Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([NH:23][C:30]([CH:27]4[CH2:29][CH2:28]4)=[O:31])[CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17]2)[N:3]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: O=C(Cl)C1CC1
Product: Cc1ccc2c(N3CCN(CCc4cccc(NC(=O)C5CC5)c4)CC3)cccc2n1
Yield: 70 %

Procedure:
The title compound was prepared in 70% yield according to the general procedure for the preparation of the amides (Method B) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and cyclopropanecarbonyl chloride.
Reaction SMILES: N1C=CC=CC=1.[C:7]([O:12][CH2:13][CH2:14][O:15][CH:16](O)[C:17]([Cl:20])([Cl:19])[Cl:18])(=[O:11])[C:8]([CH3:10])=[CH2:9].O=CC(Cl)(Cl)[Cl:25].CC(C(OCCO)=O)=C>C(OCC)C.S(Cl)(Cl)=O>[C:7]([O:12][CH2:13][CH2:14][O:15][CH:16]([Cl:25])[C:17]([Cl:20])([Cl:19])[Cl:18])(=[O:11])[C:8]([CH3:10])=[CH2:9]
Reactant: C=C(C)C(=O)OCCOC(O)C(Cl)(Cl)Cl
Reactant: O=CC(Cl)(Cl)Cl
Agent: C=C(C)C(=O)OCCO
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: C=C(C)C(=O)OCCOC(Cl)C(Cl)(Cl)Cl
Temperature: 20 °C

Procedure:
Pyridine (75 ml) in 500 ml of diethyl ether and 65 ml of thionyl chloride are mixed while being stirred and cooled by an ice-water bath in a flask provided with a mechanical stirrer, a reflux condenser and a dropping funnel. A solution of 220 g of crystalline 2-(1-hydroxy-2,2,2-trichloroethoxy)ethyl methacrylate (m.p. 44-45° C; prepared by the addition of chloral to glycol monomethacrylate) in 500 ml of diethyl ether is slowly added to the mixture during continuous stirring and cooling. After all of the hydroxy compound has been added into the reactor, the reaction mixture is stirred and cooled for further 2 hours. It is then warmed to the temperature 20° C, the precipitated pyridine hydrochloride is filtered off and ether is removed by distillation. The distillation residue is heated in the presence of 20 g of powdered copper to the temperature 80° C at the pressure 15 Torr for 2 hrs and then it is rectified through an effective column. By a repeated fraction distillation, 180 g of 2-(1,2,2,2-tetrachloroethoxy)ethyl methacrylate was obtained, having b.p. 96 - 97° C 0.1 Torr and refractive index nD25 1.4900. Elemental analysis: found C 32.20%, H 3.58%, Cl 47.35%; calculated C 32.46%, H 3.40%, Cl 47.90%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)N=N[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[C:27]1(C)C=CC(C)=C[CH:28]=1.C12CC(C=C1)C=C2>O>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[CH:27]=[CH:28][C:10]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[N:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:15][CH:16]=1
Reactant: Brc1ccc(-c2nnc(-c3ncccn3)nc2-c2ccc(Br)cc2)cc1
Reactant: Cc1ccc(C)cc1
Agent: C1=CC2C=CC1C2
Solvent: O
Product: Brc1ccc(-c2ccc(-c3ncccn3)nc2-c2ccc(Br)cc2)cc1

Procedure:
In a 200 mL three-neck flask were put 2.4 g (5.0 mmol) of 5,6-bis(4-bromophenyl)-3-(pyrimidin-2-yl)-1,2,4-triazine, 60 mL of para-xylene, 2.1 mL (19 mmol) of 2,5-Norbornadiene, and the mixture was refluxed under a nitrogen gas stream at 150° C. for 12 hours. After a certain time, water was added to the mixture, and an aqueous layer was extracted with toluene. The extract was washed with a saturated saline together with the organic layer, and the organic layer was then dried over magnesium sulfate. The mixture was subjected to gravity filtration, and the obtained filtrate was concentrated to give a solid. The obtained solid was recrystallized with chloroform/hexane, so that 1.6 g of a target substance, light-yellow solid was obtained in a yield of 67%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.[C:24]([O:28][C:29](=[O:38])[NH:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33][CH2:32]1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29](=[O:38])[NH:30][CH:31]1[CH2:32][CH2:33][CH:34]([NH:37][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:9])[C:10]3[CH:15]=[C:14]([F:16])[C:13]([CH3:17])=[CH:12][C:11]=3[O:18][CH3:19])=[CH:6][N:5]=2)[CH2:35][CH2:36]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CCS(=O)c1ncc(C(=O)c2cc(F)c(C)cc2OC)c(N)n1
Product: COc1cc(C)c(F)cc1C(=O)c1cnc(NC2CCC(NC(=O)OC(C)(C)C)CC2)nc1N

Procedure:
The same procedure as described in Example 326 was used, starting with (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(5-fluoro-2-methoxy-4-methyl-phenyl)-methanone (Example 341) and (trans4-amino-cyclohexyl)-carbamic acid tert-butyl ester (Astatech) to give [4-[4-amino-5-(5-fluoro-2-methoxy-4-methyl-benzoyl)-pyrimidin-2-ylamino]-cyclohexyl]-carbamic acid tert-butyl ester as a white solid. MS (M+H)+, 474
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][CH:7]([CH2:9][CH:10]=[O:11])[CH3:8])[CH3:3].S(=O)(=O)(O)[OH:13]>>[CH:7]1([CH3:8])[CH2:6][CH2:5][CH:4]([C:2]([OH:13])([CH3:3])[CH3:1])[CH:10]([OH:11])[CH2:9]1
Reactant: CC(C)=CCCC(C)CC=O
Reactant: O=S(=O)(O)O
Product: CC1CCC(C(C)(C)O)C(O)C1

Procedure:
The above-mentioned problems are resolved by the production method of this invention wherein citronellal is treated with aqueous sulfuric acid solution of 0.02 to 1.0 wt. % in concentration to produce para-menthane-3,8-diol. In case of recovering the produced para-menthane-3,8-diol, a method is preferably adopted, wherein after the reaction product is extracted with an aliphatic hydrocarbon solvent of 5 to 8 in carbon number, the extract is cooled down at temperature higher than the melting point of said aliphatic hydrocarbon solvent and of -10° C. or less to crystallize para-menthane-3,8-diol.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH3:23][C:24]1[S:28][C:27]([C:29](=O)[CH2:30][NH:31][C:32](=O)[C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)=[CH:26][CH:25]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:23][C:24]1[S:28][C:27]([C:29]2[S:10][C:32]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=3)=[N:31][CH:30]=2)=[CH:26][CH:25]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1ccc(C(=O)CNC(=O)c2ccc(C(F)(F)F)cc2)s1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1ccc(-c2cnc(-c3ccc(C(F)(F)F)cc3)s2)s1
Temperature: 25 °C
Reaction time: 48 h
Yield: 53.9 %

Procedure:
To a stirred suspension of Lawesson's Reagent (2.3 g, 0.0057 mole) in approximately 40 ml of toluene was added a mixture of N-[2-(5-methylthienyl)-2-oxoethyl]-4-trifluoromethylbenzamide (3.0 g, 0.011 mole) in toluene (35 ml). After complete addition the reaction mixture was heated at reflux for approximately four hours, then was allowed to cool to room temperature and stirred for two days. The solvent was removed from the reaction mixture by evaporation under reduced pressure, leaving an oil. The oil was dissolved in a small amount of methylene chloride and purified by column chromatography on silica gel, eluting with methylene chloride, yielding 1.0 g of 5-(5-methylthien-2-yl)-2-(4-trifluoromethylphenyl)thiazole as a solid, m.p. 150°-152° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13]C)=[O:12])=[CH:6][CH:5]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Br>O1CCCC1>[F:15][C:16]1[CH:17]=[C:18]([CH2:19][CH:10]([C:7]2[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=2)[C:11]([OH:13])=[O:12])[CH:21]=[CH:22][CH:23]=1
Reactant: Fc1cccc(CBr)c1
Reactant: COC(=O)Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)C(Cc1cccc(F)c1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 62.9 %

Procedure:
To a solution of 10.8 g of 60% sodium hydride in 400 mL of tetrahydrofuran was added 44.7 g of methyl 4-fluorophenylacetate dropwise. Then, 50 g of 3-fluorobenzyl bromide was added dropwise. The mixture was then heated to reflux for approximately 18 hours. After this time, the reaction was cooled to room temperature and filtered. The filtrate was partitioned between ether and 5% aqueous sodium bicarbonate, and the ether extracts were dried over magnesium sulfate and concentrated to 77.57 g of a yellow oil. The crude product was combined with 275 mL of methanol, 20 mL of 50% aqueous NaOH and 50 mL of H2O and the mixture was refluxed for about 18 hours. The reaction was then cooled to room temperature, concentrated and partitioned between water and ether. The aqueous extracts were made acidic with concentrated HCl and extracted with ether. The ether extracts were dried over MgSO4, filtered, concentrated and the crude product was triturated with hexane to afford 43.62 g of a white solid; mp 92°-94° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[S:14][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:16][C:11]3=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.CCOCC>C(Cl)Cl>[CH3:27][O:28][C:29]1[CH:30]=[CH:31][C:32]([S:35]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[N:13]=[C:12]4[S:14][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:16][C:11]4=[CH:10][CH:9]=3)[CH:5]=[CH:6][CH:7]=2)(=[O:37])=[O:36])=[CH:33][CH:34]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)Nc1nc2ccc(-c3cccc(N)c3)nc2s1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)Nc2cccc(-c3ccc4nc(NC(C)=O)sc4n3)c2)cc1
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 38.2 %

Procedure:
N-(5-(3-aminophenyl)thiazolo[5,4-b]pyridin-2-yl)acetamide (102.6 mg, 0.361 mmol) was suspended in DCM (2.7 ml) and pyridine (0.050 ml, 0.61 mmol) and 4-methoxybenzene-1-sulfonyl chloride (107.2 mg, 0.519 mmol) were added. The reaction was stirred under nitrogen at room temperature for about 100 minutes. The, reaction was treated with Et2O and filtered. Solid washed with Et2O, MeOH, and Et2O, then collected and purified on HPLC (10% to 95% MeCN/water with 0.1% TFA over 30 minutes) to afford N-(5-(3-(4-methoxyphenylsulfonamido)phenyl)thiazolo[5,4-b]pyridin-2-yl)acetamide (62.7 mg, 38% yield). MS (ESI pos. ion) m/z: 455. Calculated exact mass for C21H18N4O4S2 454.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:30][CH3:31])[C:25](OCC)=[O:26])[C:5]1=[O:32])[CH:2]=[CH2:3].[N+](=[CH:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[N-]>C(Cl)Cl.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[CH2:1]([C@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:30][CH3:31])[CH2:25][O:26][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:5]1=[O:32])[CH:2]=[CH2:3]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(=O)OCC)C1=O
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)COCC(=O)OCC)C1=O

Procedure:
To a solution of 203 mg (0.47 mmol) of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)piperidin-2-one (Example 9, Step B) and rhodium(II)acetate dimmer (10.4 mg, 0.047 mmol) in CH2Cl2 (1.90 mL) was added dropwise ethyl diazoacetate (286 μL, 2.35 mmol) at 25° C. After being stirred at 25° C. for 14h, the reaction was concentrated under reduced pressure and purified by chromatography on silica gel (20% to 30% EtOAc/Hexanes, gradient elution) to provide the title compound as a colorless liquid:
Reaction SMILES: [N+:1]([C:4]([N+:8]([O-:10])=[O:9])(O)[CH2:5]C)([O-:3])=[O:2].[CH2:11]([CH:17]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:18]([OH:20])=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl[CH:30](Cl)C>>[N+:1]([C:4]([N+:8]([O-:10])=[O:9])([CH3:5])[CH2:30][O:19][C:18](=[O:20])[CH:17]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([O-:3])=[O:2]
Reactant: CCC(O)([N+](=O)[O-])[N+](=O)[O-]
Reactant: CC(Cl)Cl
Reactant: CCCCCCCCC(CCCCCC)C(=O)O
Product: CCCCCCCCC(CCCCCC)C(=O)OCC(C)([N+](=O)[O-])[N+](=O)[O-]
Temperature: 70 °C
Yield: 60 %

Procedure:
Dinitropropanol (25.5 g, 0.17 mol), 2-hexyldecanoic acid (48.7 g, 0.19 mol) and 50 g of polyphosphoric acid were added to 50 mL of dichloroethane and the resulting mixture was slowly stirred using a stirrer. The solution thus obtained was slowly heated to 70° C. and then reacted for 15 hr (overnight). After the reaction, the temperature of the reactor was lowered to room temperature, and the stirrer was powered off. When the temperature of the reactor was room temperature, the dichloroethane layer was decanted, followed by extraction with a 1 N sodium hydroxide aqueous solution and then distillation under reduced pressure, affording 2,2-dinitropropyl-2-hexyldecanoate (39.6 g, yield: 60%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([CH:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].[B-](F)(F)(F)[F:24].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([F:24])([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])=[CH:4][CH:3]=1
Reactant: F[B-](F)(F)F
Reactant: CCOC(=O)C(C(=O)OC(C)(C)C)c1ccc(Cl)nn1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(C(=O)OC(C)(C)C)c1ccc(Cl)nn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76.4 %

Procedure:
To a solution of 1-tert-butyl 3-ethyl 2-(6-chloropyridazin-3-yl)malonate 45A (86.5 g, 288 mmol) in THF (2400 mL) was added NaH (12.65 g, 316 mmol). The reaction was stirred at 0° C. for 15 min. A cloudy solution of Selectfluor (112 g, 316 mmol) in DMF (dry, 800 mL) was added drop-wise at 0° C. and then the reaction was allowed to warm to ambient temperature over a 2 hrs. The reaction was then quenched with saturated NH4Cl (250 mL) and reduced in volume to about 1500 mL. To this mixture, Et2O (300 mL) and water (50 mL) were added. Layers were separated, and the aqueous layer was extracted with Et2O (3×300 mL). The combined organic layers were then washed with saturated NaHCO3 solution (3×150 mL), dried with MgSO4, filtered, and concentrated to dryness via rotary evaporation. The residue was purified via MPLC (Hex:EtOAc, 8:2) to provide 1-tert-butyl 3-ethyl 2-(6-chloropyridazin-3-yl)-2-fluoromalonate 45B (70.2 g, 220 mmol, 77%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.24 (t, J=7.20 Hz, 3 H) 1.46 (s, 9 H) 4.28-4.43 (m, 2 H) 8.14 (s, 2 H). ESI-MS:m/z 319.2 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:5])[CH3:4].C=O.[C:8]([OH:11])(=[O:10])[CH3:9]>>[C:3]([N:2]([CH2:9][C:8]([OH:11])=[O:10])[CH3:1])(=[O:5])[CH3:4]
Reactant: CC(=O)O
Reactant: CNC(C)=O
Agent: C=O
Product: CC(=O)N(C)CC(=O)O
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A 1 L autoclave was charged with N-methylacetamide (IX) (160 g, 2.2 mole), Co(OAc)2.4H2O (33 g, 0.13 mole), and acetic acid (1 L). After sealing the autoclave, 2200 psi (15,172 kPa) CO:H2 (70:30) was established at 25° C. with stirring at 2000 rpm. The contents of the autoclave were heated to 130° C. and 3200 psi (22,069 kPa) CO:H2 (70:30) was established. After approximately 0.5 h, rapid gas uptake was observed. The reaction mass was cooled to 85° C. Under a constant 3200 psi (22,069 kPa), 47 Wt. % formalin (180 mL, 2.97 mole) was delivered at 6 mL/min. The reaction was stirred at 85° C. for 30 min. after the formalin addition was complete. Then the reaction was cooled to 25° C., removed from the autoclave, and assayed for N-acetylsarcosine. This resulted in a 92% yield of (XX).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]([NH:38]C(OC(C)(C)C)=O)[CH2:15][C@H:16]([OH:37])[C@@H:17]([NH:25][C:26](=[O:36])[C@H:27]([CH:33]([CH3:35])[CH3:34])[NH:28][C:29]([O:31][CH3:32])=[O:30])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:9][CH:8]=1.CO.[ClH:48]>O1CCOCC1>[ClH:48].[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]([CH2:13][N:14]([NH2:38])[CH2:15][C@H:16]([OH:37])[C@@H:17]([NH:25][C:26](=[O:36])[C@H:27]([CH:33]([CH3:35])[CH3:34])[NH:28][C:29]([O:31][CH3:32])=[O:30])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:11][CH:12]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2cnccn2)cc1)NC(=O)OC(C)(C)C)C(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2cnccn2)cc1)C(C)C

Procedure:
3.4 g (5.5 mmol) of 1-[4-(pyrazin-2-yl)-phenyl]-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-N-(N-methoxycarbonyl-(L)-valyl)amino-6-phenyl-2-azahexane in 100 ml of 4 N hydrogen chloride in dioxane (Aldrich) and 10 ml of methanol are stirred at room temperature for 2 hours. The solvents are removed; dioxane is added twice to the residue and evaporated off. The title compound is obtained in the form of a viscous oil, with the compound crystallising out on trituration with ether. M.p.: 194-198° C. TLC: Rf =0.35 (methylene chloride/methanol 10:1). HPLC20-100 : tRet =9.77.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][CH:7]([C:13]([OH:15])=[O:14])[CH2:8][CH2:9][C:10]([OH:12])=[O:11].[CH3:16][CH:17](O)[CH3:18].[C:20]1(C)[CH:25]=CC=C[CH:21]=1>>[NH2:6][C@H:7]([C:13]([O:15][CH:20]([CH3:25])[CH3:21])=[O:14])[CH2:8][CH2:9][C:10]([O:12][CH:17]([CH3:18])[CH3:16])=[O:11]
Reactant: NC(CCC(=O)O)C(=O)O
Reactant: Cc1ccccc1
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Product: CC(C)OC(=O)CC[C@H](N)C(=O)OC(C)C

Procedure:
(Buckley III, T. F.; Rapoport, H. J. Org. Chem. 1984, 48, 4222) Concentrated sulfuric acid (11 mL) was added to a suspension of d,l-glutamic acid (0.17 mol, 25 g) in 2-propanol/toluene (675 mL, 1/1). The solution was refluxed for 24 hours using a Soxhlet apparatus containing 3 Å molecular sieves, and then evaporated to approximately 100 mL. The residue was diluted with cold saturated NaHCO3 (300 mL), adjusted to pH 9.5 and extracted with CH2Cl2 (4×150 mL). The combined extracts were dried over Na2SO4 and concentrated in vacuo to give diisopropyl glutamate as an oil (38.6 g): 1H NMR (Buckley III, T. F.; Rapoport, H. J. Org. Chem. 1984, 48, 4222) (300 MHz) δ 5.04 (heptet, J=6.3 Hz, 1 H), 5.01 (heptet, J=6.3 Hz, 1 H), 3.41 (dd, J=8.6, 5.3 Hz, 1 H), 2.42 (t, J=7.7 Hz, 2 H), 2.05 (m, 1 H), 1.82 (m, 1 H), 1.26 (d, J=6.3 Hz, 6 H), 1.23 (d, J=6.3 Hz, 6 H); 13C NMR (75 MHz) δ 175.14, 172.67, 68.47, 67.72, 53.87, 31.00, 29.84, 21.78.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH3:12])=[C:6]([NH2:13])[CH:5]=1.[NH2:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([O:25][C:26]([F:29])([F:28])[F:27])[CH:22]=[CH:21][C:19]=2[N:20]=1.[C:30](N1C=CN=C1)(N1C=CN=C1)=S>C(Cl)CCl>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([CH2:11][CH3:12])[C:30]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([O:25][C:26]([F:29])([F:27])[F:28])[CH:22]=[CH:21][C:19]=4[N:20]=3)=[N:13][C:6]=2[CH:5]=1)=[O:14]
Reactant: CCNc1ccc(C(=O)OC)cc1N
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: CCn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)OC)ccc21
Yield: 54.9 %

Procedure:
1-Ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methyl ester (3.70 g) was prepared by following General Procedure D starting from 3-amino-4-ethylamino-benzoic acid methyl ester (3.0 g), 2-amino-6-(trifluoromethoxy)benzothiazole (4.4 g), 1,1′-thiocarbonyldiimidazole (3.5 g), and EDC (3.6 g). LCMS: m/z 438; and 1H NMR (DMSO-d6, 400 MHz): δ 8.25 and 8.05 (0.59 and 0.53, 1H, m), 7.93 (2H, m), 7.75 (1H, m), 7.59 (1H, m), 7.38-7.37 (1H, m), 4.25-4.23 (2H, m), 3.88 (3H, s), 1.35-1.31 (3H, t), —NH proton signal was not observed.
Reaction SMILES: O=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].C([O-])(=O)C.[NH4+:14].C[O-].[Na+]>CO>[NH2:14][C@H:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: [NH4+]
Reactant: CCC(=O)CC(=O)OC
Agent: CC(=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC[C@@H](N)CC(=O)OC
Temperature: 80 °C
Reaction time: 16 h
Yield: 63.5 %

Procedure:
Ru(OAc)2((R)-dm-segphos) (1.21 g, 1.28 mmol), methyl 3-oxopentanoate (50.0 g, 384 mmol), ammonium acetate (29.6 g, 384 mmol) and methanol (500 mL) were placed in a 1 L stainless steel autoclave under nitrogen atmosphere, and then the mixture was stirred under a hydrogen pressure of 3 MPa at 80° C. for 16 hours. After completion of the reaction, the solvent was removed by evaporation. To the residue, toluene (500 mL) was added, and then a 28% solution of sodium methoxide in methanol (66.7 g, 346 mmol) was added at room temperature. After the additions, the mixture was stirred at room temperature for 1 hour, and then the precipitate was filtered off. The filtrate was evaporated and the residue was then distilled to give methyl (3R)-3-aminopentanoate (32.0 g, colorless oil) in 63.5% yield. The enantiomeric excess of the product obtained above was determined to be 98.4% ee by HPLC analysis using a CHIRALCEL OD-H column after conversion into methyl (3R)-3-(4-nitrobenzoylamino)pentanoate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[C:21]([C:25](O)=[O:26])[N:22]([CH3:24])[CH:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.F[P-](F)(F)(F)(F)F.[N:42]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:46]2C=CC=CC=2N=N1.CN.C1COCC1.C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[C:21]([C:25]([NH:42][CH3:46])=[O:26])[N:22]([CH3:24])[CH:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1
Reactant: CC1Cc2ccc(-c3cc(C(=O)O)n(C)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)c1cc(-c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)C(C)C3)cn1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-1-methyl-1H-pyrrole-2-carboxylic acid (12.0 mg, 0.0260 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.0192 g, 0.0433 mmol) in DMF (0.5 mL) was stirred at r.t. for 3 min. and then methylamine in THF (2.0M, 0.2 mL, 0.4 mmol) was added. To this mixture, triethylamine (15.4 uL, 0.110 mmol) was slowly added and the mixture was stirred for 1 h at r.t. The mixture was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=475.3.
Reaction SMILES: [H-].[Na+].[C:3]([O:9]C)(=O)[C:4]([CH3:7])([CH3:6])[CH3:5].[C:11](#[N:13])[CH3:12].[H][H]>C1(C)C=CC=CC=1.O>[C:3]([CH2:12][C:11]#[N:13])(=[O:9])[C:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: COC(=O)C(C)(C)C
Reactant: [H][H]
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)CC#N
Temperature: 85 °C

Procedure:
55 grams of sodium hydride (as an 80 weight % suspension in white oil) were suspended in 500 ml of dry toluene, 106 grams (0.914 mole) of methyl pivalate added and the mixture heated to 85° C. Then under vigorous stirring there was dropped in 77 grams (1.87 moles) of acetonitrile within 4 hours. Stirring was continued subsequently at 85° C. until the end of the development of hydrogen. The thickly liquid reaction mass was cooled to room temperature, treated with 700 ml of water, stirred vigorously for 30 minutes and the two phases separated in a separatory funnel. The aqueous phase was acidified with 31 weight % of hydrochloric acid at a pH 1-2 and 0° C. The precipitated pivaloylacetonitrile was filtered off with suction, washed until neutral with ice water and dried to constant weight at 25 Torr and 40° C. There were obtained 106 grams (93% of theory) of analytically pure pivaloylacetonitrile having a melting point of 65°-68° C.