Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:17]([O-])=O)=[C:10]([S:13]([OH:16])(=[O:15])=[O:14])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].CN(C=O)C>CO.[Pd]>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH2:17])=[C:10]([S:13]([OH:16])(=[O:15])=[O:14])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc([N+](=O)[O-])c(S(=O)(=O)O)cc21
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)N1CCc2cc(N)c(S(=O)(=O)O)cc21
Yield: 79.4 %

Procedure:
A suspension of 1-acetyl-5-nitroindoline-6-sulfonic acid (Compound 2-3 in Scheme II) (9.0 g) in 250 mL of methanol was hydrogenated in the presence of 0.5 g of 10% Pd/C for 3 h. DMF (˜250 mL) was added to dissolve the precipitated product. The catalyst was removed by filtration through Celite® and the filtrate was concentrated to give a solid. The solid was suspended in methanol (50 mL), filtered and washed with small amount of methanol and ether. Drying under vacuum afforded 6.4 g of the desired amine as an off-white solid.
Reaction SMILES: [N:1]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[C:11](O)=[O:12].Cl.CNOC.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC.C(Cl)Cl>[C:14]([N:1]1[C@H:2]([CH:11]=[O:12])[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Agent: CNOC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 62.5 %

Procedure:
To a round-bottomed flask equipped with stirring was added Boc-L-Tic-OH (Bachem) (1 g, 3.6 mmol) and CH2Cl2 (20 mL), followed by TEA (0.5 mL, 3.6 mmol) and N,O-dimethylhydroxylamine hydrochloride. The reaction mixture was cooled to 0° C., EDC (690 mg, 3.6 mmol) and HOBT (550 mg, 3.6 mmol) were added, and the reaction mixture was stirred at 0° C. for 1 h then at RT for 18 h. The organic layer was washed with 0.5 N HCl, satd NaHCO3, and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to afford a colorless oil. Into a round bottomed flask equipped with magnetic stirring, was added the oil dissolved in Et2O (15 mL), and the flask was cooled to −78° C. LiAlH4 (1M in Et2O, Aldrich) (3.2 mL, 3.2 mmol) was added, and after 30 min the reaction was warmed to RT. The organic layer was washed with 0.5 N HCl, satd NaHCO3, and brine. After drying the organic layer over Na2SO4, it was filtered and concentrated in vacuo to afford (3S)—N-Boc-1,2,3,4-tetrahydroisoquinoline-3-carbaldehyde as a colorless oil (588 mg).
Reaction SMILES: FC1C=C(C[C@H](NC(=O)CN2C3CCCCC=3C(C(F)(F)F)=N2)C2N(C3C=CC(OC)=CC=3)C=CN=2)C=C(F)C=1.Cl.[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[O:50][C:51]([CH:54]([NH2:64])[CH2:55][C:56]3[CH:61]=[C:60]([F:62])[CH:59]=[C:58]([F:63])[CH:57]=3)=[CH:52][N:53]=2)=[CH:45][CH:44]=1.[F:65][C:66]1[CH:67]=[C:68]2[C:72](=[CH:73][CH:74]=1)[NH:71][CH:70]=[C:69]2[CH2:75][C:76](O)=[O:77]>>[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[O:50][C:51]([CH:54]([NH:64][C:76](=[O:77])[CH2:75][C:69]3[C:68]4[C:72](=[CH:73][CH:74]=[C:66]([F:65])[CH:67]=4)[NH:71][CH:70]=3)[CH2:55][C:56]3[CH:61]=[C:60]([F:62])[CH:59]=[C:58]([F:63])[CH:57]=3)=[CH:52][N:53]=2)=[CH:45][CH:44]=1
Reactant: O=C(O)Cc1c[nH]c2ccc(F)cc12
Reactant: NC(Cc1cc(F)cc(F)c1)c1cnc(-c2ccc(Cl)cc2)o1
Agent: COc1ccc(-n2ccnc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)cc1
Agent: Cl
Product: O=C(Cc1c[nH]c2ccc(F)cc12)NC(Cc1cc(F)cc(F)c1)c1cnc(-c2ccc(Cl)cc2)o1

Procedure:
The title compound was prepared according to the method presented for the synthesis of compound 5F of Example 5 utilizing 19E and 2-(5-fluoro-1H-indol-3-yl)acetic acid. 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.81 (d, J=8.5 Hz, 2H), 7.43 (d, J=8.5 Hz, 2H), 7.38-7.23 (m, 2H), 7.16 (s, 1H), 7.05 (d, J=9.3 Hz, 1H), 6.95 (dd, J=10.3, 7.7 Hz, 1H), 6.61 (t, J=9.0 Hz, 1H), 6.50 (dd, J=14.6, 7.6 Hz, 3H), 5.27 (q, J=7.4 Hz, 1H), 3.72 (s, 2H), 3.08 (dd, J=13.7, 7.1 Hz, 1H), 2.95 (dd, J=13.7, 7.4 Hz, 1H). MS (m/z) 510.1 [M+H]+.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([O:9]C)=[CH:5][C:4]=1[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20]C)=[C:16]([F:22])[CH:15]=1)=[O:13].Cl>>[F:22][C:16]1[CH:15]=[C:14]([C:12]2[O:13][C:3]3[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=3[CH:11]=2)[CH:19]=[CH:18][C:17]=1[OH:20]
Reactant: COc1ccc(OC)c(CC(=O)c2ccc(OC)c(F)c2)c1
Agent: Cl
Product: Oc1ccc2oc(-c3ccc(O)c(F)c3)cc2c1

Procedure:
The ketone 125 (1 g, 3.3 mmol) was heated with pyr-HCl at 180-200° C. until TLC indicated reaction completion. The reaction was worked up by partitioning between 2 N HCl aq and EtOAc and washing the EtOAc with saturated NaHCO3, brine, and drying over MgSO4. The solution was filtered, concentrated and chromatographed on silica gel to yield 0.48 g of impure pdt. The product thus obtained was recrystallized from EtOAc/hexanes to yield desired product plus a small amt of unidentified impurity: Mp=218-222° C.; 1H NMR (DMSO-d6) δ 10.39 (s, 1 H), 9.20 (s, 1 H), 7.74 (t, 1 H, J=8.7 Hz), 7.37 (d, 1 H, J=8.8 Hz), 6.96-6.94 (m, 2 H), 6.79-6.70 (m, 3 H); MS 243 (M−H)−
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:25]=[CH:24][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>>[CH2:26]([N:28]([CH2:29][CH3:30])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:25]=[CH:24][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1)[CH3:27]
Reactant: FC(F)(F)c1ccc(-c2nsc3cc(OCCCCBr)ccc23)cc1
Reactant: CCNCC
Product: CCN(CC)CCCCOc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
According to the method in example 7, 6-(4-Bromo-butoxy)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole and Diethylamine were converted to yield Diethyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amine, MS: 423 (MH+).
Reaction SMILES: C(O[C:4](=[O:15])[C:5]([N:10]1[CH:14]=[CH:13][N:12]=[N:11]1)=[CH:6][N:7](C)C)C.[CH3:16][C:17]([CH3:29])([CH3:28])[CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26]N)=[N:24][CH:25]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH3:16][C:17]([CH3:29])([CH3:28])[CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[C:4](=[O:15])[C:5]([N:10]3[CH:14]=[CH:13][N:12]=[N:11]3)=[CH:6][NH:7]2)=[N:24][CH:25]=1
Reactant: CCOC(=O)C(=CN(C)C)n1ccnn1
Reactant: CC(C)(C)COc1ccc(NN)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CC(C)(C)COc1ccc(-n2[nH]cc(-n3ccnn3)c2=O)nc1

Procedure:
171 mg (0.8 mmol) of the compound from Example 3A and 455 mg (purity 35%, 0.8 mmol) of the compound from Example 12A are initially introduced into 7 ml ethanol. 31 mg (0.2 mmol) p-toluenesulfonic acid monohydrate are added and the mixture is stirred under reflux for 64 h. Thereafter, it is concentrated and the residue is purified by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product fractions are combined, the solvent is removed and the residue is dried under a high vacuum.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[N:17][C:18]=3[C:28]3[CH:29]=[N:30][NH:31][CH:32]=3)[N:13]=2)=[CH:8][CH:7]=1.Cl>CN1C(=O)CCC1>[C:22]1([C:21]2[C:12]([C:9]3[CH:8]=[CH:7][C:6]([CH:2]=[O:1])=[CH:11][CH:10]=3)=[N:13][C:14]3[C:19]([CH:20]=2)=[C:18]([C:28]2[CH:29]=[N:30][NH:31][CH:32]=2)[N:17]=[CH:16][CH:15]=3)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: c1ccc(-c2cc3c(-c4cn[nH]c4)nccc3nc2-c2ccc(C3OCCO3)cc2)cc1
Agent: Cl
Solvent: CN1CCCC1=O
Product: O=Cc1ccc(-c2nc3ccnc(-c4cn[nH]c4)c3cc2-c2ccccc2)cc1
Temperature: 80 °C

Procedure:
To a solution of 2-[4-(1,3-dioxolan-2-yl)phenyl]-3-phenyl-5-(1H-pyrazol-4-yl)-1,6-naphthyridine (1-2) (1.0 g, 2.4 mmol) in NMP (25 mL) was added 6N HCl (10 mL). The reaction was heated at 80° C. for 1 hour. The reaction mixture was cooled to room temperature, slowly quenched into saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum to give 4-[3-phenyl-5-(1H-pyrazol-4-yl)-1,6-naphthyridin-2-yl]benzaldehyde (1-3) as a white solid. MS (M+H)+: calculated 377.42; found 377.51
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[NH:13]1[CH:17]=[C:16]([CH2:18][OH:19])[N:15]=[CH:14]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:13]1[CH:17]=[C:16]([CH2:18][OH:19])[N:15]=[CH:14]1
Reactant: COc1cc([N+](=O)[O-])ccc1F
Reactant: OCc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1cc([N+](=O)[O-])ccc1-n1cnc(CO)c1

Procedure:
A mixture of 1-fluoro-2-methoxy-4-nitro-benzene (1.0 g, 5.8 mmol), (1H-imidazol-4-yl)-methanol (602 mg, 6.1 mmol) and cesium carbonate (2.86 g, 8.8 mmol) in 40 ml of acetonitrile was refluxed overnight. The reaction mixture was concentrated in vacuo, diluted with water and extracted with ethyl acetate. Chromatography on Si—NH2 (Isolute) using ethyl acetate as an eluent gave the title compound as a yellowish solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[NH:21][C:12]3[N:13]=[CH:14][CH:15]=[C:16]([C:17]([NH:19][NH2:20])=[O:18])[C:11]=3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:22]#[C:23]Br>CN(C)C(=O)C.C(OCC)(=O)C>[C:1]1([CH2:7][CH2:8][C:9]2[NH:21][C:12]3=[N:13][CH:14]=[CH:15][C:16]([C:17]4[O:18][C:23]([NH2:22])=[N:20][N:19]=4)=[C:11]3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CBr
Reactant: NNC(=O)c1ccnc2[nH]c(CCc3ccccc3)cc12
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Nc1nnc(-c2ccnc3[nH]c(CCc4ccccc4)cc23)o1
Reaction time: 8 h
Yield: 44.1 %

Procedure:
To a solution of 2-(2-phenylethyl)-1H-pyrrolo[2,3-b]pyridine-4-carbohydrazide (104 mg, 0.371 mmol) in N,N-dimethylacetamide (1 mL) was added a solution of cyanogen bromide (47 mg, 0.445 mmol) in N,N-dimethylacetamide (0.5 mL) at room temperature, and the resulting mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate), and recrystallized from N,N-dimethylformamide/water to give the title compound (50 mg, yield 44%) as pale-yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].[Cl:13][O-].[Na+]>C(O)C>[Cl:13][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][N:8]=1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: [O-]Cl
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc2[nH]nc(Cl)c2c1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
5-Nitro-1H-indazole (2.0 g, 12.3 mmol) was suspended in 40 ml ethanol and sodium hypochlorite solution (123 ml, 2.0 M, 246 mmol) was added. The mixture was heated to 75° C. and stirred overnight. The solvent was evaporated to dryness to afford the title compound. (2.4 g, 100%), MS (ES+) m/e 198 [M+H]+.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:21]([O:25][CH2:26][C:27]([F:44])([F:43])[C:28]([F:42])([F:41])[C:29]([F:40])([F:39])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1)[CH2:22][CH2:23][CH3:24]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][C:35]2[CH:34]=[CH:33][C:32]([O:31][CH2:30][C:29]([F:39])([F:40])[C:28]([F:42])([F:41])[C:27]([F:43])([F:44])[CH2:26][O:25][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:37][CH:36]=2)=[O:17])=[CH:19][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1ccc(C(=O)O)cc1
Reactant: CCCCOCC(F)(F)C(F)(F)C(F)(F)COc1ccc(O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCOc1ccc(C(=O)Oc2ccc(OCC(F)(F)C(F)(F)C(F)(F)COCCCC)cc2)cc1
Yield: 12.1 %

Procedure:
0.45 g (0.0016 moles) of 4-decyloxybenzoic acid and 0.58 g (0.0016 moles) of 4-(5-butoxy-2,2,3,3,4,4-hexafluoropentoxy)phenol (prepared essentially as in Example 5) were dissolved in 25 ml of methylene chloride. N,N-dicyclohexylcarbodiimide (0.35 g, 0.0017 moles) was added to the reaction mixture, followed by 0.05 g of 4-(N,N-dimethylamino)pyridine. The resultant mixture was stirred at room temperature under nitrogen for 18 hours. The resulting urea precipitate was removed from the product solution by filtration, and the filtrate was concentrated on a rotary evaporator at reduced pressure. The crude product was purified by flash chromatography on silica gel (chloroform) to yield 0.12 g of 4-(5-butoxy-2,2,3,3,4,4-hexafluoropentoxy)phenyl 4-decyloxybenzoate.
Reaction SMILES: [Cl-].[OH:2][NH3+:3].C([O-])(=O)C.[Na+].[F:9][C:10]([F:23])([F:22])[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=1)=O>O.C(O)C>[F:9][C:10]([F:23])([F:22])[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=1)=[N:3][OH:2]
Reactant: [NH3+]O
Reactant: CSc1ccc(C(=O)CC(F)(F)F)cc1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CSc1ccc(C(CC(F)(F)F)=NO)cc1
Yield: 59.4 %

Procedure:
Hydroxylammonium chloride (1.07 g, 15.4 mmol) and sodium acetate (1.85 g, 22.5 mmol) are dissolved in 10 ml of water. To this solution are added 2.35 g (10.0 mmol) of 3,3,3-trifluoro-1-(4-methylsulfanyl-phenyl)-propan-1-one in 30 ml of ethanol. The reaction mixture is heated to reflux for 6.5 hr. The reaction mixture was concentrated by rotary evaporation and poured into water. The product is extracted with CH2Cl2, and the organic layer is washed with water, followed by drying over anhydrous MgSO4. After evaporation of the solvent, the product is purified by column chromatography on silica gel with CH2Cl2-Hexane (2:1) as eluent. 1.48 g of white solid melting at 106-107° C. are obtained (59%). 1H NMR (CDCl3), δ[ppm]: d 2.51 (s, 3H), 3.73 (q, 2H), 7.26 (d, 2H), 7.57 (d, 2H), 8.23 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[O-:14][CH2:15][CH3:16].[Na+].N1C=CC=CC=1C1C=CC=CN=1.C(OCC)(=O)C>CO>[CH2:15]([O:14][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:16]
Reactant: CC[O-]
Reactant: CCOC(=O)Nc1ccccc1Br
Agent: [Na+]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)Nc1ccccc1OCC
Yield: 83.7 %

Procedure:
2.44 g of the 2-bromo-1-ethoxycarbonylaminobenzene was added to a solution containing 680 mg of sodium ethoxide, 170 mg of cupric chloride dihydrate, and 156 mg of 2,2'-bipyridine in 40 ml of methanol, and the mixture was heated under reflux for 1.5 hours. After the temperature was brought to room temperature, ethyl acetate was added thereto, and the resulting mixture was washed with water and dried over Glauber's salt. The solvent was distilled off, and the obtained crude crystals were recrystallized from a n-hexane/ethyl acetate solvent mixture, to obtain 1.75 g (yield: 84%) of the desired compound. The spectrum data of the compound was in agreement with the spectrum data of the separately synthesized reference compound.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[C:23]([CH:25]3[CH2:28][CH2:27][CH2:26]3)[N:22]=[C:21]([C:29]([CH3:32])([CH3:31])[CH3:30])[N:20]=2)[CH2:15][CH2:14]1)C)(C)(C)C.[ClH:34]>O1CCOCC1>[ClH:34].[C:29]([C:21]1[N:20]=[C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][CH2:11][CH2:10][CH2:9][NH:7][CH3:6])[CH2:18][CH2:17]2)[CH:24]=[C:23]([CH:25]2[CH2:28][CH2:27][CH2:26]2)[N:22]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CN(CCCCN1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CNCCCCN1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1

Procedure:
0.5 g of {4-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-butyl}-methyl-carbamic acid tert-butyl ester (1.06 mmol) were treated with 10 ml of a 4 N solution of hydrochloric acid in dioxane for 16 h. The solvent was evaporated to yield 0.6 g of the deprotected amine as its hydrochloride salt.
Reaction SMILES: [N:1]([C:4]1[CH2:5][C@@H:6]2[CH2:20][C:19](=[O:21])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])=[N+]=[N-].[C:22]([O:25][CH:26]=[CH2:27])(=[O:24])[CH3:23].C(=O)(O)[O-].[Na+]>ClCCl>[C:22]([O:25][CH:26]1[CH2:27][N:1]1[C:4]1[CH2:5][C@@H:6]2[CH2:20][C:19](=[O:21])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])(=[O:24])[CH3:23]
Reactant: [N-]=[N+]=NC1=C(C(=O)OCc2ccccc2)N2C(=O)C[C@H]2C1
Reactant: C=COC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OC1CN1C1=C(C(=O)OCc2ccccc2)N2C(=O)C[C@H]2C1
Reaction time: 72 h
Yield: 19 %

Procedure:
A solution of benzyl 2-azido-carbapen-2-em-3-carboxylate (5.3 mg, 19 micromol) and vinyl acetate (100 microliter) in dry dichloromethane (200 microliter) was treated with excess sodium bicarbonate and kept 3 days at ambient temperature. The mixture was filtered through florisil, the florisil was washed with ethyl acetate (25 ml), and the combined filtrate and wash was evaporated under vacuum. The residue was chromatographed on one 20 cm×20 cm 250 micron silica gel preparative thin layer chromatography plate developed with 9:1 (v/v) diethyl ether-ethyl acetate. Product was eluted with ethyl acetate and the eluate evaporated under vacuum to provide 1.2 mg (19%) benzyl 2-(2-acetoxyaziridin-1-yl)-carbapen-2-em-3-carboxylate; IR (CH2Cl2): 1770, 1735 cm-1 ; NMR (CDCl3): δ 1.92 bt (J=6.5 Hz, 1H), 2.08 t (J=7 Hz, 1H), 2.13 s (3H), 2.70 dd (J, 6 Hz, J2 =17 Hz, 1H), 2.76 dd (J1 =6 Hz, J2 =17 Hz, 1H), 2.86 dd (J1 =2 Hz, J2 =15 Hz, 1H), 3.24 dd (J1 =5 Hz, J2 =15 Hz, 1H), 4.16 m (1H), 4.79 bt (J=7 Hz, 1H), 5.17 s (2H), 7.37 m (5H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13](B4OC(C)(C)C(C)(C)O4)[CH:12]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1.Br[C:27]1[CH:31]=[CH:30][S:29][C:28]=1[C:32]#[N:33].O>COCCOC.C(=O)([O-])[O-].[Cs+].[Cs+].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>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13]([C:27]4[CH:31]=[CH:30][S:29][C:28]=4[C:32]#[N:33])[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: Cc1ccn2c(-c3cccc(B4OC(C)(C)C(C)(C)O4)c3)cnc2c1
Reactant: N#Cc1sccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccn2c(-c3cccc(-c4ccsc4C#N)c3)cnc2c1
Yield: 57.1 %

Procedure:
A mixture of 7-methyl-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]imidazo[1,2-α]pyridine (350 mg, 1.0 mmol) and 3-bromo-2-cyanothiophene (200 mg, 1.0 mmol) in 1,2-dimethoxyethane (10 ml) and caesium carbonate (5 ml of a 2M solution) was degassed for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (125 mg, 0.1 mmol) was then added and the mixture heated at reflux for 20 hours, poured into water (50 ml) and extracted with ethyl acetate (2×25 ml). The combined organic phases were dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo. Purification by flash chromatography eluting with 3% methanol in dichloromethane gave the title compound as a colourless oil (180 mg, 57%). Oxalate salt, white powder, m.p. 193-195° C. (Found C, 62.07; H, 3.66; N, 10.19. C19H13N3S.C2H2O4 requires C, 62.21; H, 3.73; N, 10.36). 1H NMR (360 MHz, d6-DMSO) δH 2.42 (3H, s), 6.91-6.93 (1H, m), 7.53 (1H, s), 7.68-7.82 (6H, m), 7.89 (1H, s), 8.01 (1H, s), 8.18 (1H, d, J 5), 8.63 (1H, d, J 7); m/z (ES+) 316 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]=[CH:5][C:6]1([CH3:12])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.[H][H]>CO.[C].[Pd]>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1([CH3:12])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: [H][H]
Reactant: COC(=O)C=CC1(C)CCOCC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCC1(C)CCOCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100.2 %

Procedure:
To a solution of 220 g (1.19 mmol) of 3-(4-methyltetrahydropyran-4-yl)acrylic acid methyl ester in methanol (15 mL) was added 40 mg of palladium-carbon, replaced with hydrogen gas, and then stirred for 12 hours at room temperature. After the reaction mixture was filtered through Celite, the solvent was removed under a reduced pressure. The obtained residue was purified by column chromatography (silica gel 20 g, developing solvent: ethyl acetate) to obtain 222 mg (yield 100%) of 3-(4-methyltetrahydropyran-4-yl)propionic acid methyl ester (IX-144). Its physical property is shown below.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][C:30]1[N:31]=[C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:33][C:34]=1[CH3:35])[CH2:6][O:7][C:8]1[C:12]([CH:13]=O)=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[N:9]=1.C(OP([CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])(OCC)=O)C.CN(C)C=O.[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][C:30]1[N:31]=[C:32]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[O:33][C:34]=1[CH3:35])[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:50]/[C:51]([O:53][CH2:54][CH3:55])=[O:52])=[CH:11][N:10]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:20]=2)[N:9]=1
Reactant: COc1cc(COc2nn(-c3ccc(C(F)(F)F)cc3)cc2C=O)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1cn(-c2ccc(C(F)(F)F)cc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
To a mixture of 3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-[4-(trifluoromethyl)phenyl]-1H-pyrazole-4-carbaldehyde (3.30 g), ethyl diethylphosphonoacetate (1.32 g) and N,N-dimethylformamide (50 mL) was added sodium hydride (60% in oil, 0.236 g) at room temperature, and the mixture was stirred for 30 min at the same temperature. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration, and recrystallized from tetrahydrofuran to give ethyl (2E)-3-{3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-2-propenoate as a colorless powder (2.59 g, yield 69%). melting point: 205-206° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:3]=1.[CH3:12][O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([O:21][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:3]=2)=[CH:17][CH:16]=1
Reactant: CS(=O)(=O)c1cccc(Br)c1
Reactant: COC(=O)c1ccc(O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Oc2cccc(S(C)(=O)=O)c2)cc1
Temperature: 25 °C

Procedure:
1-Bromo-3-methanesulfonyl-benzene (11.0 mmol) (see Intermediate 11) and 4-hydroxy-benzoic acid methyl ester (1.2 mmol) are dissolved in toluene (0.1M). Palladium acetate (0.02 mmol), biphenyl-2-yl-di-tert-butyl-phosphane (0.03 mmol) and tri-basic potassium phosphate (2.0 mmol) are added and the reaction heated reaction at 90° C. for 18 h. The reaction is allowed to cool to room temperature, washed with water while and then the aqueous extracted with dichloromethane. The organic portions are combined and concentrated in vacuo and purified by radial silica chromatography, eluting with ethyl acetate and hexane.