Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[N+:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][S:42](Cl)(=[O:44])=[O:43])([O-:34])=[O:33].N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:42]([CH2:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[N+:32]([O-:34])=[O:33])(=[O:43])=[O:44]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: O=[N+]([O-])c1ccccc1CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1CS(=O)(=O)Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Temperature: 50 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. (2-nitrophenyl)methansulfonyl chloride (12 mg, 0.052 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 25 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-1-(2-nitrophenyl)methansulfonamide (percentage yield: 87%), was obtained.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[CH2:15][C:16]#[N:17]>C1COCC1.C(N(CC)CC)C>[C:16]([CH2:15][N:11]1[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]1)#[N:17]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#CCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CC#N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of N-Boc piperazine (1 g) in dry THF (20 ml), triethylamine (3 ml), followed by chloroacetonitrile (5.02 ml) were added dropwise. The reaction mixture was allowed to stir at room temperature for overnight. The solvent was removed under vacuum and residue was diluted ethyl acetate (20 ml). The organic layer was concentrated to dryness under reduced pressure to afford tert-butyl 4-(cyanomethyl)piperazine-1-carboxylate, which was used for the next reaction without further purification.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([Cl:26])=[CH:28][CH:29]=2)[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(Cl)cc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (110 mg, 0.45 mmol) and triethylamine (93 μL, 0.67 mmol) in methylene chloride (25 mL) was added dropwise 4-chlorobenzoyl chloride (83 mg, 0.47 mmol) in methylene chloride (5 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with diluted aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. Yield: 97 mg (56%) of the title compound as white crystals: mp 204-205° C.; [α]21D −46° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 383 (19, M+).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][C:5](=[O:9])[C:4]1=[O:10])[CH3:2].[H-].[Na+].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].ClCCl>CO>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][N:6]1[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[C:4](=[O:10])[C:5]1=[O:9])[CH3:19]
Reactant: CCN1CCNC(=O)C1=O
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)CN1CCN(CC)C(=O)C1=O
Yield: 72 %

Procedure:
As described for example 119a, 1-ethyl-piperazine-2,3-dione was reacted with sodium hydride followed by reaction with ethyl bromoacetate. Aqueous workup followed by chromatography (SiO2, dichloromethane:methanol=100:0 to 94:4) afforded the title compound as a light yellow oil (yield: 72%). MS: m/e=229.4 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:3][CH2:4][CH2:5][NH2:6].[CH3:19][C:20]([CH3:22])=O>[Pt]=O.C(O)C>[CH3:1][N:2]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:3][CH2:4][CH2:5][NH:6][CH:20]([CH3:22])[CH3:19]
Reactant: CC(C)=O
Reactant: COc1ccc(CCN(C)CCCN)cc1OC
Agent: O=[Pt]
Solvent: CCO
Product: COc1ccc(CCN(C)CCCNC(C)C)cc1OC
Yield: 100 %

Procedure:
3.87 g of N-methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)-1,3-propanediamine and 15 ml of acetone were dissolved into 50 ml of ethanol. To this was added 0.1 g of platinum oxide and then hydrogenetion was made at room temperature and under pressure of 3 kg/cm2. At the end of 3 hours catalyst was concentrated after filtering and 4.52 of marked compound was obtained as yellow oily matter (yield: 100%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:22])[O:5][C:6]1[CH:7]=[C:8]([OH:21])[CH:9]=[C:10](B2OC(C)(C)C(C)(C)O2)[CH:11]=1.Br[C:24]1[N:25]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:26]([C:29]2[S:30][CH:31]=[CH:32][N:33]=2)=[CH:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[OH:21][C:8]1[CH:9]=[C:10]([C:24]2[N:25]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:26]([C:29]3[S:30][CH:31]=[CH:32][N:33]=3)=[CH:27][CH:28]=2)[CH:11]=[C:6]([O:5][C@@H:4]([CH3:22])[CH2:3][O:2][CH3:1])[CH:7]=1
Reactant: COC[C@H](C)Oc1cc(O)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CC(C)(C)OC(=O)n1c(Br)ccc1-c1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC[C@H](C)Oc1cc(O)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 80.8 %

Procedure:
3-[(1S)-2-Methoxy-1-methylethoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (3.30 g, 10.7 mmol) synthesized in Example (38c) and t-butyl 2-bromo-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (4.10 g, 12.5 mmol) synthesized in Example (1g) were dissolved in a mixed solvent of 1,4-dioxane (100 mL) and water (25 mL), and [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride dichloromethane complex (400 mg, 0.490 mmol) and potassium carbonate (7.20 g, 52.1 mmol) were added, followed by stirring at 50° C. for 4 hours under nitrogen atmosphere. After the reaction solution was cooled to room temperature, water (200 mL) was added, and extraction was carried out with ethyl acetate (400 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=25%-40%) to afford the desired compound (3.72 g, yield 81%) as a pale yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:13][S:12][C:11]=2[CH:22]=1.[CH2:23]([NH:25][CH2:26][CH2:27][OH:28])[CH3:24]>>[CH2:23]([N:25]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:13][S:12][C:11]=2[CH:22]=1)[CH2:26][CH2:27][OH:28])[CH3:24]
Reactant: Fc1ccc(-c2csc3cc(OCCCCBr)ccc23)cc1
Reactant: CCNCCO
Product: CCN(CCO)CCCCOc1ccc2c(-c3ccc(F)cc3)csc2c1

Procedure:
In analogy to example 3.1, 6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and 2-(ethylamino)ethanol were converted to yield 2-(Ethyl-{4-[3-(4-fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-amino)-ethanol as colorless oil, MS: 388 (MH+).
Reaction SMILES: C(N1CC[CH2:6][CH:5](CCN2C(OC)=NC3C2=NC(O[C@@H](C)CCC)=NC=3N)[CH2:4]1)C.[CH3:29][C@H:30]([O:34][C:35]1[N:43]=[C:42]2[C:38]([N:39]=[C:40]([O:53][CH3:54])[N:41]2[CH2:44][CH2:45][CH2:46][CH:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)=[C:37]([NH2:55])[N:36]=1)[CH2:31][CH2:32][CH3:33].IC(C)C>>[CH3:29][C@H:30]([O:34][C:35]1[N:43]=[C:42]2[C:38]([N:39]=[C:40]([O:53][CH3:54])[N:41]2[CH2:44][CH2:45][CH2:46][CH:47]2[CH2:52][CH2:51][N:50]([CH:5]([CH3:6])[CH3:4])[CH2:49][CH2:48]2)=[C:37]([NH2:55])[N:36]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCC3CCNCC3)c2n1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCN(CC)C3)c2n1
Solvent: CC(C)I
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCC3CCN(C(C)C)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 46 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9-[3-(4-piperidinyl)propyl]-9H-purin-6-amine and 2-iodopropane.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].CN(C=O)C.[H-].[Na+].Br[CH2:18][CH:19]=[CH2:20]>O>[CH2:20]([O:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5])[CH:19]=[CH2:18]
Reactant: COC(=O)C(C)(C)CO
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOCC(C)(C)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of methyl 3-hydroxy-2,2-dimethylpropanoate (5.59 g, 1 eq.) and DMF (42 ml) at 0° C. was slowly added NaH (60% in mineral oil, 1.69 g, 1 eq.). After 30 min, 3-bromoprop-1-ene (5.12 g, 1 eq.) was added. The reaction mixture was warmed to room temperature and stirred overnight. Water was carefully added. The resulting mixture was extracted with EtOAc, dried over MgSO4 and concentrated to yield a light-yellow oil to be used in the next step without purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH3:21])[C:11]3[C:16]([C:17]=2[C:18]#[N:19])=[CH:15][CH:14]=[C:13]([Cl:20])[CH:12]=3)[CH:6]=[N:7][CH:8]=1.[O:22]=[C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25](=[O:32])[N:24]1[CH2:33][CH2:34][S:35](Cl)(=[O:37])=[O:36].C(N(CC)CC)C>ClCCl>[Cl:20][C:13]1[CH:12]=[C:11]2[C:16]([C:17]([C:18]#[N:19])=[C:9]([C:5]3[CH:4]=[C:3]([CH2:2][NH:1][S:35]([CH2:34][CH2:33][N:24]4[C:23](=[O:22])[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[C:25]4=[O:32])(=[O:36])=[O:37])[CH:8]=[N:7][CH:6]=3)[N:10]2[CH3:21])=[CH:15][CH:14]=1
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Reactant: Cn1c(-c2cncc(CN)c2)c(C#N)c2ccc(Cl)cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(-c2cncc(CNS(=O)(=O)CCN3C(=O)c4ccccc4C3=O)c2)c(C#N)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A flask is charged with 2-(5-aminomethyl-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile (Example 186e, 0.050 g, 0.160 mmol) and dichloromethane (2 mL). 2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonyl chloride (0.068 g, 0.239 mmol) and triethylamine (0.045 mL, 0.319 mmol) are added and the reaction is stirred at room temperature for 5 min. The reaction mixture is washed with water and extracted with dichloromethane twice. The combined organic phase is separated, dried over sodium sulfate and concentrated in vacuo to give a residue which is purified by silica gel flash chromatography (dichloromethane-methanol, 19:1) to afford 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethane sulfonic acid [5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amide as a white solid. MS (ESI) m/z 537.3 (M+H)+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:13][CH2:14][CH:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:16]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:25]([O-])(=[O:27])C.[Na+]>ClCCl>[CH2:6]([O:13][CH2:14][CH:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH:25]=[O:27])[CH:21]=2)[O:16]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(=O)[O-]
Reactant: c1ccc(COCC2CCc3ccccc3O2)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc2c(c1)CCC(COCc1ccccc1)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
Phosphorous oxychloride (0.863 ml, 9.26 mmol) was added very slowly and under inert atmosphere on N-methylformanilide (1.14 ml, 9.26 mmol) and the mixture was left under stirring at room temperature for 30 minutes. After that 2-(benzyloxymethyl)chromane (1.569 g, 6.18 mmol) was added stirring at 65° C. for 1.5 h. Subsequently the mixture was diluted with dichloromethane (30 ml), added with a 15% sodium acetate solution (20 ml), the phases were separated and the organic phase was washed successively with a 1M hydrochloric acid solution and a sodium chloride saturated solution. After drying and removing the solvent by evaporation under reduced pressure, a residue was obtained which was purified by flash chromatography through a silica gel column. Eluting with hexane:ethyl acetate, 10:1, 0.921 g of the title product were recovered (53% yield).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH:19]=[O:20])=[CH:13][CH:12]=1.ClCCl>N1CCC[C@@H]1C(O)=O>[Cl:1][CH:18]([CH2:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=1)[CH:19]=[O:20]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(CCC=O)cc1
Agent: O=C(O)[C@H]1CCCN1
Solvent: ClCCl
Product: COc1ccc(CC(Cl)C=O)cc1
Temperature: 25 °C
Yield: 71 %

Procedure:
N-Chlorosuccinimide (980 mg, 0.0073 mol) was added to a mixture of 3-(4-methoxyphenyl)propanal (1.0 g, 6.1 mmol) and D-proline (40 mg, 0.3 mmol) in dichloromethane (10 mL, 200 mmol) at 0° C. The reaction mixture was warmed to RT after 1 h, quenched with water, and extracted with dichloromethane. The organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate in hexanes to give the desired product (860 mg). 1H NMR (400 MHz, CDCl3): 9.52 (s, 1H), 7.18 (dd, 2H), 6.84 (dd, 2H), 4.36 (m, 1H), 3.80 (s, 3H), 3.32 (m, 1H), 3.02 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@H:4](/[CH:5]=[C:6](\[CH3:9])/[CH:7]=O)[C@H:3]1[C:10]([O:12][CH3:13])=[O:11].Cl.[CH:16]([O:19][NH2:20])([CH3:18])[CH3:17].N1C=CC=CC=1>C(OCC)(=O)C>[CH:16]([O:19][N:20]=[CH:7]/[C:6](/[CH3:9])=[CH:5]/[C@@H:4]1[C@@H:3]([C:10]([O:12][CH3:13])=[O:11])[C:2]1([CH3:14])[CH3:1])([CH3:18])[CH3:17]
Reactant: COC(=O)[C@@H]1[C@@H](/C=C(\C)C=O)C1(C)C
Reactant: CC(C)ON
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1[C@@H](/C=C(\C)C=NOC(C)C)C1(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 69.9 %

Procedure:
Under nitrogen atmosphere, a mixture of 0.30 g of methyl (1R)-trans-2,2-dimethyl-3-[(E)-2-methyl-3-oxo-1-propenyl]cyclopropanecarboxylate, 0.17 g of O-isopropylhydroxylamine hydrochloride and 2 ml of pyridine was stirred at room temperature for 6 hours. Then, ethyl acetate was added to the reaction mixture, and the mixture was washed with 1 mol/L hydrochloric acid and saturated brine respectively. The organic layer was dried over anhydrous magnesium sulfate, then, filtrated, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.27 g of methyl (1R)-trans-3-[(E)-3-isopropoxyimino-2-methyl-1-propenyl]-2,2-dimethylcyclopropanecarboxylate:
Reaction SMILES: C([C:9]1[CH2:20][N:12]2[C:13](=[O:19])[N:14]=[C:15]([O:17][CH3:18])[CH:16]=[C:11]2[N:10]=1)(=O)C1C=CC=CC=1.[H-].[Na+].I[CH2:24][CH3:25].O>CN(C)C=O>[CH2:24]([N:14]1[C:15]([O:17][CH3:18])=[CH:16][C:11]2=[N:10][CH:9]=[CH:20][N:12]2[C:13]1=[O:19])[CH3:25]
Reactant: CCI
Reactant: COc1cc2n(c(=O)n1)CC(C(=O)c1ccccc1)=N2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(OC)cc2nccn2c1=O
Reaction time: 2 h
Yield: 29.1 %

Procedure:
A stirred solution of 11 g of 2-benzoyl-7-methoxyimi-dazo[1,2-c]pyrimidin-5-one in 33 ml of dry dimethylformamide was treated with 1.27 g of 80% of sodium hydride and was stirred for another hour. 8 g of iodoethane were added dropwise over 10 minutes and stirring was continued for two hours after which the mixture was poured into iced water. The mixture was filtered to obtain 2.3 g of 6-ethyl-7-methoxyimidazo[1,2-c]pyrimidin-5-one as a yellow crystalline solid melting at 159°-60° C.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl[C:30]1[N:35]=[N:34][C:33]([C:36]([O:38][CH3:39])=[O:37])=[CH:32][CH:31]=1>C1(C)C=CC=CC=1>[C:14]([NH:13][C:11]1[CH:10]=[CH:9][C:3]2[C:4](=[O:6])[N:35]3[N:34]=[C:33]([C:36]([O:38][CH3:39])=[O:37])[CH:32]=[CH:31][C:30]3=[N:1][C:2]=2[CH:12]=1)(=[O:16])[CH3:15]
Reactant: COC(=O)c1ccc(Cl)nn1
Reactant: CCOC(=O)c1ccc(NC(C)=O)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc2nc3cc(NC(C)=O)ccc3c(=O)n2n1

Procedure:
A solution of ethyl 2-amino-4-(acetylamino)benzoate (4.03 g, 18.13 mmol, Example 4, Step A), p-toluenesulfonic acid, monohydrate (0.5 g, 2.63 mmol) and methyl 6-chloro-3-pyridazinecarboxylate [3.13 g, 18.14 mmol, prepared according to the procedure of Barlin, G. B. and Yap, C. Y. (Aust. J. Chem. 1977, 30, 2319-2322)] in 500 mL of toluene was refluxed under Dean-Stark conditions for 12 h. The mixture was concentrated, dissolved into chloroform, washed with saturated sodium bicarbonate solution, dried (MgSO4), filtered and concentrated. Medium pressure chromatography (silica gel, 5% methanol in chloroform) afforded methyl 7-acetylamino-10-oxo-10H-pyridazino[6,1-b]-quinazoline-2-carboxylate as a yellow solid, mp 281°-285° C., dec.
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:10][C:9](=[O:11])[O:8][C:6]1=O)[CH:2]([CH3:4])[CH3:3].C(O)(=O)C.[CH2:16]([O:18][P:19]([CH2:39][NH2:40])([CH2:21][CH:22]([C:27](=[O:38])[NH:28][C@H:29]([C:34](=[O:37])[NH:35][CH3:36])[CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[CH3:17]>>[CH2:16]([O:18][P:19]([CH2:39][N:40]1[C:9](=[O:11])[CH2:10][C@H:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[C:6]1=[O:8])([CH2:21][CH:22]([C:27](=[O:38])[NH:28][C@H:29]([C:34](=[O:37])[NH:35][CH3:36])[CH2:30][CH:31]([CH3:32])[CH3:33])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[CH3:17]
Reactant: CCOP(=O)(CN)CC(CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NC
Reactant: CC(C)C[C@H]1CC(=O)OC1=O
Solvent: CC(=O)O
Product: CCOP(=O)(CC(CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NC)CN1C(=O)C[C@H](CC(C)C)C1=O
Yield: 42.5 %

Procedure:
In a manner analogous to that described in Example 24(A), from 0.17 g (1.09 mmol) of 2(S)-isobutylsuccinic anhydride and 0.32 g (0.73 mmol) of (aminomethyl)[(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid ethyl ester acetate, there was obtained 0.16 g of [[(S)-2-isobutylsuccinimido]methyl][(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid ethyl ester.
Reaction SMILES: [S:1]([CH2:11][N:12]=[C:13]=[O:14])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH:15](=O)[CH2:16][CH3:17].[Na].O1CCN=C1>C(O)C>[CH2:16]([CH:17]1[O:14][CH:13]=[N:12][CH:11]1[S:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:3])=[O:2])[CH3:15]
Reactant: CCC=O
Reactant: Cc1ccc(S(=O)(=O)CN=C=O)cc1
Agent: C1=NCCO1
Agent: [Na]
Solvent: CCO
Product: CCC1OC=NC1S(=O)(=O)c1ccc(C)cc1
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a stirred suspension of tosylmethylisocyanate (TosMIC, 3.90 g, 20 mmol) and propionaldehyde (1.5 mL 20.4 mmol) in 60 mL dry ethanol, finely powdered sodium cyamide (0.098 g, 2 mmol) was added. The reaction mixture became clear and white crystals of oxazoline began to precipitate in 15 min. The reaction was continuously stirred for an additional 30 min. The mixture was filtered and the crystals were washed with ether-hexane (1:1) before drying. Compound 15 was attained in 81% yield (4.1 g). The structure was confirmed by 1H NMR in CDCl3. LC-MS: [M+1]=254. Purity was >98%.
Reaction SMILES: [NH2:1][C@@H:2]1[C:26](=[O:27])[N:4]2[C:5]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[O:15])=[C:6]([C@H:9]3[CH2:13][CH2:12][CH2:11][O:10]3)[CH2:7][S:8][C@H:3]12.C1(N=C=NC2CCCCC2)CCCCC1.[C:43]([O:47][C:48]([NH:50][C@H:51]([C:55]1[CH:60]=[CH:59][C:58]([OH:61])=[CH:57][CH:56]=1)[C:52](O)=[O:53])=[O:49])([CH3:46])([CH3:45])[CH3:44]>C1COCC1>[C:43]([O:47][C:48]([NH:50][C@H:51]([C:55]1[CH:60]=[CH:59][C:58]([OH:61])=[CH:57][CH:56]=1)[C:52]([NH:1][C@@H:2]1[C:26](=[O:27])[N:4]2[C:5]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[O:15])=[C:6]([C@H:9]3[CH2:13][CH2:12][CH2:11][O:10]3)[CH2:7][S:8][C@H:3]12)=[O:53])=[O:49])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(O)cc1
Reactant: COc1ccc(COC(=O)C2=C([C@H]3CCCO3)CS[C@@H]3[C@H](N)C(=O)N23)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: COc1ccc(COC(=O)C2=C([C@H]3CCCO3)CS[C@@H]3[C@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)c4ccc(O)cc4)C(=O)N23)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-Methoxybenzyl (6R,7R)-7-amino-3-[(R)-tetrahydrofuran-2-yl)ceph-3-em-4-carboxylate (136mg, 0.35mmol) [See example 6] in THF (10ml) was stirred in an ice bath with dicyclohexylcarbodiimide (108mg, 0.52mmol) then (R)-2-t-butoxycarbonylamino-2-(4-hydroxyphenyl)acetic acid (139mg, 0.52mmol) in THF (3ml) was added dropwise over 2 min. The mixture was stirred at 0° C. for 30 min then at room temperature for 30 min. It was filtered and evaporated and the residue chromatographed on silica gel eluting with ethyl acetate/hexane mixtures. The title compound was obtained as a white solid (212mg, 95%); δH (CDCl3) 1.10-2.0 (4H,m), 1.42 (9H,s), 3.18 and 3.43 (2H,ABq, J 17Hz), 3.80 (3H,s), 3.77-3.88 (2H,m), 4.89 (1H,d, J 5Hz), 5.10 (1H,t, J 7Hz), 5.11 (1H,d, J 5Hz), 5.19 (2H, s), 5.65 (1H,d, J 5Hz exch), 5.69 (1H,dd, J 4,9Hz), 6.72 (2H,d, J 8Hz), 6.81 (1H,d, J 9Hz exch), 6.88 (2H,d, J 9Hz), 7.10 (2H,d, J 8Hz) and 7.33 (2H,d,J 9Hz). (Mass spectrum: +ve ion (3-nitrobenzyl alcohol, sodium acetate) MNa+ (938)].
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:8]([C@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][OH:17])[CH2:10]2)[C:7]2[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:6]=2[N:5]=1)[CH3:3].[NH2:23][C:24]1[C:29]([C:30]#[N:31])=[C:28](Cl)[N:27]=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:23][C:24]1[C:29]([C:30]#[N:31])=[C:28]([NH:1][C@H:2]([C:4]2[N:8]([C@H:9]3[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][OH:17])[CH2:10]3)[C:7]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:6]=3[N:5]=2)[CH3:3])[N:27]=[CH:26][N:25]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1[C@H]1CCCN(CCO)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1[C@H]1CCCN(CCO)C1
Temperature: 90 °C
Reaction time: 3 h
Yield: 33.4 %

Procedure:
A mixture of 2-{(S)-3-[2-((S)-1-aminoethyl)-6-fluorobenzoimidazol-1-yl]piperidin-1-yl}ethanol (35.6 mg, 0.12 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (18 mg, 0.12 mmol), and DIPEA (40 μL, 0.23 mmol) in IPA (1 mL) was stirred at 90° C. for 3 h. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue purified by column chromatography (Si—PCC, gradient 2-10% 2M NH3/MeOH in DCM) affording 285 as a colourless solid (17 mg, 35%). LCMS (Method K): RT 2.24 min [M+H]+ 425.1. 1H NMR (CD3OD, 400 MHz): δ 8.06 (1H, s), 7.58 (1H, dd, J=8.9, 5.0 Hz), 7.49 (1H, dd, J=9.6, 2.4 Hz), 7.01 (1H, dt, J=9.2, 2.4 Hz), 5.84 (1H, q, J=6.9 Hz), 4.70-4.61 (1H, m), 3.63 (2H, t, J=6.0 Hz), 3.17-3.12 (1H, m), 3.01-2.96 (1H, m), 2.83 (1H, t, J=11.0 Hz), 2.66-2.54 (2H, m), 2.39-2.24 (2H, m), 1.99-1.88 (2H, m), 1.86-1.77 (1H, m), 1.70 (3H, d, J=6.9 Hz)