Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=O)[CH2:2]1.Cl.[CH3:12][O:13][NH2:14].CC([O-])=O.[Na+].ClCCl>CO.O>[CH3:12][O:13][N:14]=[C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][CH2:2]1
Reactant: O=C1COc2ccccc21
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CON=C1COc2ccccc21
Yield: 75 %

Procedure:
To a solution of benzofuran-3(2H)-one (9) (100 g, 0.745 mol) in methanol (700 mL) was added O-methyl hydroxylamine hydrochloride (68.5 g, 0.820 mol) and NaOAc (67.3 g, 0.820 mol) at ambient temperature followed by heating to reflux for 1-3 h. The progress of the reaction was monitored by the HPLC analysis. Upon completion of the reaction, the inorganics were filtered off, and methanol was recovered from the filtrate to provide residue. The residue was subjected to extractive work-up using dichloromethane (500 mL) and water (1 L) followed by recovery of the organic layer to obtain the product meeting the desired specifications. Yield—75-83%.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[F:9][C:10]([F:26])([F:25])[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.O.[Cl-].[Na+]>O1CCCC1.C(OCC)(=O)C>[F:9][C:10]([F:25])([F:26])[C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]([OH:24])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:19][CH:18]=2)=[CH:15][CH:16]=1
Reactant: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: CCCCCC[Mg]Br
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCC(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reaction time: 1.5 h
Yield: 72.5 %

Procedure:
Add hexyl magnesium bromide (2.0M in ethyl ether, 8 mL, 16 mmol) to 4′-trifluoromethyl-biphenyl-4-carbaldehyde (2.0 g, 8 mmol) (prepared in a manner substantially similar to preparation 25, or other methods known in the art) in tetrahydro-furan (30 mL) at 0° C. under inert atmosphere. Stir 1.5 hours. Quench reaction with saturated solution of ammonium chloride, dilute with ethyl acetate. Wash organic phase with water then saturated sodium chloride solution. Dry organic fraction with Na2SO4, filter, and concentrate under reduced pressure. Purify on silica gel chromatography (0-30% Ethyl acetate/hexanes gradient) to provide 1.95 g of title compound (73%).
Reaction SMILES: Cl[S:2]([C:5]1[C:13]2[C:9](=[N:10][O:11][N:12]=2)[C:8]([F:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1C=CC=CC=1.Cl>C1C=CC=CC=1.C(Cl)(Cl)Cl>[F:14][C:8]1[C:9]2=[N:10][O:11][N:12]=[C:13]2[C:5]([S:2]([O:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:4])=[O:3])=[CH:6][CH:7]=1
Reactant: Oc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(F)c2nonc12
Agent: Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Oc1ccccc1)c1ccc(F)c2nonc12

Procedure:
1.0 g of the compound obtained in Example 1 and 1 g of phenol were dissolved in 5 ml of benzene. Next, after dripping in a chilled mixed solution of 5 ml of benzene and 1 ml of pyridine, the solution was allowed to react for 4 hours at room temperature. After dripping in 50 ml of chilled 10% hydrochloric acid, the solution was extracted with benzene, water washed, and then dried with magnesium sulfate and reduced pressure concentrated. The remaining solid was subjected to chloroform mobile phase; silica gel column chromatography (2 cm ×60 cm) to prepare 2 ml fractions. These were then subjected to thin layer chromatography (silica gel, chloroform) and the fractions with an Rf range in the vicinity of 0.73 were collected. After reduced pressure condensation, the substance was recrystallized using n-hexane. The resulting 0.4 g of white needle shaped crystals had a melting point of between 120° to 121° C.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:11]([OH:16])(=[O:15])[C:12]([CH3:14])=O.[H][H]>CC(O)C.[Pd]>[F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH:4][CH:12]([CH3:14])[C:11]([OH:16])=[O:15]
Reactant: [H][H]
Reactant: CC(=O)C(=O)O
Reactant: Nc1ccc(F)c(F)c1F
Agent: [Pd]
Solvent: CC(C)O
Product: CC(Nc1ccc(F)c(F)c1F)C(=O)O
Yield: 91.4 %

Procedure:
2,3,4-Trifluoroaniline (4.18 g) and pyruvic acid (2.75 g) were dissolved in IPA (40 ml). After adding 10% Pd-C (0.21 g), the mixture was stirred at 40° C. under atmospheric pressure in a hydrogen atmosphere for 3 hours. After filtering off Pd-C, the obtained filtrate was concentrated under reduced pressure. Thus the title compound (5.69 g) was obtained as colorless crystals. Various spectral data of this product was identical with those of a specimen synthesized separately.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:11]=[C:10]([CH3:12])[C:9](=[O:13])[NH:8][C:7]1=[O:14].[C:15]([O-:18])(=[S:17])[CH3:16].[K+]>CC(C)=O>[C:15](=[O:18])([S:17][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:11]=[C:10]([CH3:12])[C:9](=[O:13])[NH:8][C:7]1=[O:14])[CH3:16]
Reactant: CC([O-])=S
Reactant: Cc1cn(COCCCl)c(=O)[nH]c1=O
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)SCCOCn1cc(C)c(=O)[nH]c1=O
Yield: 67.1 %

Procedure:
92.0 mg (421 μmol) 1-[(2-chloroethoxy)methyl]-5-methyl-2,4(1H,3H)-pyrimidinedione were suspended in 6 ml acetone and 60.1 mg (526 μmol) potassium thioacetate were added and the reaction mixture was heated to reflux for 6 hours. The suspension was concentrated in vacuo and ethyl acetate was added. The organic layer was washed with water, dried over Na2SO4 and evaporated. The crude product was purified by flash chromatography on silica gel (ethyl acetate/hexane 9:1) to give 73 mg of the desired product. MS (ISP): 259.1 (MH+), 281.1 (MNa+). 1H-NMR (DMSO-d6): 1.76 (d, 3H), 2.32 (s, 3H), 3.01 (t, 2H), 3.58 (t, 2H), 5.04 (s, 2H), 7.57 (d, 1H), 11.32 (s, br, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][S:5][N:6]=1.[CH2:13]([I:15])[CH3:14]>CC(C)=O>[I-:15].[Cl:1][C:2]1[C:3]([C:7]2[CH:8]=[N+:9]([CH2:13][CH3:14])[CH:10]=[CH:11][CH:12]=2)=[N:4][S:5][N:6]=1
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CCI
Solvent: CC(C)=O
Product: CC[n+]1cccc(-c2nsnc2Cl)c1
Product: [I-]

Procedure:
A solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (1.13 g, 5.7 mmol) and ethyl iodide (22.65 g, 17 mmol) in acetone (15 ml) was stirred at 40° C. for 16 h. The precipitate was collected by filtration giving the title compound. Yield: 510 mg (26%).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([S:12]([NH2:15])(=[O:14])=[O:13])=[N:5][N:6]2[CH3:11].C[O-].[Na+].CO.C(O)(=O)C[C:23](CC(O)=O)(C(O)=O)[OH:24]>CS(C)=O>[CH3:23][O:24][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([S:12]([NH2:15])(=[O:14])=[O:13])=[N:5][N:6]2[CH3:11]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: Cn1nc(S(N)(=O)=O)c2c(F)cccc21
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: COc1cccc2c1c(S(N)(=O)=O)nn2C
Temperature: 130 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
A solution containing 5 g (21.8 mmol) of 4-fluoro-1-methyl-1H-indazole-3-sulfonamide and 12.6 g of sodium methoxide (a 28% methanol solution) (65 mmol) in DMSO (50 ml), was stirred at 130° C. for one hour. After confirming the disappearance of the starting material by thin layer chromatography (TLC), the mixture was poured into ice water and acidified with citric acid. Formed crystals were collected by filtration and washed with water and IPE to obtain 3.2 g (yield: 60.9%) of the desired product. Melting point: 268°-270° C.
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:8][CH:7]=[C:6]([Cl:14])[C:3]=1[CH2:4][OH:5].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:5][CH2:4][C:3]1[C:6]([Cl:14])=[CH:7][CH:8]=[C:9]([O:10][CH:11]([CH3:12])[CH3:13])[C:2]=1[Cl:1])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)Oc1ccc(Cl)c(CO)c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Oc1ccc(Cl)c(COS(C)(=O)=O)c1Cl
Temperature: 5 °C
Yield: 94.2 %

Procedure:
To a mixture of 2,6-dichloro-3-isopropoxybenzyl alcohol (1.65 g) and triethylamine (808 mg) in dichloromethane was added methanesulfonyl chloride (884 mg) in a few minutes at 5° C. After stirring for half an hour at 5° C., the mixture was washed with diluted hydrochloric acid and then with aqueous sodium bicarbonate solution, dried, and concentrated in vacuo. The residue was crystallized from n-hexane to give 2,6-dichloro-3-isopropoxybenzyl methanesulfonate (2.07 g).
Reaction SMILES: C(OCC1C=N[C:9]2[NH:10][C:11](=[O:15])[NH:12][C:13](=[O:14])[C:8]=2[C:7]=1[CH2:18][NH:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[O:28][CH3:29])(=O)C>C1(OC2C=CC=CC=2)C=CC=CC=1.C(O)C.C(OCC)C>[CH3:29][O:28][C:21]1[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:20]=1[N:19]1[CH2:9][C:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:7]=2[CH2:18]1
Reactant: COc1ccc(OC)c(NCc2c(COC(C)=O)cnc3[nH]c(=O)[nH]c(=O)c23)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCO
Solvent: CCOCC
Product: COc1ccc(OC)c(N2Cc3[nH]c(=O)[nH]c(=O)c3C2)c1
Yield: 107.5 %

Procedure:
6-Acetoxymethyl-5-(2,5-dimethoxyanilino)methylpyrido[2,3-d]-pyrimidine-2,4(1H,3H)-dione (400 mg, 1 mmol) in diphenyl ether is heated at 210° C. for 2 hours under nitrogen. The resulting clear solution is cooled and then is diluted with a 1:1 mixture of ethanol and diethyl ether (100 mL). The yellow precipitate is collected by filtration and is washed with boiling mixture of chloroform and ethanol (1:1 v/v) to give 6-(2,5-dimethoxyphenyl)-6,7-dihydropyrrolo[3,4-d]pyrimidine-2,4(1H,3H)-dione (311 mg, 91%), mp 308°-310° C. 1H NMR (Me2SO-d6) d 3.70 (3H, s, OMe), 3.74 (3H, s, OMe), 4.67 (2H, brs, CH2), 4.98 (2H, brs, CH2), 6.28 (1H, s, H-6'), 6.31 and 6.87 (each 1H, d, H-3' and H-4' ), 8.53 (1H, s, H-2), 11.43 and 11.61 (each 1H, brs, NH, exchangeable).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:11][CH3:12])[NH:10][C:5]2=[C:4]([CH3:13])[CH:3]=1.[H-].[Na+].[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)([O-:18])=[O:17].N#N>CN(C=O)C.C(Cl)Cl>[CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:23][C:22]3[CH:25]=[CH:26][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:13])[CH:3]=1
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc([N+](=O)[O-])cc1
Reaction time: 0.08 h
Yield: 76.7 %

Procedure:
To a solution of 5.0 g (1.0 eq, 28.6 mmol) 5,7-dimethyl-2ethylimidazo[4,5-b]pyridine in 30 mL DMF under N2 at rt was added 1.37 g (1.2 eq, 34.3 mmol) of a 60% oil dispersion of NaH. After stirring for 5 minutes, 8.64 g (1.4 eq, 40.0 mmol) of p-nitrobenzyl bromide was added. The dark brown mixture was stirred for 2 hours under a blanket of N2 at rt. The mixture was diluted with 1 L CH2Cl2 and washed with 500 mL H2O and 500 mL saturated aqueous NaCl. The organic phase was dried is over MgSO4 and concentrated to a yellow oil. The oil was flash chromatographed with 50% ethyl acetate/hexane. The product-containing fractions were combined and concentrated to a yellow oil which crystallized on standing, yielding 6.81 g (76.8%) of the title compound.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH3:12][O:13][C:14]([C:16]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[NH:18][N:17]=1)=[O:15].C(N(CC)CC)C>ClCCl.CCOCC>[CH3:12][O:13][C:14]([C:16]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[N:18]([C:2]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])[N:17]=1)=[O:15]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)c1cc([N+](=O)[O-])[nH]n1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc([N+](=O)[O-])n(C(=O)OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.1 %

Procedure:
Benzyl chloroformate (5.20 mL, 35.08 mmol) was added to a cooled (0° C.) solution of 5-nitro-1H-pyrazole-3-carboxylic acid methyl ester (5.400 g, 31.54 mmol) and triethylamine (7.40 mL, 53.08 mmol) in dichloromethane (60 mL), the reaction mixture was stirred at room temperature for 2 hours, then diluted with ether and washed with water and brine, dried over anhydrous MgSO4 and filtered. The organic solvent was removed in vacuo. The residue was purified column chromatography to give 5-nitropyrazole-1,3-dicarboxylic acid 1-benzyl ester 3-methyl ester (3.28 g, 34%). 1H NMR (300 MHz, CDCl3) δ 7.34 (s, 1H), 7.32-7.24 (m, 5H), 3.89 (s, 3H).
Reaction SMILES: C1(COC([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]4=[O:33])=[CH:19][C:18]=3[F:34])[CH2:13][CH2:12]2)=O)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[O:33]=[C:24]1[N:23]([C:20]2[CH:21]=[CH:22][C:17]([CH:14]3[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]3)=[C:18]([F:34])[CH:19]=2)[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCN(C(=O)OCc4ccccc4)CC3)c(F)c2)C(=O)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCNCC3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 1.75 h

Procedure:
A solution of (S)-(-)-4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperidinecarboxylic acid phenylmethyl ester (EXAMPLE 20, Step 9, 10.44 g) in dry methylene chloride (100 mL) at 0° C. under N2 is treated with trifluoroacetic acid (24.0 mL) over one minute, and the resulting mixture is stirred at 0° C. for 1.75 hours, concentrated under reduced pressure, diluted with water (100 mL), cooled in an ice bath, adjusted to pH 11 with saturated aqueous potassium carbonate, and extracted with methanol/methylene chloride (5/95, 6×100 mL). The combined organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound, mp 163-164° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.[F:16][C:17]([F:36])([F:35])[C:18]1[CH:19]=[C:20]([C:28]2[O:32][N:31]=[C:30]([CH2:33]Cl)[N:29]=2)[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1>>[F:36][C:17]([F:16])([F:35])[C:18]1[CH:19]=[C:20]([C:28]2[O:32][N:31]=[C:30]([CH2:33][N:7]3[C:8]4[C:4](=[C:3]([C:2]([F:14])([F:1])[F:15])[C:11]([C:12]#[N:13])=[CH:10][CH:9]=4)[CH:5]=[CH:6]3)[N:29]=2)[CH:21]=[C:22]([C:24]([F:26])([F:25])[F:27])[CH:23]=1
Reactant: FC(F)(F)c1cc(-c2nc(CCl)no2)cc(C(F)(F)F)c1
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 62 from 4-(trifluoromethyl)-1H-indole-5-carbonitrile and 5-[3,5-bis(trifluoromethyl)phenyl]-3-(chloromethyl)-1,2,4-oxadiazole: MS (ESI): m/z 503 (M−1).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:25])[C@H:6]([CH2:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([OH:23])=[C:18]([CH3:24])[CH:17]=1)[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Cl[CH2:27][C:28]1[C:36]2[O:35][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[N:33][C:32]=2[CH:31]=[CH:30][CH:29]=1.C(OCC)(=O)C>CS(C)=O>[CH3:3][O:4][C:5](=[O:25])[C@H:6]([CH2:15][C:16]1[CH:17]=[C:18]([CH3:24])[C:19]([O:23][CH2:27][C:28]2[C:36]3[O:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[N:33][C:32]=3[CH:31]=[CH:30][CH:29]=2)=[C:20]([CH3:22])[CH:21]=1)[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: ClCc1cccc2nc(-c3ccccc3)oc12
Reactant: COC(=O)[C@H](Cc1cc(C)c(O)c(C)c1)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)[C@H](Cc1cc(C)c(OCc2cccc3nc(-c4ccccc4)oc23)c(C)c1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
60% Sodium hydride (20 mg, 0.495 mmol) was added to a solution of N-t-butoxycarbonyl-3,5-dimethyl-L-tyrosine methyl ester (160 mg, 0.495 mmol) in dimethyl sulfoxide (2 ml) at 18° C. and the mixture was stirred at the same temperature for 30 minutes. To the mixture was added dropwise a solution of 7-chloromethyl-2-phenylbenzoxazole (241 mg, 0.990 mmol) in dimethyl sulfoxide (3 ml) and the mixture was stirred at room temperature for 90 minutes. The reaction mixture was poured into a mixture of ice water and ethyl acetate and then extracted with ethyl acetate. The extract was washed with water and saturated saline solution in turn and dried. The solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=4) to give N-t-butoxycarbonyl-3,5-dimethyl-O-[(2-phenyl)benzoxazol-7-yl]methyl-L-tyrosine methyl ester (185 mg, 70%) as colorless crystals.
Reaction SMILES: F[C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]([S-:15])(=[S:14])OCC.[Na+]>CN(C=O)C.O.Cl>[I:9][C:7]1[CH:6]=[CH:5][C:3]2[N:4]=[C:10]([SH:15])[S:14][C:2]=2[CH:8]=1
Reactant: Nc1ccc(I)cc1F
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Sc1nc2ccc(I)cc2s1
Temperature: 95 °C
Reaction time: 5 h
Yield: 112.6 %

Procedure:
A mixture of 2-fluoro-4-iodoaniline (2.4 g, 10 mmol) and sodium O-ethyl carbonodithioate (3.2 g, 20 mmol) in DMF (8 mL) was stirred at 95° C. for 5 h. The reaction mixture was cooled to rt then diluted with water (25 mL) and 1 N aqueous HCl (20 mL). The mixture was stirred at room temperature for 1 h. The resulting precipitate was collected by filtration and washed with water. The solid was dried to afford 6-iodobenzo[d]thiazole-2-thiol as a light yellow solid (3.3 g, 100%). 1H NMR (300 MHz, CD3OD) δ 7.89 (d, J=1.2 Hz, 1H), 7.67 (dd, J=1.8, 8.7 Hz, 1H), 7.05 (d, J=8.4 Hz, 1H). LCMS (ESI) m/z 294 (M+H)+.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH:11]1([C:14](Cl)=[O:15])[CH2:13][CH2:12]1.O>C1COCC1>[C:1]([O:5][C:14]([CH:11]1[CH2:13][CH2:12]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)O
Reactant: O=C(Cl)C1CC1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butanol (9.4 mL, 100 mmol) in 50 mL of anhydrous THF is added under nitrogen during several minutes n-butyl lithium (69 mL, 110 mmol, 1.6 M solution in hexane). After 30 min, the resulting solution is treated by the drop wise addition of a THF solution (40 mL) of cyclopropanecarbonyl chloride (10 mL, 110 mmol). The reaction mixture is further stirred at reflux for 1 h, cooled to 0° C. by an ice bath, and slowly hydrolyzed by the addition of water. The aqueous layer is extracted twice with ether and the combined organic extracts are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by vacuum distillation (bp=70° C., 76 mmHg) to afford the title compound as a yellow oil.
Reaction SMILES: C([Mg]Br)C.C[Si]([O:9][CH2:10][C:11]#[CH:12])(C)C.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH2:23][C:22](=[O:26])[C@@H:21]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH2:23][C@:22]([C:12]#[C:11][CH2:10][OH:9])([OH:26])[C@@H:21]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: C#CCO[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)[C@@H]1c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CC[Mg]Br
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@](O)(C#CCO)[C@@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a cooled (−5° C.) solution of ethylmagnesium bromide (1M in tetrahydrofuran, 130 ml, 130 mmol) in tetrahydrofuran was added O-trimethylsilylpropargyl alcohol slowly. The reaction was stirred at 0° C. for 20 minutes and then at room temperature for 2 hours, before cooling to −10° C. To this was then added a solution of (2S)-1-tert-butyloxycarbonyl-2-phenylpiperidin-3-one (Desc. 1; 30 g, 108 mmol) in tetrahydrofuran keeping the temperature below 5° C. The reaction was stirred at room temperature overnight, quenched by addition of water/saturated aqueous ammonium chloride (200 ml/200 ml) and extracted with ethyl acetate (2×200 ml). The combined organic phases were dried (MgSO4) and evaporated to an oil. This oil was dissolved in ethyl acetate (400 ml) and a solution of tetrabutylammonium fluoride (1M in tetrahydrofuran, 130 ml, 130 mmol) added. After stirring at room temperature for 2 hours, water (200 ml) was added, and the two layers separated. The aqueous phase was further extracted with ethyl acetate (200 ml), the organic layers dried (MgSO4) and evaporated to give the product as an oil (50 g) which was used crude for Description 3. 1H NMR (CDCl3) δ7.53-7.55 (2H, m), 7.19-7.35 (3H, m) 5.56 (1H, s), 4.27 (2H, s), 3.99-4.03 (1H, m) 3.25 (1H, bs), 2.77-2.81 (1H, m) 2.77 (1H, bs), 2.12-2.20 (1H, m) 1.91-1.99 (2H, m), 1.77-1.83 (1H, m), 1.39 (9H, s).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11])#[CH:2].C(N(CC)CC)C.Cl[C:22]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([CH:39]3[CH2:44][CH2:43][CH2:42][N:41]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:40]3)=[CH:35][CH:34]=2)[N:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.[Cu]I>[CH3:13][O:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[C:2][C:26]1[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:22][N:23]=[C:24]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([CH:39]3[CH2:44][CH2:43][CH2:42][N:41]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:40]3)=[CH:35][CH:34]=2)[N:25]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)C1
Reactant: C#Cc1ccccc1CC(=O)OC
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(C3CCCN(C(=O)OC(C)(C)C)C3)cc2)ncc1C(F)(F)F
Temperature: 120 °C
Yield: 79 %

Procedure:
To a nitrogen de-gassed solution of methyl 2-(2-ethynylphenyl)acetate (I4) (0.137 g, 0.788 mmol) in dry DMF (7 mL) were added triethylamine (0.366 mL, 2.63 mmol) followed by tert-butyl 3-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I24) (0.300 g, 0.657 mmol), triphenylphosphine (0.026 g, 0.098 mmol), trans-dichlorobis(triphenylphosphine) palladium(II) (0.046 g, 0.066 mmol) and CuI (0.019 g, 0.098 mmol). The reaction mixture was heated under microwave irradiation at 120° C. for 20 minutes and then concentrated to dryness in vacuo and purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-70% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I25) (0.310 g, 79% yield) as a yellow sticky oil; 1H NMR (400 MHz, d6-DMSO) 10.44 (s, 1H), 8.81 (s, 1H), 7.73-7.60 (m, 3H), 7.54 (td, J=7.6, 1.3 Hz, 1H), 7.50-7.34 (m, 2H), 7.24 (d, J=8.6 Hz, 2H), 4.02-3.87 (m, 4H), 3.61 (s, 3H), 2.90-2.51 (m, 4H), 1.88 (d, J=12.0 Hz, 1H), 1.76-1.55 (m, 2H), 1.51-1.34 (m, 10H). LCMS Method C: rt 6.98 min; m/z 539.2 [M-C4H9 (t-Bu)+H]+.