Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:18]=[CH:17][S:16][C:5]=3[C:6](=[O:15])[NH:7][C:8]=2[C:9]([CH3:14])=[CH:10][C:11]=1[O:12][CH3:13].[F:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[C@@H:35]([CH3:45])[CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41]>>[F:19][C:20]1[CH:25]=[C:24]([C:2]2[C:3]3[C:4]4[CH:18]=[CH:17][S:16][C:5]=4[C:6](=[O:15])[NH:7][C:8]=3[C:9]([CH3:14])=[CH:10][C:11]=2[O:12][CH3:13])[CH:23]=[CH:22][C:21]=1[C@@H:35]([CH3:45])[CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:42])([CH3:41])[CH3:43]
Reactant: C[C@@H](CNC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)CNC(=O)OC(C)(C)C)c(F)c1
Yield: 34 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one) (1.0 g, 3.3 mmol) was reacted with (R)-tert-butyl 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propylcarbamate (1.1 g, 3.0 mmol) to afford the desired product (510 mg, 34%) as a yellow solid: ESI MS m/z 497 [C27H19FN2O4S+H]+.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C@H:7]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:17][C@H:18]([C@H:23]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[OH:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16])[CH3:14])=[O:11])[OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>>[NH2:1][C@H:2]([C@H:7]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:17][C@H:18]([C@H:23]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[OH:24])[CH2:19][CH:20]([CH3:21])[CH3:22])=[O:16])[CH3:14])=[O:11])[OH:8])[CH2:3][CH:4]([CH3:5])[CH3:6].[F:40][C:39]([C:37]([OH:43])=[O:38])([F:42])[F:41]
Reactant: COC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)C[C@H](O)[C@@H](N)CC(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
200 mg of Boc-Sta-Ala-Sta-OMe are treated with 3.5 ml of TFA at 0° C. The mixture is stirred for 20 min at RT. Then, after concentration in vacuo, the oily residued is extracted by successively adding and concentrating anhydrous ether. This gives a white solid.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[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].[Na+].[CH2:27]([O:32][C:33]([O:35][CH2:36]I)=[O:34])[CH2:28][CH2:29][CH2:30][CH3:31]>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:36][O:35][C:33]([O:32][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:34])=[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]
Reactant: CCCCCOC(=O)OCI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Product: CCCCCOC(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 86 %

Procedure:
In the same manner as in Example 81, 168 mg of the title compound was prepared from 150 mg of sodium (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 and 162 mg of (pentan-1-yl)oxycarbonyloxymethyl iodide.
Reaction SMILES: [CH3:1]O.[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([O:12][C:13](=[O:15])[CH3:14])(=O)[CH3:10].O>O1CCCC1.CN(C)C1C=CN=CC=1>[C:13]([O:12][CH2:9][C:10]1[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=1[NH:3][CH3:1])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccncc1
Reactant: CO
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: CNc1ccccc1COC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(methylamino)phenyl]methanol (1.37 g: synthesized by a method described in WO 01/32652) in tetrahydrofuran (50 mL) were added pyridine (1.05 mL), acetic anhydride (1.23 mL) and 4-dimethylaminopyridine (0.18 g), and stirred at room temperature for 8 hrs. To the reaction solution was added water (100 mL), and extracted with ethyl acetate (50 mL). The organic layer was washed sequentially with 5% aqueous solution of copper (II) sulfate (50 mL), saturated aqueous solution of sodium bicarbonate (50 mL), and saturated brine (50 mL), and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified with flash silica gel column chromatography (elute with ethyl acetate:hexane=1:5, then 1:3) to give title compound as white solid (0.38 g).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[C:9]#[N:10])[N:3]=[N:2]1.C[O-].[Na+].[O-]S(C(F)(F)F)(=O)=O.F[N+:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO>[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:2]1[N:3]=[C:4]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[C:9]#[N:10])[CH:5]=[N:1]1
Reactant: N#Cc1cccc(-c2c[nH]nn2)c1
Reactant: F[n+]1ccccc1
Agent: C[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: CO
Product: N#Cc1cccc(-c2cnn(-c3ccccn3)n2)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
3-(1H-1,2,3-Triazol-4-yl)benzonitrile (1.82 g, 10.69 mmol) was suspended in anhydrous MeOH (25 mL) under argon at ambient temperature. To this was added NaOMe (21.4 mL of 0.5 M solution in MeOH, 10.69 mmol), and the resulting reaction mixture was cooled to −78° C. A solution of N-fluoropyridinium triflate (2.95 g, 8.91 mmol) in anhydrous MeOH (5 mL) was then added dropwise via syringe. The reaction mixture was stirred at −78° C. for 30 min, then warmed to ambient temperature and stirred for an additional 18 h. The reaction mixture was partitioned between EtOAc (300 mL) and 1N aqueous NaOH (100 mL). The EtOAc layer was washed with additional 1N aqueous NaOH (6×50 mL). The EtOAc layer was dried (MgSO4), filtered and concentrated in vacuo. The resulting crude material was then chromatographed on silica gel eluting with hexanes:EtOAc (2:1) to afford EXAMPLE 5 3-(2-pyridin-2-yl-2H-1,2,3-triazol-4-yl)benzonitrile as a tan solid.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.[N:41]1([O:50]C(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.NO>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[N:16]=2)[CH2:11][C:12]([NH:41][OH:50])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (3R)-6-cyclohexyl-3-{3-[(dimethylamino)carbonyl]-1,2,4-oxadiazol-5-yl}hexanoic acid (Preparation 11) (60 mg, 0.18 mmol) and N,N-diisopropylethylamine (30 μl, 0.18 mmol) in N-N-dimethylformamide (3 ml) was treated with O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (100 mg, 0.27 mmol) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. Further N,N-diisopropylethylamine (90 μl, 0.52 mmol) was then added, followed by hydroxylamine hydrochloride (35 mg, 0.52 mmol) and the mixture was stirred at room temperature for 18 hours. The mixture was partitioned between ethyl acetate and pH 7 aqueous buffer. The layers were separated and the aqueous phase extracted with ethyl acetate (×2). The combined organic layers were washed sequentially with aqueous citric acid solution (5% w/v) and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:ethyl acetate (90:10 ) gradually changing to dichloromethane:ethyl acetate (50:50) then to dichloromethane: methanol (95:5). The residue was further purified by column chromatography on silica gel eluting with a gradient system of dichloromethane: methanol (99:1) gradually changing to dichloromethane:methanol (95:5) to afford the title compound as an oil which crystallised on standing (35 mg).
Reaction SMILES: [C:1]1([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH:29]2[CH2:34][CH2:33][N:32]([C:35]3[O:39][N:38]=[C:37]([CH:40]([CH3:42])[CH3:41])[N:36]=3)[CH2:31][CH2:30]2)=[CH:23][CH:22]=1>>[CH3:42][CH:40]([C:37]1[N:36]=[C:35]([N:32]2[CH2:31][CH2:30][CH:29]([CH2:28][O:27][C:24]3[CH:23]=[CH:22][C:21]([C:14]4[CH:15]=[CH:16][C:11]([C:9]([NH:8][CH2:7][C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)=[O:10])=[CH:12][CH:13]=4)=[CH:26][CH:25]=3)[CH2:34][CH2:33]2)[O:39][N:38]=1)[CH3:41]
Reactant: CC(C)c1noc(N2CCC(COc3ccc(Br)cc3)CC2)n1
Reactant: O=C(NCc1ccccc1)c1ccc(B(O)O)cc1
Product: CC(C)c1noc(N2CCC(COc3ccc(-c4ccc(C(=O)NCc5ccccc5)cc4)cc3)CC2)n1
Yield: 2 %

Procedure:
The title compound (2 mg, 2%) was prepared from (4-{[(phenylmethyl)amino]carbonyl}phenyl)boronic acid (51 mg, 0.2 mmol) and 4-{[(4-bromophenyl)oxy]methyl}-1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]piperidine (prepared as in Example 24, Step 1, 76 mg, 0.2 mmol) in a manner similar to Example 1, Step 1, and worked up in a manner similar to Example 9, Step 3. 1H NMR (400 MHz, CDCl3): δ 7.83 (d, 2H, J=8.6 Hz), 7.61 (d, 2H, J=8.6 Hz), 7.54 (d, 2H, J=8.9 Hz), 7.39-7.28 (m, 5H), 6.97 (d, 2H, J=8.8 Hz), 6.41 (t, 1H, J=5.7 Hz), 4.68 (d, 2H, J=5.5 Hz), 4.26-4.16 (m, 2H), 3.88 (d, 2H, J=6.4 Hz), 3.18-3.06 (m, 2H), 2.96-2.85 (m, 1H), 2.13-2.01 (m, 1H), 2.02-1.92 (m, 2H), 1.55-1.40 (m, 2H), 1.29 (d, 6H, J=7.0 Hz); LRMS (ESI), m/z 511 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>C1COCC1>[C:10]([O:14][C:15]([N:17]1[CH2:18][CH2:19][C:20]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[CH:7]=2)([OH:23])[CH2:21][CH2:22]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: Cc1cccc([Mg]Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: C1CCOC1
Product: Cc1cccc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)c1
Reaction time: 0.5 h

Procedure:
To a solution of 3-methylphenyl magnesium bromide (58 ml of a 1M solution in THF, 58.0 mmol) at 0° C. was added a solution of N-t-butoxycarbonyl piperidin-4-one (10.0 g, 53mmol) in THF (30 ml) dropwise over 20 min, and the reaction stirred under argon for a further 30 min. The reaction was quenched by addition of sat NH4Cl solution (100 ml), and diluted with EtOAc. The organic extracts were dried, (MgSO4) and the solvent evaporated in vacuo to afford the title compound of sufficient purity to be used in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([C:26]([OH:28])=O)[CH:21]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:29]=1.Cl.[NH:31]1[C:40]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35][C:34]=2[CH:33]=[N:32]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH:31]1[C:40]2[CH2:39][CH2:38][N:37]([C:26]([C:22]3[N:23]=[CH:24][N:25]=[C:20]([N:17]4[CH2:18][CH2:19][CH:14]([N:10]5[CH2:9][CH2:8][C:7]6[CH:29]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=6[NH:12][C:11]5=[O:13])[CH2:15][CH2:16]4)[CH:21]=3)=[O:28])[CH2:36][CH2:35][C:34]=2[CH:33]=[N:32]1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ncn3)CC1)C(=O)N2
Reactant: c1n[nH]c2c1CCNCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CCc5cn[nH]c5CC4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
65 mg (0.16 mmol) 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid and 35 mg (0.20 mmol) 1,4,5,6,7,8-hexahydro-pyrazolo[4,3-d]azepine hydrochloride in 80 μL (0.57 mmol) TEA and 0.80 mL DMF were combined with 68 mg (0.18 mmol) HATU and the mixture was stirred overnight at RT. Then the reaction mixture was purified twice by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: O[C:2]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:22])[CH3:21]>C(OCC)(=O)C.CCCCCC>[CH3:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH:2]1[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:18])([CH3:17])[CH3:19])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:22])[CH3:21]
Reactant: COc1ccccc1C1(O)c2cc(NC(=O)CC(C)(C)C)c(C)c(C)c2OC1(C)C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccccc1C1c2cc(NC(=O)CC(C)(C)C)c(C)c(C)c2OC1(C)C
Yield: 82 %

Procedure:
Using N-(3-hydroxy-3-(2-methoxyphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 246, the title compound was synthesized in the same manner as in Example 271. Yield: 82%. Melting point: 169-170° C. (ethyl acetate-hexane).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:8][C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:10][C:4]=2[N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:30]=1[F:36].O>CN(C=O)C>[F:36][C:30]1[C:31]([CH3:35])=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][N:3]1[C:4]2[CH:10]=[C:9]([N:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)[CH:8]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[C:5]=2[N:6]=[C:2]1[CH3:1]
Reactant: COC(=O)c1cc(N2CCOCC2)cc2nc(C)[nH]c12
Reactant: Cc1cccc(CBr)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C)n2Cc1cccc(C)c1F
Temperature: 80 °C
Reaction time: 18 h
Yield: 48 %

Procedure:
A mixture of methyl 2-methyl-5-(4-morpholinyl)-1H-benzimidazole-7-carboxylate prepared as described in Example 26, step d (500 mg, 1.82 mmol), K2CO3 (502 mg, 3.64 mmol) and 1-(bromomethyl)-2-fluoro-3-methylbenzene (389 mg, 1.91 mmol) in DMF (25 mL) was stirred at 80° C. for 18 h. The reaction mixture was cooled, poured into water (100 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel chromatography eluted with EtOAc:MeOH=100:1 to give the desired product (350 mg, 48%) as a red solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 2.24 (d, 3H, J=1.8 Hz), 2.47 (s, 3H), 3.09 (t, 4H, J=4.8 Hz), 3.75 (t, 4H, J=4.8 Hz), 3.86 (s, 3H), 5.51 (s, 2H), 6.62 (t, 1H, J=7.5 Hz), 7.00 (t, 1H, J=7.5 Hz), 7.22 (t, 1H, J=7.5 Hz), 7.32 (d, 1H, J=2.4 Hz), 7.36 (d, 1H, J=2.4 Hz); LC-MS: m/e=398 [M+1]+
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[NH:10][C:11]([NH:13][C:14](=[NH:17])[NH:15][CH3:16])=[O:12].[CH3:18]C#N.COC(OC)N(C)C>C(NC(N)=O)(=N)N>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[N:10]1[CH:16]=[N:15][C:14]([NH:17][CH3:18])=[N:13][C:11]1=[O:12]
Reactant: CNC(=N)NC(=O)Nc1c(Cl)cccc1Cl
Reactant: CC#N
Agent: COC(OC)N(C)C
Agent: Cl
Agent: N=C(N)NC(N)=O
Product: CNc1ncn(-c2c(Cl)cccc2Cl)c(=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a magnetically stirred suspension of 11.88 g. (40 mmol) of 1-(2',6'-dichlorophenyl)-3-methylamidinourea hydrochloride in 30 ml. of CH3CN is added 9.52 g. (80 mmol) of N,N-dimethylformamide dimethylacetal in 20 ml. of CH3CN. The solid material begins to dissolve immediately but in a few minutes, before the starting material amidinourea has dissolved, another fine particle white solid begins to precipitate out. The reaction mixture is stirred at ambient temperature for 1 hour then heated to reflux for 2 hours. After 2 hours the reaction mixture is allowed to come to ambient temperature and the white solid precipitate filtered out to yield the desired product, melting point 270° C.; TLC (EtoAc 9:1); one major spot, one minor spot at origin. A small sample recrystallized from CH3OH/EtoAc gave 1 spot on TLC. (9.6 g. 89%). The product is recrystallized from MeOH to yield -1-(2',6'-dichlorophenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:56])[C@@H:24]([NH:25][C:26](=[O:55])[C@@H:27](C4C=CC(C(OC(C)(C)C)=O)=CC=4N)[NH:28][C:29]([N:31]4[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[C:33](=[O:39])[C:32]4=[O:40])=[O:30])[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:57][O:58][C:59](=[O:61])[CH3:60])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[C:63]1([CH3:73])[CH:68]=[CH:67][C:66]([S:69]([OH:72])(=[O:71])=[O:70])=[CH:65][CH:64]=1.[C:74](#[N:76])[CH3:75]>>[C:63]1([CH3:73])[CH:64]=[CH:65][C:66]([S:69]([OH:72])(=[O:70])=[O:71])=[CH:67][CH:68]=1.[C:8]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:56])[C@@H:24]([NH:25][C:26](=[O:55])[C@@H:27]([C:63]4[CH:64]=[CH:65][C:74]([NH2:76])=[CH:75][CH:68]=4)[NH:28][C:29]([N:31]4[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[C:33](=[O:39])[C:32]4=[O:40])=[O:30])[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:57][O:58][C:59](=[O:61])[CH3:60])=[O:16])[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC#N
Reactant: CCN1CCN(C(=O)N[C@@H](C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(COC(C)=O)CS[C@H]23)c2ccc(C(=O)OC(C)(C)C)cc2N)C(=O)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCN1CCN(C(=O)N[C@@H](C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(COC(C)=O)CS[C@H]23)c2ccc(N)cc2)C(=O)C1=O

Procedure:
In the manner described in Example 11, 4.815 g of 3-acetoxymethyl-7β-[(2R)-2-(4-BOC-aminophenyl)-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester are reacted with 2.2 g of p-toluenesulphonic acid monohydrate in 40 ml of acetonitrile and worked up. 3-Acetoxymethyl-7β-[(2R)-2-(4-aminophenyl)-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester p-toluenesulphonate is obtained. [α]D20 =+15°±1° (0.94% in CH3OH).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10](=[O:13])[NH:9][C:7]=2[N:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH:22]1[O:26][CH2:25][CH2:24][O:23]1.O>CN(C)C=O.C(Cl)(Cl)Cl>[O:23]1[CH2:24][CH2:25][O:26][CH:22]1[CH2:21][N:9]1[C:7]2[N:8]=[C:3]([O:2][CH3:1])[N:4]=[CH:5][C:6]=2[CH:12]=[CH:11][C:10]1=[O:13]
Reactant: COc1ncc2ccc(=O)[nH]c2n1
Reactant: BrCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1ncc2ccc(=O)n(CC3OCCO3)c2n1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a suspension of 0.50 g of 2-methoxypyrido(2,3-d)pyrimidin-7(8H)-one in 7.5 mL of N,N-dimethylformamide, 0.59 g of potassium carbonate was added at room temperature, the temperature was increased to 60 to 80° C., and the mixture was stirred for 1 hour. Thereto was added 0.35 mL of 2-bromomethyl-1,3-dioxolan at 80° C., the temperature of the reaction mixture was increased to 103° C., and the mixture was stirred for 3 hours 30 minutes. The reaction mixture was cooled to room temperature, and water and chloroform were added thereto. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of chloroform:methanol=75:1 to obtain 0.60 g of 8-(1,3-dioxolan-2-ylmethyl)-2-methoxypyrido(2,3-d)pyrimidin-7(8H)-one as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.Cl[CH2:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][CH2:27][C:28]2[N:29]=[C:30]([C:34]3[O:35][CH:36]=[CH:37][CH:38]=3)[O:31][C:32]=2[CH3:33])=[C:24]([O:41][CH3:42])[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:35]1[CH:36]=[CH:37][CH:38]=[C:34]1[C:30]1[O:31][C:32]([CH3:33])=[C:28]([CH2:27][O:26][C:25]2[CH:39]=[CH:40][C:22]([CH2:21][O:1][C:2]3[C:6]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:4]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:3]=3)=[CH:23][C:24]=2[O:41][CH3:42])[N:29]=1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOC(=O)CCc1cn(-c2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 49 %

Procedure:
A mixture of ethyl 3-(3-hydroxy-1-phenyl-1H-pyrazol-4-yl)propionate (0.40 g), 4-(4-chloromethyl-2-methoxyphenoxymethyl)-2-(2-furyl)-5-methyloxazole (0.57 g), potassium carbonate (276 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxy]-1-phenyl-1H-pyrazol-4-yl]propionate (420 mg, yield 44%) was obtained as colorless crystals-from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 97–98° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[C:10]([F:17])[CH:9]=2)=[CH:6][C:5]([C:18]2[CH2:19][NH:20][C:21](=[O:23])[CH:22]=2)=[CH:4][N:3]=1>CO.[Pd]>[NH2:1][C:2]1[C:7]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[C:10]([F:17])[CH:9]=2)=[CH:6][C:5]([CH:18]2[CH2:22][C:21](=[O:23])[NH:20][CH2:19]2)=[CH:4][N:3]=1
Reactant: Nc1ncc(C2=CC(=O)NC2)cc1-c1ccc(C(=O)O)c(F)c1
Agent: [Pd]
Solvent: CO
Product: Nc1ncc(C2CNC(=O)C2)cc1-c1ccc(C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 4-(2-amino-5-(5-oxo-2,5-dihydro-1H-pyrrol-3-yl)pyridin-3-yl)-2-fluorobenzoic acid (100 mg, 0.319 mmol) in MeOH (15 mL) under N2 atmosphere was added Pd—C (67.9 mg, 0.064 mmol). The reaction mixture was stirred at room temperature for 24 h under H2 balloon. The reaction mixture was filter through Celite and washed with methanol. The filtrate was evaporated. The crude was proceed for next step. LCMS(m/z): 316.2 (MH+), 0.338 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[C:21]1([C@H:27]([NH2:29])[CH3:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCO>[F:14][C:13]([F:16])([F:15])[C:10]([CH2:12][NH:29][C@@H:27]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:28])([OH:11])[CH2:9][C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:19][CH3:20])([CH3:18])[CH3:17]
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Reactant: C[C@@H](N)c1ccccc1
Solvent: CCO
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CN[C@H](C)c1ccccc1)C(F)(F)F
Temperature: 50 °C
Yield: 116.9 %

Procedure:
To a stirred solution of racemic 2-{2-[5-fluoro-2-(methyloxy)phenyl]-2-methylpropyl}-2-(trifluoromethyl)oxirane (600 mg, 2.05 mmol), which may be prepared according to WO04/063163, in anhydrous EtOH (3 mL) was added (R)-(+)-1-phenylethylamine (1.31 mL, 10.3 mmol). The reaction mixture was then stirred and heated at 50° C. under nitrogen for 5 days, cooled to room temperature and evaporated in vacuo. The residue was applied to a 70 g silica SPE cartridge and eluted with 0.5% NH3 in toluene. The appropriate fractions were combined and evaporated in vacuo to give a colourless oil (991 mg). 710 mg of this oil was separated by chiral HPC on a 2 inch×15 cm Chiralpak AD column eluted with 25% acetonitrile/ammonium phosphate (pH 4.9) with a flow rate of 70 mL/min to give Intermediate 19 (2S isomer, 230 mg) after 17.5 min and Intermediate 20 (2R isomer, 200 mg) after 24.8 min.