Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[CH2:8][S:7][C:6]([NH:9][NH2:10])=[N:5][N:4]=1.C(N(CC)CC)C.[N+:18]([C:21]1[CH:43]=[CH:42][C:24]([O:25][CH:26]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:27](Cl)=[O:28])=[CH:23][CH:22]=1)([O-:20])=[O:19]>C(#N)C.C(OCC)(=O)C>[N+:18]([C:21]1[CH:43]=[CH:42][C:24]([O:25][CH:26]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:27]([NH:10][NH:9][C:6]2[S:7][CH2:8][C:3]([CH3:2])=[N:4][N:5]=2)=[O:28])=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: CCCCCCCCCCCCC(Oc1ccc([N+](=O)[O-])cc1)C(=O)Cl
Reactant: CC1=NN=C(NN)SC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCCCCCCCC(Oc1ccc([N+](=O)[O-])cc1)C(=O)NNC1=NN=C(C)CS1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
A mixture of 24.25 g (0.134 m) of (5-methyl-6H-1,3,4-thiadiazin-2-yl)-hydrazine hydrochloride (2b) and 25.9 g (0.256 m) of triethylamine in 170 ml of acetonitrile is cooled to 0° C. A solution of 46.8 g (0.122 m) of 2-(4-nitrophenoxy)tetradecanoyl chloride (3b) in 50 ml of ethyl acetate is added slowly to the mixture keeping the temperature at 0-5° C. over an hour. The resulting mixture is stirred at 0° C. for 30 min, then warmed up to room temperature and stirred for another hour. After the reaction is complete, 170 ml of ethyl acetate is added and the mixture is stirred for 15 min. The solid is collected, washed with ethyl acetate, dried, and reslurried in 300 ml of water to remove triethylamine hydrochloride. The product is collected, washed with water, and dried to give 33.0 g (55%) of 2-(2-[4-nitrophenoxy] tetradecanoyl)-1-(5-methyl 6H-1, 3,4 thiadiazin-2-yl)hydrazine (1b) with 93 area % by HPLC.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][S:10](=[O:15])(=[O:14])[N:11]([CH3:13])[CH3:12])=[CH:5][CH:4]=1.[ClH:16]>CCOC(C)=O.CCCCCC>[Cl:16][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][S:10](=[O:15])(=[O:14])[N:11]([CH3:13])[CH3:12])=[CH:5][CH:4]=1
Reactant: CN(C)S(=O)(=O)Oc1ccc(CO)cc1
Reactant: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CN(C)S(=O)(=O)Oc1ccc(CCl)cc1

Procedure:
To a solution of JRL01115 (725 mg, 3.135 mmol) in dichloromethane (10 mL) at ice/water temperature was added thionyl chloride (0.35 mL, 4.703 mmol). After stirring at room temperature for 1 h, the volatiles were removed from the reaction mixture and the oil resulted co-evaporated 3 times with chloroform (3×30 mL) to give to LWO02144 as a yellow oil (767 mg, 98%); Rf 0.52 (EtOAc/hexane, 1:1), c.f. 0.19 (JRL01115); 1H (400 MHz, CDCl3) 2.99 (6H, s, NMe2), 4.58 (2H, s), 7.28 (2H AA′BB′) and 7.42 (2H, AA′BB′); LRMS (FAB+) 403.0 [18, (M+H+NBA)+], 391.2 (21), 249.9 [100, (M+H)+], 214.0 [45, (M+H—Cl)+], 113.0 (17); HRMS (FAB+) 249.02239, C9H12ClNO3S requires 249.02264. LWO02144 was very pure and hence was used without further purification.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:23]([N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[C:24]#[CH:25]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CCN(CC)CC>[N:26]1([CH2:23][C:24]#[C:25][C:2]2[CH:7]=[CH:6][C:5]([C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][O:18]4)=[CH:12][CH:11]=3)=[O:9])=[CH:4][CH:3]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(c1ccc(I)cc1)c1ccc(OC2CCCCO2)cc1
Reactant: C#CCN1CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: O=C(c1ccc(C#CCN2CCCC2)cc1)c1ccc(OC2CCCCO2)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
A 25 mL Schlenk flask was charged with (4-iodophenyl)(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanone (408 mg, 1 mmol), Pd(PPh3)2Cl2 (18 mg, 0.025 mmol), CuI (10 mg, 0.05 mmol), Et3N (10 ml) and 1-(prop-2-ynyl)pyrrolidine (165 mg, 1.5 mmol). The flask was flushed with argon three times and the mixture was stirred at 90° C. for 3 h. The solvent was evaporated under vacuum and the residue was purified by columnchromatography to give the desired product (312 mg, 80% yield)
Reaction SMILES: N([O-])=O.[Na+].[CH3:5][C:6]1[O:10][N:9]=[C:8](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16](N)=[CH:15][CH:14]=2)[N:7]=1.S(=O)(=O)(O)O.[C-:25]#[N:26].[K+]>O>[CH3:5][C:6]1[O:10][N:9]=[C:8](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16]([C:25]#[N:26])=[CH:15][CH:14]=2)[N:7]=1
Reactant: Cc1nc(/C=C/c2ccc(N)cc2)no1
Reactant: [C-]#N
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: Cc1nc(/C=C/c2ccc(C#N)cc2)no1
Yield: 29.4 %

Procedure:
A solution of sodium nitrite (0.80g) in water (3 ml) was added during 20 min. to a stirred suspension of trans-5-methyl-3-p-aminostyryl-1,2,4-oxadiazole (2.01g) in 2N-sulphuric acid (20 ml) at 5°. The solution was maintained at 10° for one hour and then added during 30 min. to a solution of cuprous cyanide (1.01g) and potassium cyanide (2.28g) in water (8 ml) at 35°. The mixture was then heated to 70° when nitrogen ceased to be evolved. The cooled reaction mixture was filtered and the solid was washed with water and dried. The solid was triturated with boiling chloroform (150 ml) and the chloroform solution was evaporated under reduced pressure to give an orange solid which was recrystallised from ethanol (15 ml) with charcoal decolourisation to give title compound 0.62g (29.5%), m.p. 162°-163°, λmax. (EtOH) 288 nm, ε 32,300, νmax (CHBr3) 2250, (CN) 972 cm.-1 (trans CH=CH), τ (CDCl3) values include 2.27 and 2.87 (AB quartet, J = 16; trans CH=CH) and 7.36 (CH3).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10]1[CH:27]=[CH:26][C:13]([CH2:14][C:15]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[O:17][N:16]=2)=[CH:12][CH:11]=1.[C:28]([N:36]1[CH2:41][CH2:40][C:39]([CH2:48][CH:49]=O)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:38][CH2:37]1)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+].C([O-])=O>C(Cl)Cl>[C:28]([N:36]1[CH2:37][CH2:38][C:39]([CH2:48][CH2:49][N:23]2[CH2:24][CH2:25][CH:20]([C:18]3[O:17][N:16]=[C:15]([CH2:14][C:13]4[CH:12]=[CH:11][C:10]([O:9][CH3:8])=[CH:27][CH:26]=4)[N:19]=3)[CH2:21][CH2:22]2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:40][CH2:41]1)(=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=CCC1(c2ccccc2)CCN(C(=O)c2ccccc2)CC1
Reactant: COc1ccc(Cc2noc(C3CCNCC3)n2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=C[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cc2noc(C3CCN(CCC4(c5ccccc5)CCN(C(=O)c5ccccc5)CC4)CC3)n2)cc1
Reaction time: 1 h
Yield: 37.7 %

Procedure:
The TFA salt of 4-[3-(4-methoxybenzyl)-1,2,4-oxadiazol-5-yl]piperidine (29 mg, 0.076 mmol) was combined with (1-benzoyl-4-phenylpiperidin-4-yl)acetaldehyde (21 mg, 0.069 mmol) in 2 mL DCM and treated with NaBH(OAc)3 (43 mg, 0.203 mmol) at ambient temperature with agitation for 18 h. 1 mL of saturated aqueous NaHCO3 was added and agitated 1 h. The organic phase was separated and concentrated. The crude product was purified by HPLC to give 1-benzoyl-4-(2-{4-[3-(4-methoxybenzyl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl}ethyl)-4-phenylpiperidine (16.1 mg, 0.026 mmol, 38%) as the formate salt. 1H NMR (300 MHz, CD3OD) δ 7.49-7.37 (m, 9H), 7.28 (m, 1H), 7.20 (d, 2H, J=8.8 Hz), 6.86 (d, 2H, J=8.8 Hz), 4.19 (m, 1H), 3.96 (s, 2H), 3.76 (s, 3H), 3.59 (m, 1H), 3.37-3.20 (m, 3H), 3.12-2.95 (m, 3H), 2.45-1.73 (m, 13H). ES-LCMS m/z 565.29 (M+H). HRMS C35H40N4O3 m/z 565.3179 (M+H)Cal. 565.3183 (M+H)Obs..
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:9]1[C:10]([C:16]2[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=3[N:17]=2)=[N:11][C:12](Br)=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:47]2[CH2:48][CH2:49][N:50]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:51][CH:52]=2)O1.C(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.Cl[Pd]Cl>[C:1]([O:5][C:6]([N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:9]1[C:10]([C:16]2[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=3[N:17]=2)=[N:11][C:12]([C:47]2[CH2:52][CH2:51][N:50]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:49][CH:48]=2)=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1nc2ccccc2n1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC=C(c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3nc4ccccc4n3C(=O)OC(C)(C)C)n2)CC1
Temperature: 25 °C
Yield: 85.6 %

Procedure:
A mixture of tert-butyl 2-[3-[bis(tert-butoxycarbonyl)amino]-6-bromo-pyrazin-2-yl]benzimidazole-1-carboxylate (1.7068 g, 1.734 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (643.5 mg, 2.081 mmol), 4-ditert-butylphosphanyl-N,N-dimethyl-aniline; dichloropalladium (12.28 mg, 0.01734 mmol) and K2CO3 (479.3 mg, 3.468 mmol) in toluene (9.216 mL) and water (1.024 mL) was heated to 100° C. for 16 hours. The reaction mixture was allowed to cool to RT and partitioned between DCM and water. The organic layer was washed with 1M NaOH solution, dried (Na2SO4), filtered and concentrated in vacuo to give a brown oil. This was purified by column chromatography (ISCO Companion™, 40 g column, 0-20% EtOAc/Petrol) to afford the title compound as a yellow oil (1.028 g, 60% Yield). MS (ES+) 693.38
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH2:8][CH:9]([CH3:11])[O:10][C:6]=2[C:5]([Cl:12])=[CH:4][C:3]=1[Cl:13].[N:14]([O-])=O.[Na+].[Sn](Cl)Cl.[OH-].[Na+]>OS(O)(=O)=O.O.Cl>[Cl:13][C:3]1[CH:4]=[C:5]([Cl:12])[C:6]2[O:10][CH:9]([CH3:11])[CH2:8][C:7]=2[C:2]=1[NH:1][NH2:14]
Reactant: O=N[O-]
Reactant: CC1Cc2c(N)c(Cl)cc(Cl)c2O1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: CC1Cc2c(NN)c(Cl)cc(Cl)c2O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.19 g of 38A was suspended in 9 mL of concentrated H2SO4 and 9 mL of water at -5° C. A solution of 0.69 g of sodium nitrite in 4 mL of H2O was added slowly and the resulting solution was stirred at 0° C. for one hour. This solution was added slowly to a mixture of 4.51 g of tin (II) chloride in 15 mL of concentrated hydrochloric acid which was precooled to -10° C., so as to maintain -10° C. to -5° C. The mixture was slowly warmed to room temperature and stirred for 16 hours. With cooling, 50% sodium hydroxide solution was added to adjust the pH to 11. The mixture was extracted with ether. The extract was washed with water, brine, dried (MgSO4) and stripped of solvent to leave crude 5,7-dichloro-2,3-dihydro-4-hydrazino-2-methylbenzofuran (38B), as pale orange solid, m.p.: 59°-64° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].C(N(CC)CC)C.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>ClCCl.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][Si:18]([CH3:20])([CH3:19])[C:21]#[C:22][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6]
Reactant: C#C[Si](C)(C)C
Reactant: N#Cc1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cccc(C#N)c1
Temperature: 25 °C

Procedure:
To a solution of commercially available 3-iodobenzonitrile (25 g, 0.109 mol), copper (I) iodide (2.08 g, 0.0109 mol), PdCl2(PPh3)2 (3.82 g, 0.0054 mol) and triethylamine (45.7 ml, 0.327 mol) in 250 of dry dichloromethane was added 12.8 g (0.131 mol) of trimethylsilylacetylene drop wise at 0° C. over a period of 10 min. The reaction mixture was stirred at RT over night. The reaction mixture was diluted with additional dichloromethane, filtered over Celite and the filtrate was concentrated. The crude material was purified by silica gel (60-120) column chromatography using 95:5 petrolium ether/ethyl acetate as eluent. A2.1 (20 g, 92%) was obtained as a brown solid 1H NMR, 400 MHz, CDCl3: 7.79 (s, 1H), 7.67 (d, 1H), 7.59 (d, 1H), 7.43 (t, 1H), 0.26 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:32]=[CH:31][C:12]2[NH:13][C@H:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:19][CH:18]=3)[CH2:15][O:16][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].[CH2:41](Br)[CH:42]=[CH2:43]>CC(C)=O.C(OCC)(=O)C.CCCCCC.O>[CH2:43]([N:13]1[C:12]2[CH:31]=[CH:32][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]=2[O:16][CH2:15][C@H:14]1[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:19][CH:18]=1)[CH:42]=[CH2:41]
Reactant: c1ccc(COc2ccc([C@@H]3COc4cc(OCc5ccccc5)ccc4N3)cc2)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: C=CCN1c2ccc(OCc3ccccc3)cc2OC[C@H]1c1ccc(OCc2ccccc2)cc1
Yield: 84.7 %

Procedure:
A solution of (R)-7-benzyloxy-3-(4-benzyloxyphenyl)-3,4-dihydro-2H-benzo[1,4]oxazine (47.6 mg, 0.112 mmol), sodium iodide (67 mg, 0.450 mmol), potassium carbonate (31 mg, 0.224 mmol) and allyl bromide (0.04 ml, 0.473 mmol) in acetone (1 ml) was stirred for 3 hours at 50° C. under a nitrogen stream and then heated under reflux for 7 hours. After cooling, water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/5, v/v) to give (R)-4-allyl-7-benzyloxy-3-(4-benzyloxyphenyl)-3,4-dihydro-2H-benzo[1,4]oxazine (44 mg, Yield 85%).
Reaction SMILES: [CH3:1][S:2][CH2:3][S:4]([CH3:6])=[O:5].O1CCCC1.[H-].[Na+].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1>O.C(Cl)Cl>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][CH:3]([S:4]([CH3:6])=[O:5])[S:2][CH3:1])=[CH:18][CH:17]=1
Reactant: COc1ccc(CBr)cc1
Reactant: CSCS(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CC(SC)S(C)=O)cc1
Reaction time: 1 h
Yield: 50.3 %

Procedure:
1.175 g of methyl methylthiomethyl sulfoxide was dissolved in 5 ml. of tetrahydrofuran, and under cooling with ice, 0.965 g (one equivalent) of sodium hydride was added. The mixture was then stirred for 1 hour. 1.93 g of p-methoxybenzyl bromide (1 equivalent) was added, and the mixture was stirred for 22 hours at room temperature, followed by addition of 40 ml. of methylene chloride and 2 ml. of water. The reaction mixture was dried with sodium sulfate anhydride, and concentrated at reduced pressure. The residue was subjected to column chromatography (silica gel, methylene chloride) to give 1.163 g of methyl 2-(p-methoxyphenyl)-1-methylthioethyl sulfoxide in a conversion yield of 79.1%.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27].CO.C(OCC)(=O)C>C(#N)C>[C:26]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: CN1CCN(c2cccc3ccc(N)cc23)CC1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)Nc1ccc2cccc(N3CCN(C)CC3)c2c1
Temperature: 25 °C
Yield: 32.2 %

Procedure:
A solution of 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.238 g, 0.986 mmol) and triethylamine (0.144 mL, 1.08 mmol) in acetonitrile (12 mL) was chilled to 0° C. and acetyl chloride (0.077 mL, 1.08 mmol) was added all at once. The mixture was heated to reflux for 7 hours and cooled to room temperature. (TLC with 40% methanol/ethyl acetate indicated that the reaction was complete.) The solvent was removed at reduced pressure and the residue was taken up in methylene chloride. The organic solution was extracted with saturated sodium bicarbonate and brine, then it was dried over calcium sulfate and concentrated to a light tan solid (0.115 g). Trituration with hexane gave 0.09 g (33%) of the title product as a tan solid: mp 173°-177° C. A sample recrystallized from ethyl acetate was submitted for analysis: mp 177°-180° C. HRMS m/e calculated for C17H29N3O: 283.1682. Observed m/e: 283.1678.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][C:16](N)=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].Cl.NC[C:36](N)=[O:37]>>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][C@@H:16]([OH:17])[CH2:36][OH:37])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32]
Reactant: NCC(N)=O
Reactant: Cc1ccc(C(=O)NCC(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Agent: Cl
Product: Cc1ccc(C(=O)NC[C@@H](O)CO)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O

Procedure:
The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[1-(aminocarbonyl)methyl]-4-methylbenzamide by substituting (R)-(+)-3-amino-1,2-propanediol for glycineamide HCl. 1H NMR (CD3OD/400 MHz) δ8.32 (s, 1H), 7.92 (m, 1H), 7.77 (s, 1H), 7.61 (q, 1H, J=8.0 Hz), 7.53 (d, 1H, J=8.0 Hz), 7.02 (m, 2H), 5.60 (m, 2H), 3.81 (m, 1H), 3.54 (m, 3H), 3.39 (m, 1H), 2.20 (s, 3H). ESHRMS m/z 480.1117 (M+H calculated for C22H21ClF2N3O5 requires 480.1132).
Reaction SMILES: CCN(CC)CC.[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[N+:14]([O-:16])[CH:15]=1)[CH3:9].O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:15]1[N:14]=[C:13]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:12]=[CH:11][C:10]=1[CH2:8][CH3:9].[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[N+:14]([O-:16])[CH:15]=1)[CH3:9]
Reactant: O=P(Cl)(Cl)Cl
Agent: CCc1ccc(NC(=O)C(C)(C)C)[n+]([O-])c1
Solvent: CCN(CC)CC
Product: CCc1ccc(NC(=O)C(C)(C)C)nc1Cl
Yield: 5 %

Procedure:
Et3N (123 mL, 93.6 mmol) was added to a solution of 5-ethyl-2-pivalamidopyridine 1-oxide (16.0 g, 72.0 mmol) in POCl3 (250 mL) and the reaction mixture was heated at reflux for 3 days. Excess POCl3 was distilled off and the residue was poured into water. The mixture was neutralized with aqueous NaOH to pH 9. The aqueous layer was extracted with ethyl acetate. The organic layer was dried over MgSO4 and the solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel (10% EtOAc in petroleum ether) to afford N-(6-chloro-5-ethylpyridin-2-yl)pivalamide (900 mg, 5%) and unreacted 5-ethyl-2-pivalamidopyridine 1-oxide (4.8 g). 1H NMR (CDCl3, 300 MHz) δ 8.12 (d, J=8.7, 1H), 7.94 (br s, 1H), 7.56 (d, J=8.7, 1H), 2.70 (q, J=7.5, 2H), 1.30 (s, 9H), 1.23 (t, J=7.5, 3H).
Reaction SMILES: [C:1]([C:3]1([C:8]#[N:9])[CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].[N-:10]=[N+:11]=[N-:12].[Na+].[Cl-].[NH4+].Cl>CN(C=O)C>[C:1]([C:3]1([C:8]2[NH:12][N:11]=[N:10][N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(C#N)CCCC1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: N#CC1(c2nnn[nH]2)CCCC1
Temperature: 130 °C

Procedure:
A mixture of 1,1-biscyanocyclopentane (58 g), sodium azide (29.9 g, 460 mmoles) and ammonium chloride (28.5 g, 531 mmoles) in DMF (500 mL) was stirred and heated at 130° C. for 90 minutes. The cooled mixture was poured into 0.5 M HCl (1 liter) and extracted with ether (2×500 mL). The combined ether extracts were washed with water (2×200 mL), brine (100 mL), and dried (MgSO4). Filtration and concentration provided a solid which was recrystallized from isopropylether-hexane (16.8 g). Melting point 92°-94° C.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:27](=[O:28])[N:6]2[C:7]([C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].Cl.CN(C)CCCN=C=NCC.[N+:41]([C:44]1[CH:61]=[CH:60][C:47]([CH2:48][O:49][C:50]([NH:52][C@H:53]([C:57](O)=[O:58])[CH:54]([CH3:56])[CH3:55])=[O:51])=[CH:46][CH:45]=1)([O-:43])=[O:42].C(OCC)(=O)C>CN(C)C(=O)C.CN(C)C1C=CN=CC=1.[Cl-].[Na+].O>[OH:1][C@@H:2]([C@H:4]1[C:27](=[O:28])[N:6]2[C:7]([C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][O:20][C:57](=[O:58])[C@H:53]([CH:54]([CH3:55])[CH3:56])[NH:52][C:50]([O:49][CH2:48][C:47]3[CH:60]=[CH:61][C:44]([N+:41]([O-:43])=[O:42])=[CH:45][CH:46]=3)=[O:51])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C=CCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reactant: CC(C)[C@H](NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: C=CCOC(=O)C1=C(S/C=C\c2scnc2COC(=O)[C@@H](NC(=O)OCc2ccc([N+](=O)[O-])cc2)C(C)C)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.1 %

Procedure:
Allyl (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate (970 mg) was dissolved in 10 ml of N,N-dimethylacetamide. 4-Dimethylaminopyridine (281 mg), 441 mg of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, and 681 mg of N-4-nitrobenzyloxycarbonyl-L-valine were added to the solution, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 50 ml of 20% brine and 50 ml of ethyl acetate, followed by separation. The organic layer was dried over magnesium sulfate. The magnesium sulfate was removed by filtration, and the solvent was removed by distillation under the reduced pressure. The crude product was purified by column chromatography on silica gel (ethyl acetate:n-hexane=2:1, and subsequently ethyl acetate:n-hexane=5:1) to give 517 mg of allyl (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[[(Z)-2-(4-(N-4-nitrobenzyloxycarbonyl-L-valyloxymethyl)thiazol-5-yl)ethen-1-yl]thio]-1-carbapen-2-em-3-carboxylate.