Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(O)[CH2:10][CH2:11][CH3:12].S(=O)(=O)(O)O.[CH2:19](Cl)Cl>>[C:11]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[OH:8])([CH3:10])([CH3:12])[CH3:19]
Reactant: ClCCl
Reactant: Oc1ccc(F)cc1
Reactant: CCCCO
Agent: O=S(=O)(O)O
Product: CC(C)(C)c1cc(F)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
4-Fluorophenol (5 g, 45 mmol) and tent-butanol (5.9 mL, 63 mmol) were dissolved in CH2Cl2 (80 mL) and treated with concentrated sulfuric acid (98%, 3 mL). The mixture was stirred at room temperature overnight. The organic layer was washed with water, neutralized with NaHCO3, dried over MgSO4 and concentrated. The residue was purified by column chromatography (5-15% EtOAc-Hexane) to give 2-tert-butyl-4-fluorophenol (3.12 g, 42%). 1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 6.89 (dd, J=11.1, 3.1 Hz, 1H), 6.84-6.79 (m, 1H), 6.74 (dd, J=8.7, 5.3 Hz, 1H), 1.33 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([OH:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[N:9]1.Br[CH2:19][C:20]([O:22][CH3:23])=[O:21].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([O:13][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:11][C:10]([C:14]([F:17])([F:15])[F:16])=[N:9]1
Reactant: COC(=O)CBr
Reactant: Oc1cc(C(F)(F)F)nn1-c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)COc1cc(C(F)(F)F)nn1-c1ccccc1Cl
Temperature: 85 °C
Reaction time: 8 h
Yield: 53.8 %

Procedure:
A mixture of 1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-ol (0.26 g, 1 mmol), methyl bromoacetate (0.195 mL, 2 mmol) and K2CO3 (276 mg, 2 mmol) in acetonitrile (2 mL) was shaken overnight at 85° C. After cooling, solid was removed by filtration and washed with acetonitrile. The filtrate was evaporated to give a crude, which was purified by chromatography on silica gel eluting with EtOAc-Hexane (1:4) to give methyl {[1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy}acetate (180 mg). 1H-NMR (CDCl3): δ 7.52 (2H, m), 7.42 (2H, m), 5.91 (1H, s), 4.67 (2H, s), 3.80 (3H, s). MS (ES): 335 [M+H]+
Reaction SMILES: [C@@H:1]1([NH:10][C:11]2[C:20]3[CH:19]=[N:18][CH2:17][N:16]([NH2:21])[C:15]=3[N:14]=[CH:13][N:12]=2)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]1[OH:3].C(O[C:26](=[O:28])[CH3:27])(=O)C>>[C:2]([O:3][C@@H:2]1[C@H:4]([O:5][C:4](=[O:5])[CH3:6])[C@@H:6]([CH2:8][O:9][C:26](=[O:28])[CH3:27])[O:7][C@H:1]1[NH:10][C:11]1[C:20]2[CH:19]=[N:18][CH2:17][N:16]([NH2:21])[C:15]=2[N:14]=[CH:13][N:12]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)OC(C)=O
Reactant: NN1CN=Cc2c(N[C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)ncnc21
Product: CC(=O)OC[C@H]1O[C@@H](Nc2ncnc3c2C=NCN3N)[C@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
reacting said N4 -(β-D-ribofuranosyl)pyrimido[4,5-d]pyrimidine-4,8-diamine with acetic anhydride in the presence of an acid scavenger to produce N4 -(2,3,5-tri-O-acetyl β-D-ribofuranosyl)pyrimido[4,5-d]pyrimidine-4,8-diamine or, alternatively reacting said N4 -(β-D-ribofuranosyl)pyrimido[4,5-d]pyrimidine-4,8-diamine with phosphoryl chloride in trimethylphosphate at a temperature below about 10° C. to produce N4 -(5-O-phosphono-β-D-ribofuranosyl)pyrimido[4,5-d]pyrimidine-4,8-diamine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C@@H:5]([NH2:20])[C:6]1[CH:11]=[CH:10][C:9]([NH:12]C(OC(C)(C)C)=O)=[CH:8][CH:7]=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C@@H:5]([NH:20][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[CH:10][CH:11]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)C[C@@H](N)c1ccc(NC(=O)OC(C)(C)C)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H](NC(=O)c1ccccc1)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 2.25 h

Procedure:
A solution of (R)-3-amino-3-[4-(tert-butoxycarbonylamino)phenyl]-propanoic acid methyl ester [3.0 g, Reference Example 7(c)] in dimethylformamide (50 ml), was treated with benzoyl chloride (1.24 ml) and triethylamine (1.56 ml). After stirring at ambient temperature for 2.25 hours, the mixture was evaporated to dryness and the resultant solid washed with water before being fried in vacuo. The resulting white solid (3.8 g) was dissolved in dichloromethane (70 ml) and the solution was treated with trifluoracetic acid (20 ml). After stirring at ambient temperature for 45 minutes, the reaction mixture was evaporated. The residue was treated with toluene (70 ml), concentrated to dryness and the resultant material treated with dichloromethane (200 ml). The resultant suspension was treated with saturated aqueous potassium carbonate solution (20 ml) with stirring at ambient temperature for 5 minutes. The organic layer was separated, dried over magnesium sulphate, and then evaporated to give the title compound as a white foam (2.0 g).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.C(N(CC)CC)C.[S:14](Cl)([CH3:17])(=[O:16])=[O:15]>C(Cl)Cl>[CH3:17][S:14]([O:6][C@H:3]1[CH2:4][CH2:5][O:1][CH2:2]1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1CCOC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.6 %

Procedure:
A solution of tetrahydrofuran-3-ol (25.0 g, 283 mmol) in 150 ml of DCM was cooled to 0° C., to this was added triethylamine (59 ml, 425 mmol) and mesylchloride (26.0 ml, 340 mmol), stirred the reaction mixture for 4 h at room temperature. TLC indicated reaction completion, it was diluted with DCM (100 ml), washed with water and brine solution, dried over anhydrous sodium sulfate, organic layer was evaporated to yields (44.0 g) of title product which was used as such for the next step.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:43][CH:44]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH2:45][NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50]>C(Cl)Cl>[Br:1][C:2]1[S:6][C:5]([C:7]([NH:43][CH:44]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH2:45][NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:50])[CH3:51])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)s1
Reactant: CC(C)(C)OC(=O)NCC(N)c1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(NC(=O)c1ccc(Br)s1)c1ccccc1
Reaction time: 16 h
Yield: 299.5 %

Procedure:
To a solution of 5-bromo-2-thiophenecarboxylic acid (3.2 g, 15.2 mmol), PyBrOP (8.5 g, 18.2 mmol) and diisopropylethyl amine (10.6 mL, 60.9 mmol) in DCM (76 mL) at 25° C. was added 1,1-dimethylethyl (2-amino-2-phenylethyl)carbamate (3.6 g, 3.14 mmol) [prepared in Preparation 1]. After 16 h, the solution was partitioned between H2O and washed with DCM. The combined organic fraction were dried (Na2SO4), concentrated and purified via column chromatography (silica, 1% MeOH in DCM) affording the title compound (4 g, 62%) as a white solid: LC-MS (ES) m/z=426 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:11])[CH2:5][CH2:6][C:7]([CH3:10])([CH3:9])[CH:8]=1.[C:12](OCC)(=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C(OCC)C.O1CCCC1>[CH3:1][O:2][C:3]1[C:4](=[O:11])[CH:5]([C:12](=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:6][C:7]([CH3:9])([CH3:10])[CH:8]=1
Reactant: COC1=CC(C)(C)CCC1=O
Reactant: CCOC(=O)C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C(=O)C1CC(C)(C)C=C(OC)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
A solution of 2-methoxy-4,4-dimethyl-cyclohex-2-enone (12.5 g, 81.1 mmol) and diethyl oxalate (12.1 mL, 89.2 mmol) in ethyl ether was treated with a 1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran under argon atmosphere. The reaction was stirred at room temperature for 2 hours, poured into a 10% NaH2PO4 solution (500 mL) and extracted with diethyl ether (300 mL×2). The organic extracts were washed with brine, dried on Na2SO4 and evaporated to dryness. The crude material was taken up with hexane, stirred and filtered to give the title compound (16.8 g, 81.5% yield) as a yellow crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11](O)=[O:12])=[CH:4][CH:3]=1.[CH3:15][NH:16][CH3:17]>O1CCCC1>[CH3:15][N:16]([CH3:17])[C:11](=[O:12])[CH2:10][CH2:9][C:8](=[O:14])[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: CNC
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Solvent: C1CCOC1
Product: CN(C)C(=O)CCC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 30.5 g (0.155 Mol) of 4-fluoro-γ-oxobenzenebutanoic acid in 470 ml tetrahydrofuran, 35.0 g (0.216 Mol) of N,N′-carbonyldiimidazole was added with stirring and at room temperature and held at room temperature for a further 2.5 hours. Then, 13.7 g (0.304 Mol) of dimethylamine was added under strong external cooling by means of an ice-ethanol mixture. After the mixture had stood at room temperature for 12 hours, the solvent was removed in vacuo, the residue was divided between dichloromethane and 10% aqueous citric acid solution, the organic phase was dried over sodium sulphate and once again evaporated down in vacuo. After purification by column chromatography (eluant:ethyl acetate) on silica gel the crude product yielded 30.22 g (87% of theory) of colourless crystals of Rf=0.31 (eluant:ethyl acetate/glacial acetic acid 99.99/0.01).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.N1C=CC=CC=1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>C(#N)C.O>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[NH:1][C:19](=[O:20])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ccc2ccccc2n1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: O
Solvent: c1ccncc1
Solvent: CC#N
Product: O=C(Nc1ccc2ccccc2n1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.8 %

Procedure:
2-Aminoquinoline (300 mg, 2.08 mmol) was dissolved in acetonitrile. To the reaction mixture was added pyridine (0.2 mL, 2.5 mmol) and phenyl chloroformate (0.27 mL, 2.18 mmol), respectively and stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. The crude was purified by column chromatography to give phenyl quinolin-2-ylcarbamate (296 mg, 54%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[O:12][C:11](=[O:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32]Br)=[CH:26][CH:25]=1)(=[O:23])[CH3:22]>CCO>[C:21]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][O:19][C:15]2[CH:14]=[C:13]3[C:18]([C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:10][C:11](=[O:20])[O:12]3)=[CH:17][CH:16]=2)=[CH:26][CH:25]=1)(=[O:23])[CH3:22]
Reactant: O=c1cc(OCc2ccccc2)c2ccc(O)cc2o1
Reactant: CC(=O)c1ccc(CCCBr)cc1
Solvent: CCO
Product: CC(=O)c1ccc(CCCOc2ccc3c(OCc4ccccc4)cc(=O)oc3c2)cc1
Yield: 76.6 %

Procedure:
Alkylation of 4-benzyloxy-7-hydroxycoumarin (2.68; 0.01 mole) with 1-(4-acetylphenyl)-3-bromopropane (2.41g; 0.01 mole) as described in example 45 gave 3.28g (77%) of title compound of m.p. (EtOH) 117°νmax (mull) 1725, 1682, 1620cm-1 ; τ(DMSO) 7.92 (2H, m); 7.48(3H, s); 7.18 (2H, m); 5.94(2H, t, J 6.4Hz); 6.69(2H, s); 6.16 (1H,s); 3.17-2.00(12H,m). (Found; C, 75.14; H, 5.52; C21H24O5 requires; C, 75.68; H, 5.65%
Reaction SMILES: C(Cl)(Cl)Cl.[NH2:5][CH:6]1[C:14]2[C:9](=[C:10]([CH3:17])[CH:11]=[C:12]([CH3:16])[C:13]=2[OH:15])[CH2:8][CH2:7]1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(N(CC)CC)C>[CH3:18][S:19]([NH:5][CH:6]1[C:14]2[C:9](=[C:10]([CH3:17])[CH:11]=[C:12]([CH3:16])[C:13]=2[OH:15])[CH2:8][CH2:7]1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(C)c2c(c1O)C(N)CC2
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)c2c(c1O)C(NS(C)(=O)=O)CC2
Reaction time: 4 h
Yield: 22.7 %

Procedure:
Into 100 ml of a chloroform solution containing 1.77 g of 1-amino-4,6-dimethyl-7-hydroxyindane and 2 ml of triethylamine was added dropwise 1.72 g of methanesulfonyl chloride at a room temperature, the mixture was stirred at the same temperature for 4 hours. The reaction mixture was washed with a diluted hydrochloric acid, water, a saturated sodium bicarbonate aqueous solution, water and a saturated sodium chloride aqueous solution, in this order, then dried with anhydrous sodium sulfate. The solvent was removed by evaporation and the residue was recrystallized from ether-n-hexane to obtain 0.58 g of 1-methanesulfonylamino-4,6-dimethyl-7-hydroxyindane in the form of colorless powdery substance. Melting point: 114°-116° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][NH:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[NH:15][C:16]1[N:21]=[C:20](SC#N)[C:19]([N+:25]([O-:27])=[O:26])=[CH:18][N:17]=1.Cl.[F:35][C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[O:42][CH2:41][CH2:40][C@H:39]2[NH2:46].O>CS(C)=O.CCN(C(C)C)C(C)C>[CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][NH:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[NH:15][C:16]1[N:21]=[C:20]([NH:46][C@H:39]2[C:38]3[C:43](=[CH:44][CH:45]=[C:36]([F:35])[CH:37]=3)[O:42][CH2:41][CH2:40]2)[C:19]([N+:25]([O-:27])=[O:26])=[CH:18][N:17]=1
Reactant: COc1ccc(CNc2ccc(C#N)cc2Nc2ncc([N+](=O)[O-])c(SC#N)n2)c(OC)c1
Reactant: N[C@@H]1CCOc2ccc(F)cc21
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2ccc(C#N)cc2Nc2ncc([N+](=O)[O-])c(N[C@@H]3CCOc4ccc(F)cc43)n2)c(OC)c1
Temperature: 25 °C

Procedure:
A solution of 4-(2,4-dimethoxybenzylamino)-3-(5-nitro-4-thiocyanatopyrimidin-2-ylamino)benzonitrile (139 mg) in anhydrous DMSO (3 mL) was added to solution of (R)-6-fluorochroman-4-amine hydrochloride (79 mg) in anhydrous DMSO (3 mL) and DIEA (0.21 mL), the resulting dark red solution was stirred at RT under an atmosphere of Ar over which time the solution lighten to yellow. Upon completion of the reaction, the mixture was cooled to 0° C. with an ice bath, and water (25 mL) was added (exotherm). The resulting yellow solid was collected via filtration, washed with additional water, air dried, then dissolved in CH2Cl2, the organic solution was dried (MgSO4), filtered and evaporated to yield the titled compound (quant.), NMR CDCl3 1H δ 9.0 (s, 1H), 8.6 (d, 1H), 7.7 (br s, 1H), 7.4 (dd, 1H), 7.1 (d, 1H), 7.0-6.8 (m, 4H), 6.5-6.4 (m, 2H), 5.2 (br s, 1H), 4.3 (s, 2H), 4.2 (br s, 2H), 3.8 (s, 6H), 2.2 (br s, 1H), 1.8 (br s, 1H); 19F δ −123 ppm; MH+=572.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC[C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([Cl:52])[CH:47]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH2:15][C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([Cl:52])[CH:47]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: Clc1cccc(CCBr)c1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(CCc3cccc(Cl)c3)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(2-bromoethyl)-3-chlorobenzene and isolated as light yellow gum. MS (m/e): 421.3 (MH+).
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)[CH3:2].BrCC#N.[N:14]([C:17]1[CH:42]=[CH:41][C:20]([CH2:21][O:22][C:23]([NH:25][CH2:26][CH2:27][CH2:28][C@H:29]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:30]([OH:32])=[O:31])=[O:24])=[CH:19][CH:18]=1)=[N+:15]=[N-:16]>C(#N)C>[N:14]([C:17]1[CH:42]=[CH:41][C:20]([CH2:21][O:22][C:23]([NH:25][CH2:26][CH2:27][CH2:28][C@H:29]([NH:33][C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[C:30]([O:32][CH2:2][C:1]#[N:4])=[O:31])=[O:24])=[CH:19][CH:18]=1)=[N+:15]=[N-:16]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccc(N=[N+]=[N-])cc1)C(=O)O
Agent: N#CCBr
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccc(N=[N+]=[N-])cc1)C(=O)OCC#N
Reaction time: 1 h
Yield: 103.7 %

Procedure:
N,N-Diisopropylethylamine (173 μL, 0.991 mmol) and subsequently bromoacetonitrile (314 μL, 4.50 mmol) were added to a solution of (S)-5-((((4-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)pentanoic acid (Compound tk57) (367 mg, 0.901 mmol) in acetonitrile (1 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 1 hour and then concentrated under reduced pressure, and the resulting crude product was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (S)-cyanomethyl 5-((((4-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)pentanoate (Compound tk58) (417.2 mg, quant.).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1)=[O:7].[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=1)=[O:18]>>[Cl:14][C:10]1[CH:9]=[C:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:29]2[CH2:30][CH2:31][CH:26]([C:22]3[CH:21]=[C:20]([NH:19][C:17](=[O:18])[CH:16]([CH3:15])[CH3:32])[CH:25]=[CH:24][CH:23]=3)[CH2:27][CH2:28]2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(CCCCCl)c1cccc(Cl)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(Cl)c3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme E using 5-chloro-1-(3-chlorophenyl)-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 441.1 (M+H)+.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[CH3:7][S:8][C:9]1[N:10]=[C:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:15]2=[O:31])[S:12][CH:13]=1>O.C(O)(C)C.C(Cl)(Cl)Cl>[CH3:7][S:8]([C:9]1[N:10]=[C:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]([CH2:23][C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[C:15]2=[O:31])[S:12][CH:13]=1)=[O:1]
Reactant: O=S([O-])OO
Reactant: CSc1csc(-n2c(=O)n(CC(=O)OC(C)(C)C)c3ccccc32)n1
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: CS(=O)c1csc(-n2c(=O)n(CC(=O)OC(C)(C)C)c3ccccc32)n1
Reaction time: 2 h

Procedure:
A solution of OXONE® in H2O (0.5 mL) was added to a solution of tert-butyl {3-[4-(methylthio)-1,3-thiazol-2-yl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}acetate from Step C (110 mg, 0.291 mmol) in isopropanol (1 mL) and CHCl3 (1 mL) at 0° C. After 2 h, the mixture was quenched with saturated aqueous NaCl and extracted with CHCl3 (2×10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—90:10 to 50:50, to give the title compound. MS: m/z=394 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[C:8](F)[C:7]([CH3:12])=[CH:6][C:3]=1[C:4]#[N:5].[OH:13][C:14]([C@H:17]1[CH2:21][CH2:20][NH:19][C@H:18]1[CH3:22])([CH3:16])[CH3:15].C(=O)([O-])[O-].[Li+].[Li+]>>[Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([N:19]2[CH2:20][CH2:21][C@H:17]([C:14]([OH:13])([CH3:16])[CH3:15])[C@@H:18]2[CH3:22])[C:7]([CH3:12])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1cc(C#N)c(Cl)c(Cl)c1F
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: Cc1cc(C#N)c(Cl)c(Cl)c1N1CC[C@H](C(C)(C)O)[C@@H]1C

Procedure:
Using 2,3-dichloro-4-fluoro-5-methylbenzonitrile (1.02 g), (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (1.04 g) and lithium carbonate (776 mg), the title compound was obtained as a colorless solid (yield: 68 mg) by an operation similar to that in Example 3.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][C:3]#[C:4][CH3:5].[C:7]1(=[O:13])[O:12][C:10](=[O:11])[CH:9]=[CH:8]1>C1(C)C=CC=CC=1.CS(O)(=O)=O>[C:10]([O:12][CH2:5][CH2:4][C:3]#[C:2][CH3:1])(=[O:11])/[CH:9]=[CH:8]\[C:7]([O:6][CH2:1][CH2:2][C:3]#[C:4][CH3:5])=[O:13]
Reactant: CC#CCCO
Reactant: O=C1C=CC(=O)O1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CC#CCCOC(=O)/C=C\C(=O)OCCC#CC

Procedure:
15 g of 3-pentyn-1-ol was reacted with 8.35 g of maleic anhydride in 25 ml of toluene and in the presence of one drop of methanesulfonic acid. 11.5 g of DPTNM was isolated from the reaction mixture (bp=134-140° C./full vacuum GC purity=98.8%). 1H NMR data: 1.77(t, J=3 Hz, CH3), 2.52 (m, CH2CC), 4.22(t, J=7 Hz, CH2 --O), 6.22(s, maleate olefin CHs).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(=[O:12])[O:11][CH2:10][CH2:9]1>C(#N)C>[C:2]1([NH:1][CH2:10][CH2:9][C:8]([OH:12])=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCO1
Reactant: Nc1ccccc1
Solvent: CC#N
Product: O=C(O)CCNc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Aniline (9.11 mL, 100 mmol) was dissolved in acetonitrile (100 mL) and heated to reflux while β-propiolactone (Sigma, 6.29 mL, 100 mmol) in acetonitrile (20 mL) was added dropwise for 30 minutes. The mixture was refluxed for 3 hours and then stirred overnight at ambient temperature. The mixture was concentrate under reduced pressure, and chromatographed on silica gel eluting with 40-to-100% ethyl acetate in hexane to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 2.69 (t, J=6.27 Hz, 2H), 3.48 (t, J=6.44 Hz, 2H), 6.66 (dd, J=8.81, 1.02 Hz, 2H), 6.75 (t, J=7.46 Hz, 1H), 7.20 (dd, J=8.65, 7.29 Hz, 2H). MS (DCI) m/z 166.05 (M+H)+.
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH:13]2[CH2:18][CH2:17][CH:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C@:23]1([CH3:29])[CH2:27][O:26][C:25](=[O:28])[NH:24]1)=[CH:7]2.[F:30][C:31]([F:43])([F:42])[O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O.C(OC(=O)C)C>[C:19]([C@H:16]1[CH2:17][CH2:18][C@H:13]([O:12][C:11]2[C:2]([C:36]3[CH:35]=[CH:34][C:33]([O:32][C:31]([F:30])([F:42])[F:43])=[CH:38][CH:37]=3)=[C:3]3[C:8](=[CH:9][CH:10]=2)[CH:7]=[C:6]([C@:23]2([CH3:29])[CH2:27][O:26][C:25](=[O:28])[NH:24]2)[CH:5]=[CH:4]3)[CH2:14][CH2:15]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2Br)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2-c2ccc(OC(F)(F)F)cc2)CC1
Temperature: 95 °C
Reaction time: 0.08 h

Procedure:
(R)-4-[5-Bromo-6-(4-tert-butyl-cyclohexyloxy)-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (0.2079 g, 0.0004516 mol), 4-trifluoromethoxy phenylboronic acid (0.130 g, 0.000632 mol), tetrakis(triphenylphosphine)palladium(0) (0.03 g, 0.00002 mol) and sodium carbonate (0.191 g, 0.00181 mol) were added to a capped 40 mL EPA vial equipped with a magnetic stir bar. The vial was degassed and purged with nitrogen. 1,2-Dimethoxyethane (5.00 mL, 0.0481 mol) was added and the mixture was stirred for 5 minutes. Water (3.00 mL, 0.166 mol) was then added and the mixture was heated at 95° C. After 3 h, HPLC analysis showed that the reaction was complete. Ethylacetate (5 mL) and water (5 mL) were added and the layers were separated. The combined organic phase was then dried over MgSO4, filtered, concentrated and purified by flash chromatography (0-55% EtOAc in hexane) to give 204.1 mg of the title compound (83% yield).