Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:4]1[S:5][C@@H:6]2[C@@H:23]([CH2:24][CH3:25])[C:22](=[O:26])[N:7]2[C:8]=1[C:9]([O:11]CC1C=CC([N+]([O-])=O)=CC=1)=[O:10])=[O:3].C([O-])(O)=O.[Na+:31]>C1COCC1.CCO.O.[Pd]>[CH3:1][S:2]([C:4]1[S:5][C@@H:6]2[C@@H:23]([CH2:24][CH3:25])[C:22](=[O:26])[N:7]2[C:8]=1[C:9]([O-:11])=[O:10])=[O:3].[Na+:31]
Reactant: CC[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S(C)=O)S[C@H]12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC[C@H]1C(=O)N2C(C(=O)[O-])=C(S(C)=O)S[C@H]12
Reaction time: 2 h

Procedure:
A solution of p-nitrobenzyl (5R,6S)-2-methylsulfinyl-6-ethyl-pen-2-em-3-carboxylate (50 mg) in THF (9 ml) is diluted with EtOH (4.5 ml) and H2O (7.0 ml) containing NaHCO3 (10.6 mg). The resulting solution is added to a prereduced mixture of 10% Pd/C (100 mg) in EtOH (4.5 ml) and the resulting mixture is rapidly stirred under a H2 atmosphere for 2 hours. The mixture is filtered to remove the catalyst which is washed with H2O (2×25 ml). The combined filtrate is extracted with Et2O (2×50 ml) concentrated under vacuum to ca. 10 ml volume, and lyophilized to yield the title compound.
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[CH:15]([C@:18]1([C:24]([N:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][C:30]([C:36]([F:39])([F:38])[F:37])=[CH:31][CH:32]=3)[CH2:27]2)=[O:25])[CH2:22][CH2:21][C@@H:20]([NH2:23])[CH2:19]1)([CH3:17])[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:15]([C@:18]1([C:24]([N:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][C:30]([C:36]([F:39])([F:37])[F:38])=[CH:31][CH:32]=3)[CH2:27]2)=[O:25])[CH2:22][CH2:21][C@@H:20]([NH:23][CH:5]2[CH2:6][CH2:7][C:2]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)([OH:1])[CH2:3][CH2:4]2)[CH2:19]1)([CH3:17])[CH3:16]
Reactant: O=C1CCC(O)(c2ccccn2)CC1
Reactant: CC(C)[C@]1(C(=O)N2CCc3ccc(C(F)(F)F)cc3C2)CC[C@@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)[C@]1(C(=O)N2CCc3ccc(C(F)(F)F)cc3C2)CC[C@@H](NC2CCC(O)(c3ccccn3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-hydroxy-4-pyridin-2-yl-cyclohexanone (42.3 mg, 0.221 mmol) of step D-2 and (1R,3S)-3-isopropyl-3-{[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}cyclopentanamine (103 mg, 0.221 mmol) of Step C-2 in CH2Cl2(8 mL) was added sodium triacetoxyborohydride (200 mg, 1.0 mmol). After being stirred at room temperature overnight, the reaction was quenched with aqueous NaOH. The solution was extracted with CH2Cl2. The organic layer was concentrated in vacuo. The residue was purified via HPLC to provide two diastereomers. Isomer 1: LCMS calculated for C30H38F3N3O2: (M+H)+530; found 530.1. Isomer 2: MS found 530.1.
Reaction SMILES: FC(F)(F)S(O/[CH:7]=[CH:8]\[C:9]([O:11][CH2:12][CH3:13])=[O:10])(=O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)#[N:25]>O1CCOCC1>[C:24]([C:26]1[CH:31]=[C:30](/[CH:7]=[CH:8]\[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:29]=[CH:28][CH:27]=1)#[N:25]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CCOC(=O)/C=C\OS(=O)(=O)C(F)(F)F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)/C=C\c1cccc(C#N)c1
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a solution of ethyl (Z)-3-{[(trifluoromethyl)sulfonyl]-oxy}-2-propenoate (330 mg, 1.25 mmol) in 5 ml anhydrous dioxane was added potassium phosphate (398 mg, 1.88 mmol), 3-cyanophenyl boronic acid (185 mg, 1.25 mmol), and tetrakis (triphenylphosphine)palladium(0) (36 mg, 0.031 mmol). Reaction mixture was heated to reflux and stirred overnight. Mixture was filtered through a pad of Celite, diluted with 50 ml ethyl acetate, washed with 2×50 ml water, 2×50 ml saturated brine solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Residue was chromatographed on silica gel using 5% EtOAc in hexane as the eluent to give ethyl (Z) 3-(3-cyanophenyl)-2-propenoate (240 mg, 71%) as a clear oil after drying. ES-MS (M+H+): 216.05
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.Cl.[NH:31]1[CH:35]=[C:34]([CH2:36][CH2:37][C:38]([OH:40])=O)[N:33]=[CH:32]1.[NH2:41][C@H:42]([CH2:60][C:61]1[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][CH:62]=1)[C:43]([N:45]1[CH2:48][C:47]([CH:54]2[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]2)([CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:46]1)=[O:44]>CN(C=O)C>[CH:54]1([C:47]2([CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:46][N:45]([C:43](=[O:44])[C@H:42]([NH:41][C:38](=[O:40])[CH2:37][CH2:36][C:34]3[N:33]=[CH:32][NH:31][CH:35]=3)[CH2:60][C:61]3[CH:62]=[CH:63][C:64]([O:67][CH3:68])=[CH:65][CH:66]=3)[CH2:48]2)[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]1
Reactant: O=C(O)CCc1c[nH]cn1
Reactant: CCCCCC1(C2CCCCC2)CN(C(=O)[C@H](N)Cc2ccc(OC)cc2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCC1(C2CCCCC2)CN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=O)CCc2c[nH]cn2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.3 %

Procedure:
100 mg (0.311 mmol) of TBTU and 0.1 ml (0.715 mmol) of triethylamine are added to 55 mg (0.311 mmol) of 3-(1H-imidazol-4-yl)propionic acid hydrochloride in 1 ml of DMF. After 10 minutes, 99 mg (0.256 mmol) of (R)-2-amino-1-(3-cyclohexyl-3-pentylazetidin-1-yl)-3-(4-methoxyphenyl)propan-1-one dissolved in 1 ml of DMF are added. After stirring for 118 hours at ambient temperature, the reaction medium is extracted with a 1/2 heptane/EtOAc mixture and washed with 1N sodium hydroxide and a saturated sodium chloride solution. The organic phase is dried over MgSO4, filtered and concentrated. The residue is purified on a silica column (eluent 9/1 DCM/MeOH). 72 mg of N—[(R)-2-(3-cyclohexyl-3-pentylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide are obtained in the form of a white powder, with a yield of 55%.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=O)(C)(C)C>C(O)(C(F)(F)F)=O>[NH:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(OC[C@@H]2CCCN2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 72.5 %

Procedure:
A mixture of methyl (S)-4-[1-(tert-butoxycarbonyl)-2-pyrrolidinylmethoxy]benzoate (3.34 g, 9.96 mmol) in TFA (20 mL) and CH2Cl1 (35 mL) was stirred at room temp for 15 hr. The mixture was concentrated in vacuo and made basic with sat. NaHCO3. The mixture was extracted with CHCl3, washed with brine, and dried over Na2CO3. The organic layer was evaporated to give 1.70 g (73%) methyl (S)-4-(2-pyrrolidinylmethoxy)benzoate as a yellow oil. 1H-NMR (CDCl3) δ1.54-1.61 (m, 1 H), 1.77-1.86 (m, 2 H), 1.87-1.97 (m, 1 H), 2.00 (bs, 1 H), 2.93-3.06 (m, 2 H), 3.52-3.57 (m, 1 H), 3.88 (s, 3 H), 3.90-3.99 (m, 2 H), 6.92 (d, J=9.0 Hz, 2 H), 7.98 (d, J=9.0 Hz, 2H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[CH:16]=[N:15][C:14](Br)=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)[N:12]=1)=[O:10].[N:29]1[CH:34]=[CH:33][CH:32]=[N:31][C:30]=1[CH2:35][OH:36]>>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[CH:16]=[N:15][C:14]([O:36][CH2:35][C:30]2[N:31]=[CH:32][CH:33]=[CH:34][N:29]=2)=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)[N:12]=1)=[O:10]
Reactant: OCc1ncccn1
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(Br)c(-c2ccc(OC(F)(F)F)cc2)n1
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCc2ncccn2)c(-c2ccc(OC(F)(F)F)cc2)n1

Procedure:
In analogy to example 64, however by starting from 5-bromo-6-(4-trifluoromethoxy-phenyl)-pyrazine-2-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide (example 21e) and pyrimidin-2-yl-methanol the title compound was obtained as an off-white solid. MS (ISP) (M+H+)=490.2.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].Cl.[Cl:6][C:7]1[CH:12]=[CH:11][C:10](CC#N)=[CH:9][C:8]=1[C:16]([F:19])([F:18])[F:17]>O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:2][C:1]([OH:4])=[O:3])=[CH:9][C:8]=1[C:16]([F:17])([F:18])[F:19]
Reactant: CC(=O)O
Reactant: N#CCc1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Product: O=C(O)Cc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
According to a method similar to Example (17-1), using [4-chloro-3-(trifluoromethyl)phenyl]methanol (2.00 g, 5.59 mmol) as a starting material, [4-chloro-3-(trifluoromethyl)phenyl]acetonitrile was obtained. Acetic acid (6 ml) and concentrated hydrochloric acid (6 ml) were added to the obtained [4-chloro-3-(trifluoromethyl)phenyl]acetonitrile and the mixture was stirred at 100° C. for 2 hours. After the temperature of the reaction mixture was returned to room temperature, the mixture was poured into water and extracted with ethyl acetate. The organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure to give crude [4-chloro-3-(trifluoromethyl)phenyl]acetic acid. Methanol (12 ml) and concentrated sulfuric acid (1.0 ml) were added to the crude product obtained in the above and the mixture was stirred at 50° C. for 1 hour. The temperature of the reaction mixture was returned to room temperature and the solvent was removed under reduced pressure. After ethyl acetate was added thereto, the organic layer was successively washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=10/1) to give methyl[4-chloro-3-(trifluoromethyl)phenyl]acetate (1.08 g, two-step total yield: 45%).
Reaction SMILES: [CH3:1][C:2]1[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[N:12]=[C:11]([C:13]([F:15])([F:16])[F:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccc(C(F)(F)F)nc1C
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(C(F)(F)F)nc1CBr
Temperature: 15 °C
Reaction time: 3 h

Procedure:
434.4 g (1.866 mol) of ethyl 2-methyl-6-trifluoromethylnicotinate (preparation similar to Heterocycles 129, 46, 1997) and 398.5 g (2.239 mol) of N-bromosuccinimide in 3 500 ml of carbon tetrachloride in the presence of 30.6 g (0.1866 mol) of α,α-azaisobutyronitrile are heated at 75° C., with irradiation from a 150 Watt lamp. After 3 hours, the reaction is terminated, the mixture is cooled to 15° C. and precipitated succinimide is removed by filtration. After evaporation of the solvent, the residue is distilled under reduced pressure. This gives ethyl 2-bromomethyl-6-trifluoromethylnicotinate as an oily product (260.2 g, 44.7% of theory, b.p. 74° C./0.04 mmHg).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[O:13][C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[C:11]([C:21]1[CH:26]=[CH:25][C:24]([C:27]3([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:29][CH2:28]3)=[CH:23][CH:22]=1)[C:10]2=[O:39])=[O:4].[OH-].[Li+]>C1COCC1.CCOC(C)=O>[C:35]([O:34][C:32]([NH:31][C:27]1([C:24]2[CH:23]=[CH:22][C:21]([C:11]3[C:10](=[O:39])[C:9]4[C:14](=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[CH:7][CH:8]=4)[O:13][C:12]=3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:26][CH:25]=2)[CH2:28][CH2:29][CH2:30]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: COC(=O)c1cccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc12
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(C(=O)O)cccc4c3=O)cc2)CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.4 %

Procedure:
To a solution of 3-[4-(1-tert-butoxycarbonylamino-cyclobutyl)-phenyl]-4-oxo-2-phenyl-4H-chromene-8-carboxylic acid methyl ester (31 mg, 0.059 mmol) in THF (2 mL) was added a solution of 2 M aqueous lithium hydroxide (2 mL) and the reaction stirred at RT for 18 h. The reaction mixture was diluted with EtOAc, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound as an off-white solid (30 mg, 100%). LCMS (Method G): RT=3.81 min, [M+H]+=512.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:14][CH3:15].Br[CH2:17][CH2:18][CH:19]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[O:22][CH2:21][CH2:20]1.[I-].[K+]>CC(=O)CC>[O:22]1[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH:19]([CH2:18][CH2:17][N:11]2[CH2:10][CH2:9][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([O:14][CH3:15])[CH:4]=3)[CH2:13][CH2:12]2)[CH2:20][CH2:21]1
Reactant: BrCCC1CCOc2ccccc21
Reactant: COc1cc(C2CCNCC2)ccc1O
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1cc(C2CCN(CCC3CCOc4ccccc43)CC2)ccc1O

Procedure:
1-[2-(3,4-Dihydro-1(2H)-benzopyran-4-yl)ethyl]-4-(4-hydroxy-3-methoxyphenyl)piperidine is prepared by proceeding as in Example 48 but starting with 4-(4-hydroxy-3-methoxyphenyl)piperidine, 4-(2-bromoethyl)-3,4-dihydro-2H-benzopyran (0.49 g) and potassium iodide (0.5 g) in 2-butanone (35 cc).
Reaction SMILES: [CH3:1][CH:2]([C:10]1[CH:11]=[C:12]([OH:26])[C:13]2[CH:14]([CH3:25])[C:15]3[CH2:16][CH2:17][CH:18]([CH3:24])[CH2:19][C:20]=3[O:21][C:22]=2[CH:23]=1)[CH:3]([CH3:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:27]([O:26][C:12]1[C:13]2[CH:14]([CH3:25])[C:15]3[CH2:16][CH2:17][CH:18]([CH3:24])[CH2:19][C:20]=3[O:21][C:22]=2[CH:23]=[C:10]([CH:2]([CH3:1])[CH:3]([CH3:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:11]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC1=C(CCC(C)C1)C2C
Solvent: c1ccncc1
Product: CCCCCC(C)C(C)c1cc(OC(C)=O)c2c(c1)OC1=C(CCC(C)C1)C2C
Reaction time: 24 h

Procedure:
To a solution of 1.2 g. of 3-(1,2-dimethylheptyl)-5,6,7,8-tetrahydro-1-hydroxy-6,9-dimethylxanthene in 20 ml. of dry pyridine is added 8.0 g. of acetic anhydride. The solution is stirred at 25° for 24 hours, then concentrated in vacuo. The residue is dissolved in water and extracted with hexane. The extract is washed with water until neutral, then dried and evaporated to give the title compound.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:25]=[C:24](Cl)[CH:23]=[CH:22][C:5]=1[C:6]([NH:8][CH2:9][C:10]1[S:11][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:13][CH:14]=1)=[O:7].[CH2:27]([OH:30])[CH2:28][OH:29].[Cl-].[NH4+]>C(#N)C.O.FC(F)(F)C(O)=O.[Cu]I.ClCCl.O>[NH2:3][C:4]1[N:25]=[C:24]([O:29][CH2:28][CH2:27][OH:30])[CH:23]=[CH:22][C:5]=1[C:6]([NH:8][CH2:9][C:10]1[S:11][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:13][CH:14]=1)=[O:7]
Reactant: OCCO
Reactant: Nc1nc(Cl)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Agent: [Cu]I
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: Nc1nc(OCCO)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Temperature: 65 °C
Reaction time: 2 h
Yield: 4.7 %

Procedure:
Sodium hydride (3.1 mg, 0.078 mmol, 60% in oil), catalytic amount of copper(I) iodide, 2-amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described in Example A-102 (4.0 mg, 0.011 mmol) were added sequentially to ethyleneglycol (0.7 mL), and the solution was stirred at 65° C. for 2 hours. After further stirring at 90° C., the solution was allowed to cool to room temperature. Water, dichloromethane and an aqueous solution of saturated ammonium chloride were added to the reaction solution for extraction, which was then washed with brine, then, the solvent was evaporated in vacuo. The residue was purified by reverse phase high performance liquid chromatography (acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid) was used), and trifluoroacetic acid salt of the title compound (0.26 mg, 0.00052 mmol, 4.7%) was obtained.
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:48])[NH:29][C@H:30]3[CH2:34][CH2:33][N:32]([C:35]([O:37][CH2:38][C:39]4[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=4)=[O:36])[CH2:31]3)[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O1CCCC1.O>[OH:18][CH:19]1[CH2:20][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:48])[NH:29][C@H:30]3[CH2:34][CH2:33][N:32]([C:35]([O:37][CH2:38][C:39]4[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=4)=[O:36])[CH2:31]3)[N:27]=2)[CH2:22]1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(C(=O)N[C@H]3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)cs2)C1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(N[C@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)c1csc(N2CC(O)C2)n1
Temperature: 0 °C
Yield: 98.3 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-{4-[(3S)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl]-1,3-thiazol-2-yl}azetidine (560 mg, 0.816 mmol) (obtained as described in Reference Example 52(5)) in anhydrous tetrahydrofuran (17 ml) was added successively acetic acid (56 μl, 0.980 mmol) and a solution of 1.0M tetra-n-butylammonium fluoride in tetrahydrofuran (980 μl, 0.980 mmol) in an ice bath. The mixture was stirred in the ice bath for 1.5 hours. After checking the completion of the reaction, ethyl acetate and water were added thereto and the aqueous layer was extracted with ethyl acetate. The obtained organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate→ethyl acetate:methanol (95:1) as the eluant to afford 3-hydroxy-1-{4-[(3S)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl]-1,3-thiazol-2-yl}azetidine (359 mg, yield 98%) as a white solid.
Reaction SMILES: [CH2:1]([S:3]([NH:6][C@@H:7]([C:15]([OH:17])=O)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:5])=[O:4])[CH3:2].[NH:18]1[CH2:32][CH2:31][CH2:30][C@H:19]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>C1COCC1>[CH2:1]([S:3]([NH:6][C@@H:7]([C:15]([N:18]1[CH2:32][CH2:31][CH2:30][C@H:19]1[C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])=[O:17])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)N[C@H](Cc1ccccc1)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCS(=O)(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 20 h

Procedure:
To a stirring suspension of EtSO2-D-Phe-OH (25.7 g, 100 mmol), Pro-OBn•HCl (26.6 g, 110 mmol), HOBT (13.5 g, 100 mmol) and N,N-diisopropylethylamine (43.5 mL, 250 mL) in THF (1 L) at 0° C. was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (23 g, 120 mL). After stirring for 20 h, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and 1N citric acid. The organic phase was washed twice with 1N KHCO3, twice with brine, dried with MgSO4, filtered and concentrated in vacuo. The residue was chromatographed over silica gel, eluting with a step gradient of hexanes through 50% ethyl acetate/hexanes. The product containing fractions were combined and concentrated in vacuo to give 29 g (65%) of a clear, thick oil.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[O:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:21]1[N:22]=[C:23]([NH2:39])[C:24]2[N:25]=[CH:26][N:27]([C:37]=2[N:38]=1)[C@@H:28]1[O:36][C@H:33]([CH2:34][OH:35])[C@@H:31]([OH:32])[C@H:29]1[OH:30]>>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][C:10]([N:7]2[CH2:8][CH2:9][CH:4]([CH2:1][C:2]#[C:3][C:21]3[N:22]=[C:23]([NH2:39])[C:24]4[N:25]=[CH:26][N:27]([C:37]=4[N:38]=3)[C@@H:28]3[O:36][C@H:33]([CH2:34][OH:35])[C@@H:31]([OH:32])[C@H:29]3[OH:30])[CH2:5][CH2:6]2)=[O:11])=[CH:18][CH:17]=1
Reactant: C#CCC1CCN(C(=O)Oc2ccc(Cl)cc2)CC1
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: Nc1nc(C#CCC2CCN(C(=O)Oc3ccc(Cl)cc3)CC2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
Batch: AB-10-015. 4-chlorophenyl 4-(prop-2-ynyl)piperidine-1-carboxylate, batch JR28-107 (0.624 g, 2.247 mmol) was added to a solution of 2-iodoadenosine (0.656 g, 1.669 mmol) according to general procedure 2. Yield: 0.445 g, 49%. 1H NMR (CD3OD) δ 8.30 (s, 1H), 7.37-7.07 (2×m, 4H), 5.93 (d, 1H), 4.71 (m, 2H), 4.31-4.17 (2×m, 3H), 3.91-3.75 (2×d, 2H), 3.07-2.93 (2×bt, 4H), 2.48 (d, 5H), 1.97-1.40 (2×m, 5H). m/z MH+=543.09. HPLC rt=7.3 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH3:2].[OH-].[Na+].[CH2:13](Cl)[CH:14]=[CH2:15].[Cl-].[NH4+].Cl>O>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH2:15][CH:14]=[CH2:13])[CH:7]=[CH:6][C:5]=1[OH:10])[CH3:2].[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH3:2]
Reactant: C=CCCl
Agent: CCOc1ccccc1O
Agent: Cl
Agent: [Cl-]
Solvent: O
Product: C=CCc1ccc(O)c(OCC)c1
Reaction time: 0.25 h

Procedure:
A mixture of 11.60 g of o-ethoxyphenol, 3.36 g of sodium hydroxide, 7.07 g of allyl chloride, 1.37 g of cupric chloride (CuCl2.2H2O), 1.72 g of ammonium chloride and 34 ml of water was reacted at 25° C and with stirring, for 15 minutes. The reaction solution was then neutralized with hydrochloric acid and extracted with five portions of 30 ml of ether. The resulting ethereal extract was distilled to give 5.17 g of the desired o-ethoxy-p-allylphenol and 5.22 g of the unreacted o-ethoxyphenol. There was also obtained 2.02 g of by-product 1-allyloxy-2-ethoxybenzene.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([C:10]1[S:11][C:12]([S:27][CH3:28])=[C:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].I[C:31]1[C:36]([CH3:37])=[CH:35][C:34]([N+:38]([O-:40])=[O:39])=[CH:33][N:32]=1.O>CN(C=O)C.[Cu]I.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>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8](=[NH:9])[C:10]1[S:11][C:12]([S:27][CH3:28])=[C:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:31]3[C:36]([CH3:37])=[CH:35][C:34]([N+:38]([O-:40])=[O:39])=[CH:33][N:32]=3)[CH:19]=2)(=[O:17])=[O:16])[CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc([N+](=O)[O-])cnc1I
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(B(O)O)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2ncc([N+](=O)[O-])cc2C)c1
Temperature: 25 °C
Yield: 48 %

Procedure:
A solution of {[4-(3-dihydroxyboranyl-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.058 mmol, 40 mg, Example 140: step a), 2-iodo-3-methyl-5-nitropyridine (0.08 mmol, 21.1), CuI (0.01 mmol, 2.2) and (Ph3P)4Pd (0.006 mmol) in DMF (0.6 mL) was heated at 100° under Ar for 3 hr. The reaction mixture was allowed to cool to RT and poured in to water (20 mL). The product was extracted with CH2Cl2 (3×10 mL). CH2Cl2 extracts were combined, dried (Na2SO4) and concentrated in vaccuo. The resulting residue was purified on silica (30% EtOAc:Hexane) to obtain (Imino-{4-[3-(3-methyl-5-nitro-pyridin-2-yl)-benzenesulfonyl]-5-methylsulfanyl-thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester. Yield: 48%; 1H NMR (CDCl3) δ 9.36 (br, 1H), 8.37 and 8.25 (s, 1H each), 8.1 and 7.8 (d, J=2.4 Hz, 1H each), 7.93 (s, 1H), 7.74 (t, J=6.8 Hz, 1H), 2.7 and 2.5 (s, 3H each), 1.35 (s, 9H)