Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:29]3[CH:34]=CC(OC(F)(F)F)=C[CH:30]=3)=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[N:40]1C=C(B(O)O)C=[N:42][CH:41]=1>>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[C:13]([C:29]3[CH:34]=[N:40][CH:41]=[N:42][CH:30]=3)=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:9][CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2-c2ccc(OC(F)(F)F)cc2)CC1
Reactant: OB(O)c1cncnc1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2-c2cncnc2)CC1

Procedure:
(R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(pyrimidin-5-yl)naphthalen-2-yl)-4-methyloxazolidin-2-one was synthesized as per (R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-(trifluoromethoxy)phenyl)naphthalen-2-yl)-4-methyloxazolidin-2-one (Example 220) in 85% yield using pyrimidin-5-ylboronic acid (0.0885 g, 0.000714 mol) as the reagent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[N:24]=[N:23][C:22]([NH:25][NH:26]C(=O)CC2CCOCC2)=[CH:21][C:20]=1[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:26][NH:25][C:22]2[N:23]=[N:24][C:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[Cl:12])=[C:20]([C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=3)[CH:21]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(CC1CCOCC1)NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nn1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Product: O=C(Cc1ccc(Cl)cc1)NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nn1
Yield: 62 %

Procedure:
The title compound (90 mg, 62%) as a white solid was prepared from 2-(4-chlorophenyl)acetic acid (62 mg, 0.36 mmol) and 1-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3)hydrazine (99 mg, 0.3 mmol) according to the procedures described for N′-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3-yl)-2-(tetrahydro-2H-pyran-4-yl)acetohydrazide (Example 9A). HPLC/MS (method A): retention time 3.57 min, (M+H)+ 483.2.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:18]=[N:19][C:20](F)=[C:21]([CH3:23])[CH:22]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[O:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30]>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([N:27]4[CH2:28][CH2:29][O:25][C:26]4=[O:30])=[N:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=C1NCCO1
Reactant: Cc1cnc(N2CCN(C(=O)c3cnc(F)c(C)c3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3cnc(N4CCOC4=O)c(C)c3)CC2)c(C)c1
Yield: 38.5 %

Procedure:
By reaction and treatment in the same manner as in Example 240 and using [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](6-fluoro-5-methylpyridin-3-yl)methanone (529 mg) described in Preparation Example 148 and oxazolidin-2-one (281 mg), the title compound (245 mg) was obtained.
Reaction SMILES: C(OC(=O)[N:7]([C:16]1[CH:21]=[CH:20][C:19](Br)=[C:18]([F:23])[N:17]=1)[CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([F:15])[CH:14]=1)(C)(C)C.C(OC(=O)[N:31]([C:40]1[CH:45]=[CH:44][C:43](Br)=[C:42](F)[N:41]=1)[CH2:32][C:33]1[CH:38]=CC(Cl)=CC=1)(C)(C)C>>[F:15][C:13]1[CH:14]=[C:9]([CH2:8][NH:7][C:16]2[CH:21]=[CH:20][C:19]([CH2:38][C:33]3[C:45]4[C:40](=[N:41][CH:42]=[CH:43][CH:44]=4)[NH:31][CH:32]=3)=[C:18]([F:23])[N:17]=2)[CH:10]=[N:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(Cl)cc1)c1ccc(Br)c(F)n1
Reactant: CC(C)(C)OC(=O)N(Cc1cncc(F)c1)c1ccc(Br)c(F)n1
Product: Fc1cncc(CNc2ccc(Cc3c[nH]c4ncccc34)c(F)n2)c1

Procedure:
was prepared following the protocol of Scheme 201, replacing 5-bromo-6-fluoro-pyridin-2-yl)-(5-fluoro-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester 631 with (5-Bromo-6-fluoro-pyridin-2-yl)-(4-chloro-benzyl)-carbamic acid tert-butyl ester 637 (prepared as described in Example 60) in Step 4. MS (ESI) [M+H+]+=391.9.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][N:10]=2)=[CH:4][C:3]=1[O:18][CH3:19].O.[Cl-].[NH4+]>O1CCCC1.[Fe]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:18][CH3:19]
Reactant: COc1cc(Oc2ccc([N+](=O)[O-])cn2)ccc1C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Oc2ccc(N)cn2)ccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a solution of 2-{[4-methyl-3-(methyloxy)phenyl]oxy}-5-nitropyridine (Reference Intermediate R3, 568 mg) in tetrahydrofuran (25 mL)/water (12.50 mL), iron (609 mg, 10.91 mmol) and then ammonium chloride (584 mg, 10.91 mmol) were added and the reaction mixture was stirred for 8 hours at room temperature. The catalyst was filtered off and the solution was diluted with an aqueous saturated solution of Na2CO3 (5 mL) and extracted with ethyl acetate (2 times 40 mL). Combined organic layers were dried over sodium sulphate, filtered and evaporated and the residue was purified by silica gel chromatography (Biotage system with a 50 g SNAP column) using a as eluent a gradient cyclohexane/ethyl acetate from 8/2 to 1/1. Evaporation afforded the title compound as light yellow oil (465 mg).
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[N:5]=[N:6][CH:7]=[C:8]([O:10][Si](C)(C)C)[N:9]=1.Cl[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1>CN(C)C=O>[O:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH:18]1[N:5]1[C:4](=[O:3])[N:9]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:8](=[O:10])[CH:7]=[N:6]1
Reactant: ClC1CCCCO1
Reactant: C[Si](C)(C)Oc1cnnc(O[Si](C)(C)C)n1
Solvent: CN(C)C=O
Product: O=c1cnn(C2CCCCO2)c(=O)n1C1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.6 %

Procedure:
3,5-Bis(trimethylsilyloxy)-1,2,4-triazine (2.5 g) and 2-chlorotetrahydropyran (1.8 g) are dissolved in dimethylformamide (1 ml), and the mixture is stirred overnight at room temperature and concentrated in vacuo. The residue is column-chromatographed over silica gel using a mixture of acetone/n-hexane (1/3) as an eluent. The first major fraction gives 1.0 g (40%) of 2,4-bis(tetrahydro-2-pyranyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine (Compound No. 87) (yield, 1.0 g; 36%), the second gives 4-(tetrahydro-2-pyranyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine (Compound No. 88) (yield, 0.8 g; 40%) and the third gives 2-(tetrahydro-2-pyranyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine (Compound No. 100) (yield, 0.6 g; 30%). Compound Nos. 87 and 88 melt at 32° C. and 116° C., respectively.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[O:11])OC(=O)[NH:7][C:6]=2[CH:13]=1.[CH:14]([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)([CH2:16][CH3:17])[CH3:15]>CN(C=O)C>[NH2:7][C:6]1[CH:13]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[C:10]([NH:22][C:21]1[CH:23]=[CH:24][C:18]([CH:14]([CH2:16][CH3:17])[CH3:15])=[CH:19][CH:20]=1)=[O:11]
Reactant: CCC(C)c1ccc(N)cc1
Reactant: O=c1[nH]c2cc(F)ccc2c(=O)o1
Solvent: CN(C)C=O
Product: CCC(C)c1ccc(NC(=O)c2ccc(F)cc2N)cc1
Temperature: 116 °C

Procedure:
To a solution of 7-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (1.00 g, 5.52 mmol) in anhydrous DMF (15 mL), 4-(sec-butyl)-aniline (B) (0.824 g, 5.52 mmol) was added and the reaction mixture was heated at 116° C. for 16 hours. The product was extracted with ethyl acetate and washed with brine. The solvent was evaporated in vacuo to leave a crude material which was purified by column chromatography (silica gel; 230-400 mesh; ethyl acetate/hexane=1:9) to give 2-amino-N-(4-sec-butyl-phenyl)-4-fluoro-benzamide (N) as white solid. Yield: 0.92 g (58%).
Reaction SMILES: [Br:1][C:2]1[N:3]([CH3:12])[C:4]2[C:9]([N:10]=1)=[C:8](Cl)[N:7]=[CH:6][N:5]=2.C(N(C(C)C)CC)(C)C.Cl.[C:23]([C:25]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)#[N:24]>CN(C=O)C>[Br:1][C:2]1[N:3]([CH3:12])[C:4]2[C:9]([N:10]=1)=[C:8]([N:28]1[CH2:27][CH2:26][C:25]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:23]#[N:24])[CH2:30][CH2:29]1)[N:7]=[CH:6][N:5]=2
Reactant: Cn1c(Br)nc2c(Cl)ncnc21
Reactant: N#CC1(c2ccccc2)CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1c(Br)nc2c(N3CCC(C#N)(c4ccccc4)CC3)ncnc21
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
8-bromo-6-chloro-9-methyl-9H-purine (200 mg, 0.80 mmol) was dissolved in DMF (4 mL). To this solution was added diisopropylethylamine (0.21 mL, 1.21 mmol). To this stirred mixture was added 4-cyano-4-phenylpiperidine hydrochloride (165 mg, 0.88 mmol) dissolved in a small amount of DMF. The resulting mixture was heated to 70° C. and stirred for 30 minutes. The solvent was removed in vacuo and the crude material was used without purification.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([O:26][CH3:27])=[O:25])=[CH2:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][C:2]1[C:3]([CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([O:26][CH3:27])=[O:25])[CH3:17])=[CH:4][C:5]2[C:6]([CH3:14])([CH3:15])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: [H][H]
Reactant: C=C(c1cc2c(cc1C)C(C)(C)CCC2(C)C)c1ccccc1C(=O)OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1C(C)c1cc2c(cc1C)C(C)(C)CCC2(C)C

Procedure:
A solution of methyl 2-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)vinyl]phenylcarboxylate (3.5 g, 9.7 mmol) in ethyl acetate, in the presence of palladium-on-charcoal (900 mg) at a pressure of 6 bar of hydrogen, is stirred at room temperature for 4 h. The mixture is filtered through Celite and then concentrated on a rotary evaporator under vacuum at 40° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Br:16][C:17]1[CH:32]=[C:31]([Br:33])[CH:30]=[C:19]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=2)=[O:21])[C:18]=1[OH:34]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Br:29][C:26]1[CH:25]=[CH:24][C:23]([NH:22][C:20](=[O:21])[C:19]2[CH:30]=[C:31]([Br:33])[CH:32]=[C:17]([Br:16])[C:18]=2[O:34][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:28][CH:27]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(Nc1ccc(Br)cc1)c1cc(Br)cc(Br)c1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3c(Br)cc(Br)cc3C(=O)Nc3ccc(Br)cc3)c2cc1OC
Temperature: 120 °C
Reaction time: 8 h
Yield: 5.1 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (116 mg), 3,5,4′-tribromosalicylanilide (900 mg), and 4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (17 mg, yield 6%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[C:10]([C:14]([OH:16])=[O:15])[CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](I)[CH3:24].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([CH3:13])=[C:10]([C:14]([O:16][CH2:23][CH3:24])=[O:15])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCI
Reactant: Cc1oc(-c2ccc(Cl)cc2)cc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(-c2ccc(Cl)cc2)oc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.1 %

Procedure:
A mixture of 5-(4-chlorophenyl)-2-methyl-3-furancarboxylic acid (4.7 g), potassium carbonate (2.8 g) and ethyl iodide (3.7 g) in N,N-dimethylformamide (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane) to give the title compound (5.0 g, 95%) as a yellow crystal.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH2:13][NH:14][C:15]([C:17]3[S:21][C:20](Br)=[N:19][C:18]=3[C:23]([F:26])([F:25])[F:24])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:2]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH2:13][NH:14][C:15]([C:17]3[S:21][C:20]([C:32]4[CH:31]=[N:30][C:29]([O:28][CH3:27])=[CH:34][CH:33]=4)=[N:19][C:18]=3[C:23]([F:26])([F:25])[F:24])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:2]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: O=C(NCC1(c2cccnc2)CCCCC1)c1sc(Br)nc1C(F)(F)F
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2nc(C(F)(F)F)c(C(=O)NCC3(c4cccnc4)CCCCC3)s2)cn1
Temperature: 110 °C

Procedure:
A mixture of 2-bromo-4-trifluoromethyl-thiazole-5-carboxylic acid (1-pyridin-3-yl-cyclohexylmethyl)-amide (44.8 mg), 2-methoxy-5-pyridineboronic acid (30.6 mg), Pd(PPh3)4 (5.8 mg) and Na2CO3 (42.4 mg) in dioxane (2 mL) and water (0.8 mL) is heated at 110° C. in an argon purged sealed vial for 2 h. The mixture is poured into water and extracted with EtOAc. The extract is concentrated and the residue is purified by PTLC (silica gel, 5% MeOH in methylene chloride) to give the title compound. MS (M+1)=477.19; RT=1.19 min. *IC50.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[N:7]([CH3:23])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:24]Br.O>C(O)(=O)C>[Br:24][C:9]1[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6][N:7]([CH3:23])[C:8]=1[NH:10][C:11]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1cc(OC)ccc1Nc1cc(C(C)(C)C)nn1C
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc(OC)ccc1Nc1c(Br)c(C(C)(C)C)nn1C
Reaction time: 0.08 h

Procedure:
To a solution of 2-(5-tert-butyl-2-methyl-2H-pyrazol-3-ylamino)-5-methoxy-benzoic acid methyl ester (Example 155, 1.34 g, 4.22 mmol) in acetic acid (27 mL), was added dropwise a solution of Br2 (6.74 g, 4.22 mmol) in acetic acid (5 mL). The reaction was stirred for 5 min, and then water (100 mL) was added. The aqueous phase was extracted with EtOAc, and the combined organic layers were washed with water, and then with NaHCO3 (10% aqueous solution) 10 times. The organic layer was then dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 5 to 10% EtOAc in hexane) to give the title compound as a light yellow solid. (1.49 g, 89%). 1H NMR (400 MHz, CDCl3) δ 1.40 (s, 9H), 3.66 (s, 3H), 3.78 (s, 3H), 4.05 (s, 3H), 6.32 (d, 1H), 7.06 (dd, 1H), 7.48 (d, 1H).
Reaction SMILES: [OH-].[K+].[CH:3]1([CH2:9]Br)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[Cl:11][C:12]1[CH:30]=[CH:29][C:15]([O:16][CH2:17][C:18]([CH3:28])([CH3:27])[C:19](=[O:26])[CH2:20][N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)=[CH:14][CH:13]=1>O.CS(C)=O>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]([CH3:27])([CH3:28])[C:19](=[O:26])[CH:20]([N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)[CH2:9][CH:3]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)=[CH:29][CH:30]=1
Reactant: CC(C)(COc1ccc(Cl)cc1)C(=O)Cn1cncn1
Reactant: BrCC1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(COc1ccc(Cl)cc1)C(=O)C(CC1CCCCC1)n1cncn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 47.7 %

Procedure:
First 5.6 g of potassium hydroxide in 12 ml of water and then 17.7 g (0.1 mol) of cyclohexylmethylbromide in 5 ml of dimethylsulphoxide were added dropwise to 29.3 g (0.1 mol) of 1-(4-chlorophenoxy)-2,2-dimethyl-4-(1,2,4-triazol-1-yl)-butan-3-one (prepared as described in Example 3) in 100 ml of dimethylsulphoxide at 20° C. The reaction mixture was subsequently stirred at room temperature for 15 hours, poured into 200 ml of water and extracted with 200 ml of methylene chloride. The organic phase was washed three times with 100 ml of water each time, dried over sodium sulphate and concentrated by distilling off the solvent. The residue was taken up in 100 ml of ether, whereupon the product crystallized out. 18.6 g (47% of theory) of 1-(4-chlorophenoxy)-5-cyclohexyl-2,2-dimethyl-4-(1,2,4-triazol-1-yl)-pentan-3-one of melting point 58°-60° C. were obtained.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9](=O)[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:12](=[NH:17])(OCC)[CH3:13].C(N(CC)CC)C>C(O)C>[CH3:13][C:12]1[NH:2][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:9]([CH3:10])[N:17]=1
Reactant: CCOC(C)=N
Reactant: CCOC(=O)C(N)C(C)=O
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1[nH]c(C)nc1C
Reaction time: 8 h
Yield: 23.8 %

Procedure:
Ethyl 2-amino-3-oxobutanoate hydrochloride (5 g) was added portionwise to a solution of ethyl ethaneimidate (34.0 g) and triethylamine (42 ml) in ethanol (500 ml), and the resulting yellow solution was stirred overnight. Solvent was removed in vacuo and the residue partitioned between water (200 ml) and ether (200 ml). The organic layer was separated and the aqueous phase further extracted with ether (2×200 ml). The dried organic extracts were evaporated in vacuo and the residue washed with cold ether and filtered to give the title compound as a white solid (1.1 g). m.p. 165-166° C.
Reaction SMILES: [C:1]([O:7][CH2:8]Br)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:10]([S:12]([C:14]1[S:15][C@@H:16]2[C@H:23]([C:24]([OH:27])([CH3:26])[CH3:25])[C:22](=[O:28])[N:17]2[C:18]=1[C:19]([O-:21])=[O:20])=[O:13])[CH3:11].[Li+]>CN(C=O)C.CCOC(C)=O>[CH2:10]([S:12]([C:14]1[S:15][C@@H:16]2[C@H:23]([C:24]([OH:27])([CH3:25])[CH3:26])[C:22](=[O:28])[N:17]2[C:18]=1[C:19]([O:21][CH2:8][O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[O:20])=[O:13])[CH3:11]
Reactant: CCS(=O)C1=C(C(=O)[O-])N2C(=O)[C@@H](C(C)(C)O)[C@H]2S1
Reactant: CC(C)(C)C(=O)OCBr
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCS(=O)C1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)[C@@H](C(C)(C)O)[C@H]2S1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Pivaloyloxymethyl bromide (29.3 mg, 0.15 mmol) is added to a suspension of lithium (5R,6R)-2-ethylsulfinyl-6-(2-hydroxy-2-propyl)-pen-2-em-3-carboxylate (29.5 mg, 0.1 mmol) in anhydrous DMF (0.5 ml). The resulting mixture is stirred under a N2 atmosphere at room temperature for 4 hours. The mixture is diluted with EtOAc, washed repeatedly with water, dried with MgSO4, filtered, and evaporated under vacuum to afford a residue of the title compound. This material is purified by preparative TLC.
Reaction SMILES: FC(F)(F)S(O[C@H:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9])(=O)=O.[NH2:15][C:16](C)([CH3:19])[CH2:17]O.C([O-])(O)=O.[Na+].CCOC(C)=O>C(Cl)Cl>[CH3:12][C@H:7]1[C:8](=[O:9])[O:10][CH2:11][C:16]([CH3:19])([CH3:17])[NH:15]1
Reactant: COC(=O)[C@@H](C)OS(=O)(=O)C(F)(F)F
Reactant: CC(C)(N)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@@H]1NC(C)(C)COC1=O
Temperature: -40 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
A solution of triflate 14 (5.00 g, 0.021 mol) in anhydrous CH2Cl2 (80 mL) under an N2 atmosphere, was cooled to −40° C. and was treated with a solution of 2-amino-2-methyl-1-propanol (2.5 folds, 4.68 g, 0.0525 mol) in anhydrous CH2Cl2 (10 mL). After stirring for 2 h at −40° C., the reaction mixture was warmed slowly to 0° C. then to room temperature and stirred overnight. The reaction mixture was treated with saturated aqueous NaHCO3 solution (100 mL). The organic phase was washed (water, brine), separated, and dried (Na2SO4). The aqueous layer was extracted with EtOAc (twice). The organic layer was separated, washed (water, brine) and dried (Na2SO4). The organic extracts were combined and concentrated to give a yellow oil. Column chromatography on silica gel using hexanes-EtOAc (1:2) to EtOAc gave 1.88 g (63%) of 15 as a light yellow oil: [α]23D −75° (c 1.0, CHCl3); 1H NMR (CDCl3) δ 4.11 (s, 2H), 3.71 (q, 1H, J=6.8), 1.39 (d, 3H, J=6.8 Hz), 1.26 (s, 3H), 1.18 (s, 3H); 13C NMR (CDCl3) δ 229.2, 77.6, 49.5, 49.3, 27.2, 24.2, 18.4; LCMS (APCI) m/z 144.3 [(M+H)+, M=C7H13NO2]; Anal. (C7H13NO2) calcd: C, 58.72; H, 9.15; N, 9.78. found: C, 58.60; H, 9.35; N, 9.79. Note: 1H NMR data is similar with the data reported in the literature for the racemic compound (Koch, T. H.; Olesen, J. A.; DeNiro, J., J. Am. Chem. Soc. 1975, 97, (25), 7285-7288).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C:12](=[O:24])[CH2:13][NH:14][C@@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:16][OH:17])=[CH:11][C:5]=2[CH2:4][O:3]1.[BH4-].[Na+]>CO.C(#N)C>[CH3:1][C:2]1([CH3:25])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:24])[CH2:13][NH:14][C@@H:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:16][OH:17])=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: CC1(C)OCc2cc(C(=O)CN[C@H](CO)c3ccccc3)ccc2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CC1(C)OCc2cc([C@@H](O)CN[C@H](CO)c3ccccc3)ccc2O1
Temperature: 0 °C
Yield: 52.9 %

Procedure:
To a cooled mixture (internal temp. 2° C.) of 1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-{[(1S)-2-hydroxy-1-phenylethyl]amino}ethanone (44.9 g) in methanol (450 ml) under nitrogen was added CaCl2.2H2O (38.7 g) in one portion resulting in a slight exotherm (max temp ˜12° C.). After the resulting clear solution had cooled to 0° C., sodium borohydride (10.5 g) was added in four portions over a 50 min period. After a further 2h at this temperature the volatile material was removed in vacuo resulting in a thick white slurry, to which ethyl acetate (500 ml) was added. The mixture was filtered through a short plug of Hyflo Supercel and the filtrate washed with water (150 ml), brine (150 ml), dried (Na2SO4) and concentrated in vacuo to give a thick orange oil. The oil was dissolved in acetonitrile (150 ml) and cooled to 5° C. for 18 h. The resulting crystals were filtered and washed with acetonitrile (3×30 ml) to give the title compound (23.9 g). The mother liquor from the filtration was concentrated in vacuo and taken up in acetonitrile (50 ml), cooled to 5° C. for 18 h to provide (after filtration and washing) a second crop of the title compound (3.4 g).
Reaction SMILES: [OH:1][CH:2]([CH2:5][NH2:6])[CH2:3][NH2:4].[ClH:7].[NH2:8][C:9](N)=N.CC(O)C>CC#N>[ClH:7].[NH:8]=[C:9]1[NH:6][CH2:5][CH:2]([OH:1])[CH2:3][NH:4]1
Reactant: NCC(O)CN
Reactant: N=C(N)N
Agent: Cl
Solvent: CC(C)O
Solvent: CC#N
Product: N=C1NCC(O)CN1
Temperature: 140 °C

Procedure:
A mixture of 2-hydroxy -1,3-diaminopropane (9.80 g, 108 mmol) and guanidine hydrochloride (10.4 g, 108 mmol) in a 100 mL RBF was heated at 140° C. under nitrogen for 5 h. The reaction mixture, while under vigorous stirring, was let cooled to 100° C. whereby a mixture of iPrOH (5 mL) and CH3CN (5 mL) were added, resulting in the formation of a slurry. After cooled to room temperature, the mixture was filtered and the solid was washed with additional CH3CN (total 30 mL). The solid was further dried under vacuum to yield a white solid. 1H NMR (400 MHz, D2O): 4.21 (m, 1 H), 3.34 (dt, J 15.2, 2.8, 2H), 3.22 (dt, J 15.2, 2.8).