a separating funnel and washed successively with water (1 × 100 mls.), 10% Na2CO3 (2 × 100 mls.) and water (3 × 100 mls.). The organic layer was dried over magnesium sulphate and evaporated under vacuum. The product was recrystallised from ethyl acetate/hexane. Wt. = 2.47 g.m.p. 98° C. (Yield = 23.92%).
Reaction SMILES: Br[C:2]1[C:7]([CH2:8][O:9][C:10]2[C:11]([CH:18]3[O:22][CH2:21][CH2:20][O:19]3)=[CH:12][C:13]([O:16][CH3:17])=[N:14][CH:15]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:23][N:24](C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:19]1[CH2:20][CH2:21][O:22][CH:18]1[C:11]1[CH:12]=[C:13]([O:16][CH3:17])[N:14]=[CH:15][C:10]=1[O:9][CH2:8][C:7]1[C:2]([C:23]#[N:24])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc(C2OCCO2)c(OCc2cccnc2Br)cn1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: COc1cc(C2OCCO2)c(OCc2cccnc2C#N)cn1
Temperature: 125 °C
Yield: 84 %

Procedure:
A mixture of 5-((2-bromopyridin-3-yl)methoxy)-4-(1,3-dioxolan-2-yl)-2-methoxypyridine (1.1 g, 3.0 mmol, 1 eq.), Zn (CN)2 (704 mg, 6.0 mmol, 2.0 eq.), and Pd(PPh3)4 (346 mg, 0.3 mmol, 0.2 eq.) in DMF (10 mL) was heated at 125° C. for 2 h under N2. The mixture was cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)picolinonitrile (820 mg, 84%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.71 (d, J=4.6 Hz, 1H), 8.12 (dd, J=8.0, 0.7 Hz, 1H), 7.88 (s, 1H), 7.60 (dd, J=8.0, 4.7 Hz, 1H), 6.95 (s, 1H), 6.16 (s, 1H), 5.37 (s, 2H), 4.18-4.00 (m, 4H), 3.92 (s, 3H). LRMS (M+H+) m/z 314.1.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1)(=[O:4])=[O:3].O.S.[Na]>CO.C1(C)C=CC=CC=1>[CH3:1][S:2]([C:5]1[CH:10]=[C:9]([CH:8]=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1)[NH2:11])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: S
Agent: [Na]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1cc(N)cc([N+](=O)[O-])c1
Yield: 57 %

Procedure:
A solution of 1-(methylsulfonyl)-3,5-dinitro-benzene (1 g; 4 mmol) in methanol (80 ml) and toluene (20 ml) was treated with a solution of sodium hydrogensulfide-hydrate (227 mg; 4 mmol) in 20 ml methanol. The mixture was then refluxed for 3 hours additional 500 mg sodium hydrogensulfide-hydrate were added and refluxed for an additional hour. After cooling, the precipitate was filtrated and the filtrate concentrated. The residual was crystallized from methanol. 500 mg (2.31 mmol; 57% yield) of a yellow solid were obtained.
Reaction SMILES: [C:1]1(=[O:22])[N:5]([CH2:6][C:7]2[N:8]=[C:9]([N:12]3[CH2:15][CH:14]([OH:16])[CH2:13]3)[S:10][CH:11]=2)[C:4](=[O:17])[C:3]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:2]12.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C.C(OCC)C>C(Cl)Cl>[C:4]1(=[O:17])[N:5]([CH2:6][C:7]2[N:8]=[C:9]([N:12]3[CH2:13][CH:14]([O:16][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:15]3)[S:10][CH:11]=2)[C:1](=[O:22])[C:2]2=[CH:21][CH:20]=[CH:19][CH:18]=[C:3]12
Reactant: CS(=O)(=O)Cl
Reactant: O=C1c2ccccc2C(=O)N1Cc1csc(N2CC(O)C2)n1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CN(c2nc(CN3C(=O)c4ccccc4C3=O)cs2)C1
Reaction time: 1 h
Yield: 67.3 %

Procedure:
To a solution of 1-(4-phthalimidomethyl-1,3-thiazol-2-yl)-3-hydroxyazetidine (864 mg, 2.74 mmol) (obtained as described in Reference Example 68(2)) in methylene chloride (35 ml) were added methanesulfonyl chloride (0.25 ml, 3.29 mmol) and triethylamine (0.46 ml, 3.29 mmol) in an ice bath and the mixture was stirred for 1 hour. After checking the completion of the reaction, the mixture was added to diethyl ether and stirred for 30 minutes. The mixture was then filtered and the solid was collected by filtration and washed with diethyl ether to afford 1-(4-phthalimidomethyl-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (726 mg, yield 67%) as a white solid.
Reaction SMILES: O(CC([NH:11][CH:12]1[C:33](=[O:34])[N:14]2[CH:15]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[O:21])[C:16](=[CH2:19])[CH2:17][S:18][C@H:13]12)=O)C1C=CC=CC=1.C(Cl)Cl.P(Cl)(Cl)(Cl)(Cl)Cl.[C:44]1([CH3:54])[CH:49]=[CH:48][C:47]([S:50]([OH:53])(=[O:52])=[O:51])=[CH:46][CH:45]=1>CO.N1C=CC=CC=1>[C:44]1([CH3:54])[CH:45]=[CH:46][C:47]([S:50]([OH:53])(=[O:51])=[O:52])=[CH:48][CH:49]=1.[NH2:11][CH:12]1[C:33](=[O:34])[N:14]2[CH:15]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=3)=[O:21])[C:16](=[CH2:19])[CH2:17][S:18][C@H:13]12
Reactant: C=C1CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: C=C1CS[C@@H]2C(N)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C

Procedure:
To a solution of 965 mg. of p-nitrobenzyl 7-phenoxyacetamido-3-methylenecepham-4-carboxylate in 10 ml. of methylene chloride were added 175 mg. of dry pyridine and 460 mg. of phosphorus pentachloride and the mixture was stirred for five hours at room temperature. Thereafter the reaction mixture was cooled to 0°C. and 50 ml. of cold methanol were added. Following a stirring period of one-hour at room temperature the reaction mixture was evaporated in vacuo to remove the solvents and the residual reaction product mixture was dissolved in a mixture of ethyl acetate and water. The pH was adjusted to pH 7 and the ethyl acetate layer was separated and was washed with water and dried. One equivalent of p-toluene sulfonic acid was added to the dried solution and on cooling 600 mg. of p-nitrobenzyl 7-amino-3-methylenecepham-4-carboxylate p-toluenesulfonate formed as a crystalline precipitate. The product was purified by recrystallization from a mixture of 12 ml. of methanol 24 ml. of ether and 15 ml. of petroleum ether.
Reaction SMILES: C1([Li])C=CC=CC=1.C(=O)=O.[CH:11](=[N:18][CH2:19][P:20](=[O:35])([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl[C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=1)=[O:38]>O1CCCC1>[CH:11](=[N:18][CH:19]([P:20]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:35])[C:37]([O:39][CH2:40][C:41]1[CH:42]=[CH:43][C:44]([N+:47]([O-:49])=[O:48])=[CH:45][CH:46]=1)=[O:38])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=P(CN=Cc1ccccc1)(Oc1ccccc1)Oc1ccccc1
Agent: O=C=O
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)C(N=Cc1ccccc1)P(=O)(Oc1ccccc1)Oc1ccccc1
Reaction time: 0.25 h

Procedure:
Phenyllithium (45 ml of a 2.3 M solution in 7:3 benzene-ether) in added to a dry-ice-cooled, stirring solution of diphenyl N-benzylidene-aminomethylphosphonate (35.1 g) in anhydrous tetrahydrofuran (500 ml). After having been stirred for 15 minutes at -78° under a nitrogen atmosphere, the solution is treated dropwise over 1 hour with p-nitrobenzyl chloroformate (10.8 g) in tetrahydrofuran (100 ml). The resulting solution is stirred an additional 2 hours at -78°, then allowed to warm to 5° over a period of 30 minutes. Evaporation of the solvent under reduced pressure leaves a residue which is partitioned between ethyl ether (500 ml) and 0.5 pH 3 phosphate buffer (200 ml). The aqueous phase is separated and extracted with ethyl ether (2 × 100 ml). The combined ethereal solution is washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography of the residue on silica gel affords p-nitrobenzyl N-benzylidene-α-amino-diphenylphosphonoacetate as well as starting material.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]([OH:17])[CH2:11][C:12](OCC)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:19][NH2:20]>CO>[C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]([OH:17])[CH2:11][C:12]([NH:19][NH2:20])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C[C@@H](O)CNC(=O)OC(C)(C)C
Reactant: NN
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC[C@H](O)CC(=O)NN
Temperature: 65 °C
Reaction time: 5 h
Yield: 70.1 %

Procedure:
A 6.50 g (26.1 mmol) of ethyl (R)-4-t-butoxycarbonylamino-3-hydroxybutyrate (optical purity: 95%e.e.) was dissolved in 26 ml of methanol, and 1.96 g (39.1 mmol) of hydrazine monohydrate was added thereto dropwise at room temperature. After the addition, the mixture was heated to 65° C. and then stirred for 5 hours. After the mixture was cooled to room temperature, stirring was conducted overnight to give 4.27 g (70%) of the title compound. Melting point: 143.6° C. Optical purity: >99.9%e.e.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C@H:10]([CH2:14][CH3:15])[C:11]([NH2:13])=[O:12].Br[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>C1(C)C=CC=CC=1>[NH2:13][C:11]([C@H:10]([NH:9][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14][CH3:15])=[O:12]
Reactant: CC[C@@H](N)C(N)=O
Reactant: CCOC(=O)CCCBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCN[C@H](CC)C(N)=O
Temperature: 80 °C

Procedure:
143.6 ml (1.035 mole) of triethylamine are added to a suspension of 47.75 g (0.345 mole) of (R)-2-amino-butanamide hydrochloride ([alpha]D25 : -26.1°; c=1, methanol) in 400 ml of toluene. The mixture is heated to 80° C. and 67.2 g (0.345 mole) of ethyl 4-bromobutyrate are introduced dropwise.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]1([F:23])[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C>CN(C)C=O.O>[F:15][C:16]1([F:23])[CH2:21][CH2:20][CH:19]([N:11]2[CH2:12][CH2:13][CH:8]([NH:7][C:6](=[O:14])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:9][CH2:10]2)[CH2:18][CH2:17]1
Reactant: O=C1CCC(F)(F)CC1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(C2CCC(F)(F)CC2)CC1
Reaction time: 8 h

Procedure:
To a stirred solution of piperidin-4-yl-carbamic acid tert-butyl ester (2.00 g, 10 mmol) and 4,4-difluorocyclohexanone (1.61 g, 12 mmol) in N,N-dimethylformamide (50 mL), kept at room temperature, acetic acid (3 mL, 50 mmol) and tetramethylammonium triacetoxyborohydride (5.24 g, 20 mmol) were subsequently added. The reaction mixture was allowed to stir overnight then diluted with water (150 mL), extracted with diethyl ether and the organic layer was discarded. The aqueous phase was made basic with ammonia and extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over sodium sulfate, evaporated to dryness and the residue was purified by column chromatography, using dichloromethane/ethanol/concentrated aqueous ammonia: 97.5/2.5/0.25 as the mobile phase. Tert-butyl [1-(4,4-difluorocyclohexyl)-piperidin-4-yl]-carbamate was obtained in fairly good yield as a white solid (2.5 g, 78%).