Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[N:7][NH:8]2)=[CH:4][C:3]=1[NH:20][C:21]([C:23]1([CH2:26][NH2:27])[CH2:25][CH2:24]1)=[O:22].[C:28](OC(=O)C)(=[O:30])[CH3:29]>CN(C)C=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](/[CH:11]=[CH:12]/[C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)=[N:7][NH:8]2)=[CH:4][C:3]=1[NH:20][C:21]([C:23]1([CH2:26][NH:27][C:28](=[O:30])[CH3:29])[CH2:25][CH2:24]1)=[O:22]
Reactant: NCC1(C(=O)Nc2cc3c(/C=C/c4ccc(F)cc4)n[nH]c3cc2F)CC1
Reactant: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)NCC1(C(=O)Nc2cc3c(/C=C/c4ccc(F)cc4)n[nH]c3cc2F)CC1
Temperature: 25 °C
Reaction time: 38 h
Yield: 32.9 %

Procedure:
To a solution of 10 mg of 1-aminomethyl-cyclopropane carboxylic acid {6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide obtained by Example 758 in 0.3 mL of N,N-dimethylformamide was added 2.9 mg of acetic anhydride, and stirred at room temperature for 38 hours under nitrogen atmosphere, and separated and purified by LC-MS, to afford 3.66 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:29][N:30](C)C(Cl)=O.C[Si](C#N)(C)C.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][C:8]([C:29]#[N:30])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)Cl
Reactant: Clc1ccc2c(-c3ccccc3)ccnc2c1
Agent: C[Si](C)(C)C#N
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Product: N#Cc1cc(-c2ccccc2)c2ccc(Cl)cc2n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 7-chloro-4-phenylquinoline (Example 39, Step 1) (3.0 g, 12.5 mmol) and m-CPBA (2.6 g, 15.0 mmol) in chloroform (50 mL) was stirred at room temperature for 3 h. The reaction was quenched with saturated aqueous NaHCO3 solution and extracted twice with dichloromethane. The combined organic layers were washed with water, brine, and dried over anhydrous MgSO4. The solvent was removed under reduced pressure and the resulting crude product was dissolved in chloroform (50 mL). N,N-Dimethylcarbamoyl chloride (2.4 mL, 25.0 mmol) and trimethylsilyl cyanide (3.4 mL, 25.0 mmol) were added to this solution and stirred at room temperature for 2 days. Saturated aqueous NaHCO3 solution was added and the mixture stirred for 30 min. The organic layer was removed, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with water, brine, and dried over anhydrous MgSO4. The solvent was removed under reduced pressure and the resulting crude product was used in the next step without further purification.
Reaction SMILES: [C:1]([C:4]1[C:9]([NH:10][C:11]([C:13]2[S:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=2)=O)=[C:8]([Cl:22])[C:7]([O:23][CH3:24])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(C1N=C(C2C=C(O)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[Cl:22][C:8]1[C:7]([O:23][CH3:24])=[CH:6][CH:5]=[C:4]2[C:9]=1[N:10]=[C:11]([C:13]1[S:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=1)[CH:2]=[C:1]2[OH:3]
Reactant: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(F)(F)F)cs2)c1Cl
Agent: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1
Product: COc1ccc2c(O)cc(-c3nc(C(F)(F)F)cs3)nc2c1Cl
Yield: 70 %

Procedure:
Compound 65d was synthesized from compound 64d as a yellow powder in 70% yield, following the procedure as described for compound 43a.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:9][N:8]([C:10]2[CH:11]=[CH:12][C:13]3[O:14][CH2:15][C:16](=[O:20])[NH:17][C:18]=3[N:19]=2)[C:7](=[O:21])[CH2:6]1)=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][C@@H:5]1[CH2:9][N:8]([C:10]2[CH:11]=[CH:12][C:13]3[O:14][CH2:15][C:16](=[O:20])[NH:17][C:18]=3[N:19]=2)[C:7](=[O:21])[CH2:6]1
Reactant: [N-]=[N+]=NC[C@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Agent: [Pd]
Solvent: CO
Product: NC[C@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.3 %

Procedure:
To a solution of 6-[(4S)-4-(azidomethyl)-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-on (688 mg, 2.39 mmol) in methanol (20 ml) was added 10% palladium on carbon catalyst (about 50% aqueous, 360 mg) at room temperature and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The catalyst was removed by filtration and washed with methanol, the filtrate and washings were concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform/methanol/triethylamine) to yield 328 mg (54%) of the title compound in the form of a colorless solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][C:17](Cl)=[N:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1.[CH2:22]([Mg]Br)[CH2:23][CH2:24][CH3:25].BrCCCC.[Mg].II.[Cl-].[NH4+]>O1CCCC1.Cl[Ni]Cl>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][C:17]([CH2:22][CH2:23][CH2:24][CH3:25])=[N:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1
Reactant: CCCC[Mg]Br
Reactant: COCCOc1ccc(-c2cn3nc(Cl)ccc3n2)cc1
Agent: Cl[Ni]Cl
Agent: II
Agent: [Cl-]
Solvent: CCCCBr
Solvent: C1CCOC1
Product: CCCCc1ccc2nc(-c3ccc(OCCOC)cc3)cn2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-[4-(2-methoxyethoxy)phenyl]-6-chloroimidazo[1,2-b]pyridazine (304 mg, 1 mmol) in tetrahydrofuran (7 mL) was added with stirring to a solution of butylmagnesium bromide (10 mmol) (prepared from 1-bromobutane (1.37 g, 10 mmol) and magnesium turnings (0.27 g, 11 mmol) and a crystal of iodine in tetrahydrofuran (8 mL)) under an atmosphere of nitrogen. [1,3-Bis(diphenyl-phosphino)propane] dichloronickel(II) (81 mg, 0.15 mmol) was added and the resulting mixture was stirred at room temperature overnight. Saturated, aqueous ammonium chloride solution was added and the resulting mixture extracted with ether (100 mL). The organic layer was washed with brine (80 mL), dried and evaporated. The residue was radially chromatographed on silica gel. Elution with 1-3% methanol in dichloromethane provided Compound 82 (8 mg) as a brown solid. 1H n.m.r. (CDCl3) δ 0.97, t, J=7.3 Hz, 3H; 1.32-1.52, m, 2H; 1.64-1.84, m, 2H; 2.83, t, J=7.5 Hz, 2H; 3.47, s, 3H; 3.72-3.82, m, 2H; 4.12-4.22, m, 2H; 6.92-7.06, m, 3H; 7.86-7.94, m, 3H; 8.10, s, 1H. Mass spectrum (APCI+) m/z 326 (M+H, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:21]4[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.C1COCC1.CN(C=O)C.[CH3:38][C:39]([CH3:43])([CH3:42])[C:40]#[CH:41]>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.[Cu]I.CCOC(C)=O.O>[CH3:38][C:39]([CH3:43])([CH3:42])[C:40]#[C:41][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:21]4[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1ncc(Br)cc12
Reactant: C#CC(C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cccnc3F)ccc1O2
Temperature: 110 °C

Procedure:
Combined (S)-3-bromo-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (80 mg, 0.187 mmol), tetrakis(triphenylphosphine)palladium (21.64 mg, 0.019 mmol), copper(i) iodide (3.57 mg, 0.019 mmol) and THF (749 μL, 0.187 mmol) and DMF (749 μL, 0.187 mmol) in a reaction tube. Added DIPA (525 μL, 3.75 mmol) then 3,3-dimethylbut-1-yne (115 μL, 0.936 mmol) and flushed the reaction tube with argon. Sealed and heated at 110° C. for 3 hours. The mixture was partioned between water (10 mL) and EtOAc (10 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on a 25-g SNAP column, eluting with 0-70% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM. The derived residue was then purified by reverse-phase HPLC (10-90% CH3CN/H2O with 0.1% TFA) to give (S)-3-(3,3-dimethylbut-1-ynyl)-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as a white powder after evaporation from DCM/hexane. Found MS: MH+=429.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:17]([OH:19])=O)[CH2:13][CH2:14][S:15][CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:33][C:34]1[S:35][CH:36]=[N:37][N:38]=1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH:12]([C:17]([NH:33][C:34]1[S:35][CH:36]=[N:37][N:38]=1)=[O:19])[CH2:13][CH2:14][S:15][CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSCCC(NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nc1nncs1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CSCCC(NC(=O)OCc1ccccc1)C(=O)Nc1nncs1
Yield: 83.8 %

Procedure:
9.5 g of N-benzyloxycarbonyl-DL-methionine, 3.4 g of triethylamine, 150 ml of chloroform, 3.7 g of ethyl chlorocarbonate and 3.4 g of 2-amino-1,3,4-thiadiazole were reacted in the same manner as in Example 1(i) to obtain 10.3 g (yield: 84%) of 2-(N-benzyloxycarbonyl-DL-methionylamino)-1,3,4-thiadiazole as white crystals having a melting point of 155°-159° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][C:10]#[N:11].Cl.[NH2:13][OH:14].CC(C)([O-])C.[K+]>CO>[OH:14][NH:13][C:10](=[NH:11])[CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: NO
Reactant: COCCOCCOCC#N
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: COCCOCCOCC(=N)NO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of crude [2-(2-methoxy-ethoxy)-ethoxy]-acetonitrile (2.60 g) in MeOH (25 mL) was added hydroxylamine hydrochloride (1.11 g). The mixture was vigorously stirred while potassium tert-butoxide (1.79 g) was added portion wise. The mixture was stirred for 2 h at RT and then refluxed (1 h). After cooling to RT it was filtered. The filtrate was concentrated under reduced pressure, leaving crude N-hydroxy-2-[2-(2-methoxy-ethoxy)-ethoxy]-acetamidine.
Reaction SMILES: C([O:3][C:4](=S)[NH:5][C:6]1[CH:11]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:9]=[C:8]([NH:16][C:17]2[N:26]=[CH:25][C:24]3[N:23]([CH3:27])[C:22](=[O:28])[CH2:21][N:20]([CH:29]([CH3:31])[CH3:30])[C:19]=3[N:18]=2)[CH:7]=1)C.[C:33]([O:37][C:38](=[O:47])[NH:39][C@H:40]1[CH2:45][CH2:44][C@@H:43]([NH2:46])[CH2:42][CH2:41]1)([CH3:36])([CH3:35])[CH3:34]>CN(C=O)C.O>[C:33]([O:37][C:38](=[O:47])[NH:39][CH:40]1[CH2:41][CH2:42][CH:43]([NH:46][C:4]([NH:5][C:6]2[CH:11]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:9]=[C:8]([NH:16][C:17]3[N:26]=[CH:25][C:24]4[N:23]([CH3:27])[C:22](=[O:28])[CH2:21][N:20]([CH:29]([CH3:31])[CH3:30])[C:19]=4[N:18]=3)[CH:7]=2)=[O:3])[CH2:44][CH2:45]1)([CH3:36])([CH3:34])[CH3:35]
Reactant: CCOC(=S)Nc1cc(Nc2ncc3c(n2)N(C(C)C)CC(=O)N3C)cc(S(C)(=O)=O)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(NC(=O)NC4CCC(NC(=O)OC(C)(C)C)CC4)cc(S(C)(=O)=O)c3)nc21
Temperature: 70 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
[3-(8-Isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenyl]-thiocarbamic acid ethyl ester (150 mg; 0.313 mmol) was dissolved in 1 ml of dry DMF, tert-butyl-cis-4-aminocyclohexylcarbamate (201 mg; 0.940 mmol) was added. The reaction mixture was stirred at 70° C., overnight, then, it was diluted with water. The precipitated formed was filtered, washed with water and dried in vacuo. 196 mg (0.311 mmol; 99% yield) of the desired compound to were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][N:6]=[N+:7]=[N-:8])[CH3:2].Cl[C:11](=[CH2:14])[C:12]#[N:13].Cl>O>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][N:6]1[CH:14]=[C:11]([C:12]#[N:13])[N:8]=[N:7]1)[CH3:2]
Reactant: C=C(Cl)C#N
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: Cl
Solvent: O
Product: CCOC(=O)Cn1cc(C#N)nn1
Temperature: 25 °C

Procedure:
4.1 g (31.9 mmol) azidoacetic acid ethyl ester and 2.8 g (31.9 mmol) 2-chloroacrylonitrile are stirred in 32 ml water at a bath temperature of 80° C. for 16 h. After cooling to RT, the solution is rendered acid with 1 N hydrochloric acid and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated in vacuo. 50 ml ethanol and 10 drops of conc. sulfuric acid are added to the residue and the mixture is stirred under reflux for 16 h. For working up, the reaction mixture is concentrated in vacuo, ethyl acetate is added to the residue, the suspension is washed with half-concentrated sodium bicarbonate solution and the organic phase is dried over sodium sulfate. The solvent is removed completely on a rotary evaporator and the solid is dried in vacuo.
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][CH:5]1[CH:10]=[C:9]([CH3:11])[CH2:8][CH2:7][C:6]1([CH:14]=[CH2:15])[CH:12]=[O:13].[NH4+].[Cl-]>>[CH3:4][CH:5]1[CH:10]=[C:9]([CH3:11])[CH2:8][CH2:7][C:6]1([CH:12]([OH:13])[CH3:1])[CH:14]=[CH2:15]
Reactant: C=CC1(C=O)CCC(C)=CC1C
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Product: C=CC1(C(C)O)CCC(C)=CC1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of methylmagnesium bromide (40 mmol, 1 M in THF) was added a solution of 2,4-dimethyl-1-vinylcyclohex-3-enecarbaldehyde (34 mmol) dropwise at 10° C. The mixture was stirred at room temperature for 1 h and was then cooled to 5° C. A sat. solution of NH4Cl was added dropwise and the mixture was extracted with MTBE (3×50 ml). The combined org. phases were washed with water and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography to give (2,4-dimethyl-1-vinylcyclohex-3-enyl)ethanol (53% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH3:17][S:18]([O:9][CH2:8][C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc(Cl)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc(Cl)nc1
Reaction time: 1 h
Yield: 88.5 %

Procedure:
To a solution of (6-chloro-3-pyridyl)methanol (4.5 g, 31.3 mmol) and triethylamine (13.2 ml, 94.7 mmol) in dichloromethane (90 ml) was dropwise added methanesulfonyl chloride (3.6 ml, 46.5 mmol) over 45 minutes at −9° C. to 4° C. under an atmosphere of nitrogen gas, followed by stirring as it was. After 1 hour, the reaction mixture was elevated to room temperature. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and a saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate and concentrated, to give the title compound (6.14 g, 88%) as a pale brown solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH2:60])=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1>C1COCC1.C(Cl)(Cl)Cl>[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH:60][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=3[CH3:1])=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1
Reactant: Cc1cccc(C(=O)O)c1C
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3cccc(C)c3C)nc12

Procedure:
From 2,3-dimethylbenzoic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+16.4° (c=0.46, CHCl3), ES-MS m/e (%): 399 (M+H+, 100).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([N:16]1[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[S:18][C:17]1=[NH:25])[CH2:13][C:14]#[CH:15].[F:26][C:27]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:28]=1[C:29](Cl)=[O:30].C(N(CC)CC)C>C(Cl)Cl>[C:21]([C:19]1[S:18]/[C:17](=[N:25]\[C:29](=[O:30])[C:28]2[CH:32]=[C:33]([C:36]([F:37])([F:38])[F:39])[CH:34]=[CH:35][C:27]=2[F:26])/[N:16]([CH2:12][CH2:13][C:14]#[CH:15])[CH:20]=1)([CH3:22])([CH3:24])[CH3:23]
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Reactant: C#CCCn1cc(C(C)(C)C)sc1=N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCCn1cc(C(C)(C)C)s/c1=N\C(=O)c1cc(C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 91.9 %

Procedure:
A mixture of 3-(but-3-ynyl)-5-tert-butylthiazol-2(3H)-imine p-toluenesulfonate (prepared as described in US20080242654) (2.6 g, 6.83 mmol) and 2-fluoro-5-(trifluoromethyl)benzoyl chloride (1.55 g, 6.83 mmol) in anhydrous CH2Cl2 (30 mL) was treated dropwise at 0° C. with triethylamine (1.91 mL, 1.38 mmol). The mixture was allowed to warm to room temperature and stirred for 14 hours. The mixture was then washed with water, brine, dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with hexane-EtOAc (2:1) to afford 2.5 g of the title compound. MS (DCI/NH3) m/z 399 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.O[CH2:10][C@@H:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(OCC)(=O)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:12][C@@H:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[CH3:10])=[CH:4][CH:3]=1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: Oc1ccc(Br)nc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[C@@H](COc1ccc(Br)nc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.4 %

Procedure:
To a solution of 6-bromopyridin-3-ol (4.90 g), tert-butyl [(1S)-2-hydroxy-1-methylethyl]carbamate (4.93 g) and triphenylphosphine (11.06 g) in THF (100 mL) was added dropwise a toluene solution (1.9 M, 22 mL) of diisopropyl azodicarboxylate, and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added ethyl acetate, and the mixture was washed with water and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (5.35 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][C@@H:24]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C@H:25]([OH:40])[CH2:26][C@@H:27]1[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]1[C:33]([NH:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([NH:23][C@@H:24]([CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C@H:25]([OH:40])[CH2:26][C@@H:27]1[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]1[C:33]([NH:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:22])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCC[C@H]1C[C@@H](O)[C@@H](N)Cc1ccccc1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Product: CC(C)(C)NC(=O)[C@@H]1CCCC[C@H]1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Yield: 44.1 %

Procedure:
In a manner analogous to that described in Example 6, 78 mg (0.26 mmol) of N-benzyloxycarbonyl-L-phenylalanine were coupled with 90 mg (0.26 mmol) of 2(S)-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-1(R)-cyclohexanecarboxamide to give 72 mg of 2(S)-[3(S)-[[N-(benzyloxycarbonyl)-L-phenylalanyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-1(R)-cyclohexanecarboxamide as a while solid; MS m/e 628 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)[CH3:2].[CH:31]([N-:34]C(C)C)(C)[CH3:32].[Li+].BrCC#N.C(OCC)(=O)C>C1COCC1>[CH2:1]([O:3][C:4](=[O:30])[CH:5]([CH:6]1[CH2:11][CH2:10][CH:9]([O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)[CH2:32][C:31]#[N:34])[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)CC1CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Agent: N#CCBr
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC#N)C1CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 50 %

Procedure:
Treat a −78° C. solution of [4-(tert-butyl-diphenyl-silanyloxy)-cyclohexyl]-acetic acid ethyl ester (4.71 g, 11.49 mmol) in THF (40 mL) with a 1.6M solution of lithium diisopropylamide in THF (7.18 mL, 14.36 mmol) and stir at −78° C. for 20 minutes under N2. Treat the reaction with bromoacetonitrile (1.71 g, 14.36 mol) and stir at −78° C. for 2 hours. Warm the reaction to room temperature and stir for 2 hours. Quench the reaction with 1N HCl at 0° C. Dilute the reaction with ethyl acetate and wash with water. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify with a 25% to 40% ethyl acetate in hexanes gradient to afford 2.62 g (50%) of the titled product. MS (m/z): 450 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([OH:23])=[CH:20][C:21]=1[OH:22])=[O:15].[N+:24]([C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30]Br)([O-:26])=[O:25]>CC(C)=O.O>[C:14]([C:16]1[CH:17]=[CH:18][C:19]([O:23][CH2:30][C:29]2[CH:28]=[C:27]([N+:24]([O-:26])=[O:25])[CH:34]=[CH:33][CH:32]=2)=[CH:20][C:21]=1[OH:22])(=[O:15])[CH3:13]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: CC(=O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCc2cccc([N+](=O)[O-])c2)cc1O
Temperature: 25 °C
Yield: 55.8 %

Procedure:
A mixture of potassium carbonate (anhydrous, 31.7 g) and cesium carbonate (catalytic amount) is pulverized with mortar and pestle, then added to a solution of 2,4-dihydroxyacetophenone (35 g) in acetone (250 ml). The mixture is refluxed for 30 minutes. A solution of m-nitrobenzyl bromide (50 g) in acetone (100 ml) is added in one portion and the reaction refluxed for 3 days. After cooling to room temperature, water is added until a precipitate forms. The product is collected on a Buchner funnel, washed with water and ether. Recrystallization from acetone provides 36.9 g (56% yield) of needles, m.p. 117°-118° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[N:24][O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1>C(#N)C>[Cl:1][C:2]1[C:3](/[C:9](=[N:24]\[O:25][CH2:26][C:27]([F:30])([F:28])[F:29])/[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(NCC(=NOCC(F)(F)F)c1ncc(Cl)cc1Cl)c1ccccc1C(F)(F)F
Solvent: CC#N
Product: O=C(NC/C(=N/OCC(F)(F)F)c1ncc(Cl)cc1Cl)c1ccccc1C(F)(F)F
Yield: 80.8 %

Procedure:
2.6 g of N-[2-(3,5-dichloropyridin-2-yl)-2-(2,2,2-trifluoroethoxyimino)ethyl]-2-(trifluoromethyl)benzamide was dissolved in 12.0 ml of acetonitrile, and the solution was irradiated with light for 48 hours in a quartz cell (manufactured by Fine, 4 clear windows for spectroscopy) using a 100 W high-pressure mercury lamp (manufactured by USHIO INC., lamp: UM-102, power supply: UM-103B-B). After completion of the reaction, the solvent was evaporated under reduced pressure, and the resulting residue was washed with 20 ml of hexane to obtain 2.1 g of the desired product as white crystals.