Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3](=[O:21])[O:4][C:5]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)([CH2:9][CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:6][C:7]=1[OH:8].ClC1C(=O)OC(CCC2CCCCC=2)(C2CCCC2)CC=1O.[Cl:44][C:45]1[CH:57]=[CH:56][C:48]2[N:49]([CH:53]([CH3:55])[CH3:54])[C:50]([SH:52])=[N:51][C:47]=2[CH:46]=1.N1C=CC(C2NC(S)=NN=2)=CC=1>>[Cl:44][C:45]1[CH:57]=[CH:56][C:48]2[N:49]([CH:53]([CH3:55])[CH3:54])[C:50]([S:52][C:2]3[C:3](=[O:21])[O:4][C:5]([CH:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)([CH2:9][CH2:10][CH:11]4[CH2:15][CH2:14][CH2:13][CH2:12]4)[CH2:6][C:7]=3[OH:8])=[N:51][C:47]=2[CH:46]=1
Reactant: O=C1OC(CCC2CCCC2)(C2CCCC2)CC(O)=C1Cl
Reactant: CC(C)n1c(S)nc2cc(Cl)ccc21
Agent: O=C1OC(CCC2=CCCCC2)(C2CCCC2)CC(O)=C1Cl
Agent: Sc1nnc(-c2ccncc2)[nH]1
Product: CC(C)n1c(SC2=C(O)CC(CCC3CCCC3)(C3CCCC3)OC2=O)nc2cc(Cl)ccc21

Procedure:
The title compound was prepared analogously to Example C(4), where 3-Chloro-6-cyclopentyl-6-(2-cyclopentyl-ethyl)-4-hydroxy-5,6-dihydro-pyran-2-one from Step 2 of example C(28) was substituted in place of 3-Chloro-6-(2-cyclohex-1-enyl-ethyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one and 5-Chloro-1-isopropyl-2-mercapto benzimidazole was substituted in place of 5-Pyridin-4-yl-4H-[1,2,4]triazole-3-thiol of that example. 1H NMR (DMSO-d6): δ 0.84-2.28 (m, 28H), 2.31 (d, J=17.0, 1H), 2.66 (d, J=17.0, 1H), 3.96 (brs, 1H), 4.55-4.67 (m, 1H), 6.93 (d, J=8.5, 1H), 7.12 (s, 1H), 7.46 (d, J=8.5, 1H); Anal. Calcd. For C27H35ClN2O3S: C, 64.46; H, 7.01; N, 5.57; Found: C, 64.85; H, 7.30; N, 5.76. ESIMS (MH+): 504.
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[OH:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[I:21])[C:16]#[N:17].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[C:7]([O:6][C:5]([NH:4][CH2:3][CH2:2][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[I:21])[C:16]#[N:17])=[O:11])([CH3:10])([CH3:9])[CH3:8]
Reactant: N#Cc1ccc(I)c(O)c1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCOc1cc(C#N)ccc1I
Temperature: 75 °C
Reaction time: 3 h

Procedure:
18.5 g (82.6 mmol) of t-butyl (2-bromoethyl)carbamate was dissolved in 200 ml of DMF. 10.1 g (41.3 mmol) of 3-hydroxy-4-iodobenzonitrile and 5.7 g (41.3 mmol) of potassium carbonate were added to the obtained solution, and they were stirred at 75° C. for 3 hours. After the treatment with ethyl acetate as the extraction solvent in an ordinary manner, the title compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C(O)(=O)C(O)=O.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]2[O:27][CH2:26][CH2:25][NH:24][CH2:23]2)[CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:24]2[CH2:25][CH2:26][O:27][CH:22]([C:18]3[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=3)[CH2:23]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: c1cncc(C2CNCCO2)c1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1ccc(CN2CCOC(c3cccnc3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
5.632 g of 4-Bromobenzyl bromide and 3.819 g of 2-Pyridin-3-yl morpholine oxalate (Array) in 50 mL of acetonitrile were stirred at room temperature and 6.229 g of potassium carbonate was added. The reaction was stirred at room temperature overnight. The solution was filtered through Celite and concentrated in vacuo to afford a brown solid. Purification is done by flash chromatography to afford product. Wt: 211 mg; 16% yield. ES MS m/z 334
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][N:6]([CH2:26][C:27]1[O:28][CH:29]=[CH:30][CH:31]=1)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]([CH3:25])([CH3:24])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:11][CH:10]=1)C.[OH-].[Na+]>C(O)C>[C:4]([CH2:5][N:6]([CH2:26][C:27]1[O:28][CH:29]=[CH:30][CH:31]=1)[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][C:16]([CH3:24])([CH3:25])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:13][CH:14]=1)([OH:32])=[O:3]
Reactant: CCOC(=O)CN(CCc1ccc(SC(C)(C)C(=O)OC(C)(C)C)cc1)Cc1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)C(C)(C)Sc1ccc(CCN(CC(=O)O)Cc2ccco2)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
1.0 g of 1,1-dimethylethyl 2-[[4-[2-[(2-ethoxy-2-oxoethyl)(2-furanylmethyl)amino]-ethyl]phenyl]-thio]-2-methyl-propanoate is treated with 6.5 ml of 1 N NaOH in 10 ml of ethanol. The mixture is stirred at 80° C. for 1 h, concentrated, dissolved in water and acidified with 1 N HCl. Three extractions with ethyl acetate and chromatography (dichloromethane/methanol 5+1) gives 744 mg as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][CH:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1.[C:21]([NH:29][NH2:30])(=O)[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:21]([C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)=[N:29][N:30]=[C:10]3[CH2:9][CH:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1
Reactant: Fc1ccccc1C1=CCC(=S)Nc2ccc(Cl)cc21
Reactant: NNC(=O)c1ccncc1
Solvent: CCCCO
Product: Fc1ccccc1C1=CCc2nnc(-c3ccncc3)n2-c2ccc(Cl)cc21

Procedure:
6 g of 7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1-benzazepine-2-thione and 27 g of isonicotinic acid hydrazide are dissolved together in 360 ml of n-butanol and heated to boiling under reflux for 24 hours. After evaporation of the resulting solution in vacuo, the residue is partitioned between toluene and water. The toluene phase is concentrated to about 100 ml. The precipitated crystals are filtered off and recrystallized from benzene. There is obtained 8-chloro-6-(2-fluorophenyl)-1-(4-pyridyl)-4H-s-triazolo[4,3-a][1]benzazepine of melting point 198°-200°.
Reaction SMILES: [CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][O:37][CH2:38][O:39][CH3:40])[CH:31]=3)=[CH:26][CH:25]=2)=[O:23])=[CH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])[CH2:2][CH2:3][CH3:4].[OH-].[Na+:42]>>[CH2:1]([CH:5]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][O:37][CH2:38][O:39][CH3:40])[CH:31]=3)=[CH:28][CH:29]=2)=[O:23])=[CH:16][CH:17]=1)[C:6]([O-:8])=[O:7])[CH2:2][CH2:3][CH3:4].[Na+:42]
Reactant: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3cccc(COCOC)c3)cc2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3cccc(COCOC)c3)cc2)cc1)C(=O)[O-]

Procedure:
In a similar manner to that described in Example 2, a reaction was carried out using ethyl 2-butyl-3-[4-[2-(3′-methoxymethoxymethylbiphenyl-4-carbonylamino)ethoxy]phenyl]propionate (573 mg), which is the product of Reference example 15(d), and aqueous sodium hydroxide (1N, 2.00 ml) and the reaction mixture was treated to afford the desired compound (472 mg) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[N:8][C:6]=2[N:7]=1.[NH:19]1[CH2:22][CH:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:19]3[CH2:22][CH:21]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH2:20]3)=[N:8][C:6]=2[N:7]=1
Reactant: C1CN(C2CNC2)CCO1
Reactant: O=Cc1nc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Clc1nc(N2CCOCC2)c2sc(CN3CC(N4CCOCC4)C3)nc2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 45.6 %

Procedure:
A mixture of 5-chloro-7-morpholin-4-yl-thiazolo[4,5-d]pyrimidine-2-carbaldehyde (250 mg, 0.88 mmol), 4-azetidin-3-yl-morpholine (150 mg, 1.05 mmol) and 4 Å molecular sieves (1.0 g) in 1,2-dichloroethane (15 mL) was stirred at RT under nitrogen atmosphere for 1.5 h. Sodium triacetoxyborohydride (280 mg, 1.32 mmol) was added and the resulting reaction mixture was stirred at RT for 16 h. The solvent was reduced in vacuo and the residue was loaded on an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with DCM/MeOH, the desired product was subsequently eluted using a mixture of 2M NH3 in MeOH and DCM. The resulting residue was further purified by column chromatography (Si—PCC, MeOH:DCM: 0:100 to 6:94 by volume). The solvents were reduced in vacuo to afford the title compound as a yellow solid (165 mg, 46%). LCMS (Method A): RT 2.31 min, [M+H]+ 411. 1H NMR (400 MHz, CDCl3): δ 4.11 (2 H, s), 3.95 (4 H, t, J=4.85 Hz), 3.83 (4 H, t, J=4.84 Hz), 3.74-3.67 (6 H, m), 3.22 (2 H, t, J=6.84 Hz), 3.12-3.11 (1 H, m), 2.34 (4 H, s)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:50]=[CH:49][CH:48]=[CH:47][C:7]=1[C:8]([NH:10][C:11]1[CH:44]=[CH:43][C:14]([C:15]([N:17]([CH3:42])[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=2[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([N:33]2[CH2:38][CH2:37][CH:36]([N:39]([CH3:41])[CH3:40])[CH2:35][CH2:34]2)=[O:32])=[O:16])=[CH:13][C:12]=1[O:45][CH3:46])=[O:9].CO[C:53](=[NH:55])[NH2:54]>C(O)C>[NH:1]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:50]=[CH:49][CH:48]=[CH:47][C:7]=1[C:8]([NH:10][C:11]1[CH:44]=[CH:43][C:14]([C:15]([N:17]([CH3:42])[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=2[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([N:33]2[CH2:38][CH2:37][CH:36]([N:39]([CH3:40])[CH3:41])[CH2:35][CH2:34]2)=[O:32])=[O:16])=[CH:13][C:12]=1[O:45][CH3:46])=[O:9])[C:53]([NH2:55])=[NH:54]
Reactant: COC(=N)N
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCC(N(C)C)CC2)ccc1NC(=O)c1ccccc1OCCCN
Solvent: CCO
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCC(N(C)C)CC2)ccc1NC(=O)c1ccccc1OCCCNC(=N)N
Yield: 18.2 %

Procedure:
A mixture of 4-[2-(3-aminoprop-1-yl)oxybenzoyl]amino-3-methoxy-N-methyl-N-[2-[5-(4-dimethylaminopiperidin-1-yl)carbonylpent-1-yl]oxy-4-methylphenyl]benzamide (275 mg) and O-methylisourea (44 mg) in ethanol (5 ml) was refluxed for 3 days. The solvent was evaporated in vacuo and the residue was purified on basic silica gel column chromatography (SiO2 17 g, 1-80% methanol in chloroform) to give 4-[2-(3-guanidinoprop-1-yl)oxybenzoyl]amino-3-methoxy-N-methyl-N-[2-[5-(4-dimethylaminopiperidin-1-yl)carbonylpent-1-yl]oxy-4-methylphenyl]benzamide (53 mg).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:42]=[CH:41][C:25]([O:26][C:27]2[CH:40]=[CH:39][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O:48][C:49](=[O:56])[C@H:50]([C@H:52]([CH2:54][CH3:55])[CH3:53])[NH2:51])(C)(C)C>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([NH:51][C@H:50]([C:49]([OH:48])=[O:56])[C@H:52]([CH2:54][CH3:55])[CH3:53])=[O:37])=[CH:39][CH:40]=2)=[CH:41][CH:42]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@H](C)[C@H](N)C(=O)OC(C)(C)C
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCCC(=O)O)cc2)cc1
Agent: Cl
Product: CC[C@H](C)[C@H](NC(=O)CCCCOc1ccc(Oc2ccc(CN(Cc3ccccc3)c3cccc(NS(C)(=O)=O)c3C)cc2)cc1)C(=O)O

Procedure:
The product from Example 234B and L-isoleucine tert-butyl ester hydrochloride were processed as described in Example 251A and 258B to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ12.09-12.71 (br.s, 1 H), 8.94 (s, 1 H), 7.93 (d, 1 H), 7.23 (m, 7 H), 7.03 (t, 1 H), 6.94 (m, 6 H), 6.82 (d, 2 H), 4.19 (dd, 1 H), 4.04 (s, 2 H), 4.00 (s, 2 H), 3.93 (t, 2 H), 2.91 (s, 3 H), 2.38 (s, 3 H), 2.21 (m, 2 H), 1.59-1.80 (m, 5 H), 1.39 (m, 1 H), 1.20 (m, 1 H), 0.84 (m, 6 H); MS (ESI+) m/z 702 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:12]=[N:11][C:10]2[NH:9][C:8](=[O:13])[C:7]([CH3:15])([CH3:14])[CH2:6][O:5][C:4]=2[CH:3]=1.[C:16]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[CH:17]=[CH2:18].CCN(C(C)C)C(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:14][C:7]1([CH3:15])[CH2:6][O:5][C:4]2[CH:3]=[C:2](/[CH:18]=[CH:17]/[C:16]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:12]=[N:11][C:10]=2[NH:9][C:8]1=[O:13]
Reactant: CC1(C)COc2cc(Br)cnc2NC1=O
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)/C=C/c1cnc2c(c1)OCC(C)(C)C(=O)N2
Yield: 87.3 %

Procedure:
A solution of 8-bromo-3,3-dimethyl-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-one (1 g, 3.6 mmol), t-butyl acrylate (1.38 g, 10.8 mmol) and DIPEA (1.86 mL, 10.1 mmol) in DMF (10 mL) was purged with Ar for 10 min. Pd(OAc)2 (81 mg, 0.36 mmol) and P(o-tol)3 (218 mg, 0.72 mmol) were added and the mixture purged again then refluxed overnight. The crude mixture was evaporated in vacuo and chromatographed over silica eluting with methanol/dichloromethane to afford the title compound (1.0 g, 87%). 1H NMR (300 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.26 (s, 1H), 7.77 (s, 1H), 7.47 (d, J=16.1 Hz, 1H), 6.53 (d, J=16.1 Hz, 1H), 4.05 (s, 2H), 1.53 (s, 9H), 1.47 (s, 6H)
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:11](=[O:13])[O:10][C:9]([C:14]3[C:15](F)=[N:16][CH:17]=[CH:18][CH:19]=3)=[N:8][C:7]=2[CH:6]=[C:5]([O:21][CH3:22])[CH:4]=1)[CH3:2].[CH3:23][N:24]([CH3:30])[C@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1>O1CCOCC1>[CH3:23][N:24]([CH3:30])[C@H:25]1[CH2:29][CH2:28][N:27]([C:15]2[C:14]([C:9]3[O:10][C:11](=[O:13])[C:12]4[C:3]([CH2:1][CH3:2])=[CH:4][C:5]([O:21][CH3:22])=[CH:6][C:7]=4[N:8]=3)=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:26]1
Reactant: CCc1cc(OC)cc2nc(-c3cccnc3F)oc(=O)c12
Reactant: CN(C)[C@H]1CCNC1
Solvent: C1COCCO1
Product: CCc1cc(OC)cc2nc(-c3cccnc3N3CC[C@H](N(C)C)C3)oc(=O)c12
Yield: 70 %

Procedure:
A solution of compound S (13.9 g, 46.4 mmol) in anhydrous 1,4-dioxane (232 mL) was treated with (S)-(−)-3-(dimethylamino)-pyrrolidine (7.50 mL, 60.3 mmol) at 100° C. under N2 for 10 minutes. The solution was concentrated, and the residue was purified using a Biotage 40M amine column using a gradient of 20-50% ethyl acetate/hexanes. The fractions containing compound 132 were combined and concentrated by rotary evaporation, dissolved in acetonitrile:water (1:1, 50 mL), and then lyophilized to afford compound 132 as a pale yellow powder (12.81 g, 70% yield). 1H NMR (CDCl3, 400 MHz) d: 8.30 (dd, 1H, J=1.5 Hz), 8.00 (dd, 1H, J=1.5 Hz), 6.95 (d, 1H, J=2.0 Hz), 6.88 (d, 1H, J=3.0 Hz), 6.72 (q, 1H, J=4.5 Hz), 3.92 (s, 3H), 3.66 (q, 1H, J=4.0 Hz), 3.48 (m, 3H), 3.21 (m, 2H), 2.78 (s, 1H), 2.26 (s, 6H), 2.12 (q, 1H, J=6.0 Hz), 1.84 (m, 1H), 1.29 (t, 3H, J=7.0 Hz); 13C NMR (CDCl3, 400 MHz) d: 165.5, 158.8, 158.1, 155.7, 151.1, 151.0, 150.6, 140.3, 117.9, 112.2, 110.6, 107.3, 107.1, 65.4, 55.9, 54.4, 49.1, 44.5, 30.3, 28.6, 15.2; ESMS m/z: 395.1 [M+H+]; Calculated for C22H26N4O3: C, 66.99; H, 6.64; N, 14.20. found: C, 66.81; H, 6.66; N, 14.14.
Reaction SMILES: [Br:1]Br.[N:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[N:5][CH:4]=1.CCOCC>C(O)(=O)C>[Br:1][C:11]1[C:12](=[O:15])[NH:13][CH:14]=[C:9]([C:6]2[CH:7]=[CH:8][N:3]=[CH:4][N:5]=2)[CH:10]=1
Reactant: BrBr
Reactant: O=c1ccc(-c2ccncn2)c[nH]1
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=c1[nH]cc(-c2ccncn2)cc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.7 g of bromine are added over a period of one minute to a solution of 4.5 g of 5-(4-pyrimidyl)-2(1H)-pyridone in 60 ml glacial acetic acid. The mixture is allowed to cool, stirred at RT for 1 hour and then poured into 100 ml of anhydrous ether and stirred for 30 minutes. The slurry is filtered and the filtered solid washed with ether and dried. The solid is suspended in 100 ml of H2O and the pH adjusted to about 6 with anhydrous K2CO3. The mixture is stirred for 15 minutes, filtered, the solid washed with H2O and briefly dried. The moist solid is added to 40 ml of 5% aqueous hydrochloric acid and the resultant mixture stirred for 30 minutes, diluted with an equal volume of isopropyl alcohol, stirred for an additional 10 minutes and filtered. The resulting solid is washed with isopropyl alcohol ether and dried, giving 3-bromo-5-(4-pyrimidyl)-2 (1H)-pyridone as a green powder, M.P. >250° C.
Reaction SMILES: Cl[CH:2]([CH2:5][O:6][CH3:7])[CH:3]=[O:4].[CH2:8]([NH2:10])[CH3:9]>C1(C)C=CC=CC=1>[CH2:8]([NH:10][CH:2]([CH2:5][O:6][CH3:7])[CH:3]=[O:4])[CH3:9]
Reactant: COCC(Cl)C=O
Reactant: CCN
Solvent: Cc1ccccc1
Product: CCNC(C=O)COC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The dimethyl acetal of 2-chloro-3-methoxypropionaldehyde (0.1 mole) and toluene (75 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Ethylamine (0.22 mole) is added to the reaction mixture with stirring at room temperature. Stirring is continued for a period of about 15 minutes. After this time the reaction mixture is heated at reflux for a period of about 1 hour. The reaction mixture is then cooled to room temperature and filtered. The filtrate is stripped of toluene and unreacted starting material under reduced pressure to yield the desired product the dimethyl acetal of 2-ethylamino-3-methoxypropionaldehyde as the residue.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([Cl:13])(Cl)=[O:11].[CH2:14]([NH:20][CH3:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C(OCC)C>[CH2:14]([N:20]([CH3:21])[C:10]([Cl:13])=[O:11])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=C(Cl)Cl
Reactant: CCCCCCNC
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCN(C)C(=O)Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 0.35 ml of (i-Pr)2NEt in 10 ml of diethyl ether at 0° C. was added phosgene (1.06 ml, 1.93 M solution in toluene) and N-hexylmethylamine (0.31 ml, 2.05 mm). The reaction mixture was allowed to warm up to 25° C., and further stirred at 25° C. for 14 h. The mixture was filtered, and the solvent was removed under vacuum. The product was used for the next step reaction without further purification. 1H NMR (CDCl3): δ 3.42 (m, 2H), 3.07 (s, 3H), 1.59 (m, 2H), 1.31 (m, 6H), 0.90 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9](Cl)=[O:10])=[CH:5][CH:4]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:31]=[C:32]([O:36][CH3:37])[C:33]=1[O:34][CH3:35])[C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH:22]1[C:27]([O:29][CH3:30])=[O:28])=[O:20].C(N(CC)CC)C.O>ClCCl>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([N:24]2[CH2:25][CH2:26][N:21]([C:19](=[O:20])[C:18]3[CH:17]=[C:16]([O:15][CH3:14])[C:33]([O:34][CH3:35])=[C:32]([O:36][CH3:37])[CH:31]=3)[CH:22]([C:27]([O:29][CH3:30])=[O:28])[CH2:23]2)=[O:10])=[CH:5][CH:4]=1
Reactant: COC(=O)C1CNCCN1C(=O)c1cc(OC)c(OC)c(OC)c1
Reactant: COc1ccc(C=CC(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1CN(C(=O)C=Cc2ccc(OC)cc2)CCN1C(=O)c1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 78.9 %

Procedure:
A solution of 4-methoxy cinnamoyl chloride (0.3 g) in dichloromethane (4 ml) is added dropwise, taking 3 minutes at 0 ° C while stirring, to a mixture of methyl 1-(3,4,5-trimethoxybenzoyl)piperazine-2-carboxylate (0.57 g), triethylamine (0.4 g) and dichloromethane (12 ml). The reaction mixture is stirred for 30 minutes at room temperature, and then poured into water, followed by extraction with dichloromethane. The organic layer is washed with dilute hydrochloric acid, an aqueous solution of sodium hydrogencarbonate and water, successively, then the solvent is distilled off. The residue is purified by means of a silica gel column chromatography to give methyl 4-(4-methoxycinnamoyl)-1(3,4,5-trimethoxybenzoyl)piperazine-2-carboxylate (0.6 g) as a colorless oily product. This product is processed with ethyl ether to give colorless powder
Reaction SMILES: [Br:1][C@H:2]1[C:28](=[O:29])[N:4]2[C:5]([C:12]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[C:6]([CH3:11])[CH2:7][S:8](=[O:10])(=[O:9])[C@H:3]12.Cl.[CH3:31]NC.C=O.C(O)(C)(C)C>C(Cl)Cl>[Br:1][C@H:2]1[C:28](=[O:29])[N:4]2[C:5]([C:12]([O:14][CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:13])=[C:6]([CH3:11])[C:7](=[CH2:31])[S:8](=[O:9])(=[O:10])[C@H:3]12
Reactant: CNC
Reactant: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@H](Br)[C@H]2S(=O)(=O)C1
Agent: C=O
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: C=C1C(C)=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@H](Br)[C@H]2S1(=O)=O
Temperature: 95 °C
Yield: 69.4 %

Procedure:
To a stirred solution of benzhydryl 7α-bromo-3-methyl-3-cephem-4-carboxylate-1,1-dioxide (2.8 g, 0.0059 mol) in methylene chloride (12 ml) were added dimethylamine hydrochloride (1.44 g, 0.0176 mol), formaldehyde (0.61 g, 0.020 mol) and t-butyl alcohol (100 ml), the mixture was heated to reflux at 95° C. for 3 hours. Solvent was removed under reduced pressure and the residue was dissolved in methylene chloride, washed with water, dried over sodium sulfate and concentrated to dryness. The residue was purified by column chromatography with a solvent gradient of 10 to 25% ethyl acetate/hexane to afford benzhydryl 7α-bromo-2-methylene-3-methyl-3-cephem-4-carboxylate-1, 1-dioxide (2.0 g, 69.5%) as a white foam. IR (Nujol) ν max 1720, 1800 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@:9]([OH:20])([CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)[C@@H:10]([CH3:13])[C:11]#[N:12].C([S:23]P([O-])(OCC)=S)C.O.CCCCCC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@:9]([OH:20])([CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)[C@@H:10]([CH3:13])[C:11]([NH2:12])=[S:23]
Reactant: CCOP([O-])(=S)SCC
Reactant: C[C@@H](C#N)[C@](O)(Cn1cncn1)c1cc(F)ccc1F
Solvent: O
Solvent: CCCCCC
Solvent: ClCCl
Product: C[C@@H](C(N)=S)[C@](O)(Cn1cncn1)c1cc(F)ccc1F
Temperature: 80 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
A mixture of (2S,3R)-3-(2,5-Difluoro-phenyl)-3-hydroxy-2-methyl-4-[1,2,4]triazol-1-yl-butyronitrile (30.5 g, 0.110 mol), diethyldithiophospate (235 ml) and H2O (110 ml) was stirred at 80° C. for 2 hrs. The reaction mixture was cooled down to r.t. n-Hexane (400 ml) and water (200 ml) was added. The whole was shaken well and the aqueous layer was separated. The remaining organic layer was further extracted with H2O (100 ml×3). All the aqueous layer was combined. Cooled down to 0° C. and neutralized and basified (PH8) with NaHCO3. This basic(PH8) aqueous layer was extracted with EtOAc (300 ml+100 ml×3). The combined organic layer was dried over Na2SO4 and concentrated in vacuo to give dark brown syrup. By addition of CH2Cl2 (100 ml) to this crude syrup, precipitate was formed. The precipitate was filtered and washed with CH2Cl2-hexane (5:1 mixture) to give (2R,3R)-3-(2,5-Difluoro-phenyl)-3-hydroxy-2-methyl-4-[1,2,4]triazol-1-ylthiobutyramide (19.2 g, 56%) as white powder. On the other hand, the filtrate was concentrated in vacuo and the residue was chromatographed on silica gel (Wako-gel C-300, CH2Cl2:MeOH=20:1) to give additional (2R,3R)-3-(2,5-Difluoro-phenyl)-3-hydroxy-2-methyl-4-[1,2,4]triazol-1-ylthiobutyramide (7.46 g, 22%) as pale brown amorphous powder. Physical form: White solid; FAB-MS: m/z 313 (M+H)+; 1H-NMR (CDCl3): 1.12(3H,d,J=7.3 Hz),3.74(1H,q,J=7.3 Hz), 4.55,5.12 (2H,ABq,J=14.5 Hz), 5.84(1H,s),6.85˜7.02(2H,m),7.15˜7.22(1H,m),7.80 (1H,s),7.89(1H,s), 7.89(1H,brs),8.43(1H,brs).