Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][O:22][CH3:23])=[C:16]([F:24])[CH:15]=1.[Cl-].[NH4+].[O:27]1CCC[CH2:28]1>CN(C)C=O>[Br:13][C:14]1[C:15]([CH:28]=[O:27])=[C:16]([F:24])[C:17]([O:20][CH2:21][O:22][CH3:23])=[CH:18][CH:19]=1
Reactant: C1CCOC1
Reactant: COCOc1ccc(Br)cc1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: COCOc1ccc(Br)c(C=O)c1F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of diisopropylamine (364 μl) in tetrahydrofuran (1 ml) was cooled to −78° C., and thereto was added dropwise n-butyl lithium (0.86 ml, 2.77M hexane solution), and the mixture was stirred at 0° C. for 10 minutes. The reaction mixture was cooled to −78° C., and thereto was added dropwise a solution of 1-bromo-3-fluoro-4-(methoxymethoxy)benzene (470 mg) in tetrahydrofuran (1 ml), and the mixture was stirred for 30 minutes. To the mixture was added dropwise N,N-dimethyl-formamide (210 μl), and the mixture was stirred at room temperature for one hour. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate, washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (48 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH3:37])[CH2:9][O:10][C:11]([NH:13][C:14]2[CH:15]=[C:16]([F:36])[C:17]([O:30][CH2:31][CH2:32][CH2:33][O:34][CH3:35])=[C:18]([CH:29]=2)[CH2:19][N:20]([CH3:28])[C:21](=[O:27])[O:22]C(C)(C)C)=[O:12])=[C:4]([CH3:38])[CH:3]=1.Cl.C(N(CC)C(C)C)(C)C.[CH2:49](OC(ON1C(=O)CCC1=O)=O)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH3:37])[CH2:9][O:10][C:11]([NH:13][C:14]2[CH:15]=[C:16]([F:36])[C:17]([O:30][CH2:31][CH2:32][CH2:33][O:34][CH3:35])=[C:18]([CH:29]=2)[CH2:19][N:20]([CH3:28])[C:21](=[O:27])[O:22][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[O:12])=[C:4]([CH3:38])[CH:3]=1
Reactant: COCCCOc1c(F)cc(NC(=O)OC[C@H](C)c2ccc(Br)cc2C)cc1CN(C)C(=O)OC(C)(C)C
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCCOc1c(F)cc(NC(=O)OC[C@H](C)c2ccc(Br)cc2C)cc1CN(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a solution of 28B (450 mg, 0.753 mmol) in EtOAc (6 mL), was added HCl (4N, 6 mL). The mixture was stirred rt for 2 h, and concentrated. The residue was dissolved in DMF (10 ml), N,N-diisopropylethylamine (0.525 ml, 3.01 mmol) was added, followed by N-(benzyloxycarbonyloxy) succinimide (206 mg, 0.828 mmol). The mixture was stirred rt for 1 h, quenched with water, extracted with EtOAc (3×30 ml). The organic layer was washed with brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0-60% EtOAc in hexanes) to give 28C (376 mg, 0.595 mmol, 79% yield). MS (ESI) m/z: 631.0 (M+H)+.
Reaction SMILES: [C:1](=[N:4][OH:5])([NH2:3])[CH3:2].[H-].[Na+].CO[C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[N:13][C:12]=1[N:17]1[CH:21]=[C:20]([CH2:22][N:23]2[CH2:39][CH2:38][C:26]3([C:31]4[S:32][C:33]([Cl:35])=[CH:34][C:30]=4[C:29]([F:37])([F:36])[CH2:28][O:27]3)[CH2:25][CH2:24]2)[C:19]([CH3:40])=[N:18]1>O1CCCC1>[Cl:35][C:33]1[S:32][C:31]2[C:26]3([CH2:25][CH2:24][N:23]([CH2:22][C:20]4[C:19]([CH3:40])=[N:18][N:17]([C:12]5[C:11]([C:10]6[O:5][N:4]=[C:1]([CH3:2])[N:3]=6)=[CH:16][CH:15]=[CH:14][N:13]=5)[CH:21]=4)[CH2:39][CH2:38]3)[O:27][CH2:28][C:29]([F:36])([F:37])[C:30]=2[CH:34]=1
Reactant: COC(=O)c1cccnc1-n1cc(CN2CCC3(CC2)OCC(F)(F)c2cc(Cl)sc23)c(C)n1
Reactant: CC(N)=NO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(-c2cccnc2-n2cc(CN3CCC4(CC3)OCC(F)(F)c3cc(Cl)sc34)c(C)n2)n1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 22.2 %

Procedure:
To a solution of acetamide oxime (154 mg, 2.1 mmol) in 7 mL tetrahydrofuran, are added under argon 139 mg of grinded 4A molecular sieves and sodium hydride (2.1 mmol; 84 mg as 60% in mineral oil). The mixture is allowed to stir for 30 min at 50° C. After cooling to room temperature, 2-(4-((2′-chloro-4′,4′-difluoro-4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran]-1-yl)methyl)-3-methyl-1H-pyrazol-1-yl)-nicotinic acid methyl ester (309 mg, 0.6 mmol) is added and then the mixture is heated at 50° C. for 40 min. Quenched after cooling with water and extracted with dichloromethane. After drying the organic phase with magnesium sulfate and evaporation of the solvent, the residue is diluted in methanol and purified using a 5 g SCX cartridge. The resulting residue is further purified by semipreparative reverse phase HPLC_MS using a XBridge column (Sum, 19×100 mm) and a gradient between 60 and 80% of B in A in 5 min at flow 25 mL/min (basic conditions A: ammonium bicarbonate 20 mM pH9 and B: acetonitrile) to give 71 mg of the title compound. MS (m/z): 533 (M+1).
Reaction SMILES: [CH:1]([C:4]1[N:26]=[C:7]2[CH:8]=[C:9]([NH:12][C:13]([C:15]3[N:19]([CH3:20])[N:18]=[CH:17][C:16]=3[C:21]([O:23]CC)=[O:22])=[O:14])[CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].O.[OH-].[Li+]>CO.O>[CH:1]([C:4]1[N:26]=[C:7]2[CH:8]=[C:9]([NH:12][C:13]([C:15]3[N:19]([CH3:20])[N:18]=[CH:17][C:16]=3[C:21]([OH:23])=[O:22])=[O:14])[CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(C(C)C)nc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)c1nc2cc(NC(=O)c3c(C(=O)O)cnn3C)ccn2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.7 %

Procedure:
A mixture of ethyl 5-(2-isopropyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylate (330 mg, 926 μmol) and lithium hydroxide monohydrate (155 mg, 3.7 mmol) in methanol (6 ml) and water (2 ml) is stirred for 18 hours at 25° C. The solvents are evaporated, the white residue is dissolved in water and acidified with 37% aqueous hydrochloric acid. The precipitated white solid is collected by filtration, washed with water and dried affording 5-(2-isopropyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (285 mg, 93.7%) as a white solid. Mp.: >250° C. MS: m/z=327.3 (M−H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[OH:26][CH2:27][CH2:28][N:29]([CH2:39][CH2:40][OH:41])[S:30]([C:33]1[S:34][C:35](Cl)=[CH:36][CH:37]=1)(=[O:32])=[O:31]>>[OH:26][CH2:27][CH2:28][N:29]([CH2:39][CH2:40][OH:41])[S:30]([C:33]1[S:34][C:35]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:36][CH:37]=1)(=[O:32])=[O:31]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: O=S(=O)(c1ccc(Cl)s1)N(CCO)CCO
Product: O=S(=O)(c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1)N(CCO)CCO

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (178 mg, 0.5 mmol) and 5-chloro-thiophene-2-sulfonic acid bis-(2-hydroxy-ethyl)-amide (example B.40) (143 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (60 mg, 20%). MS (ISP) 622.0 [(M+NH4)+]; mp 137° C.
Reaction SMILES: BrC(C)[C:3](=[O:11])[CH:4]([CH3:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[OH-].[K+]>O>[OH:11][C:3]1[CH:8]([CH3:9])[O:7][C:5](=[O:6])[C:4]=1[CH3:10]
Reactant: CCOC(=O)C(C)C(=O)C(C)Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC1=C(O)C(C)OC1=O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To ethyl 4-bromo-2-methyl-3-oxopentanoate (7.49 g, 31.6 mmol) was added cold potassium hydroxide (4.7 g, 84 mmol) in water (36 mL) at 0° C., the resulting mixture was vigorously stirred at 0° C. for 4 h. The reaction mixture was extracted with methylene chloride (2×100 mL), the alkaline phase was acidified to ph 1 by 6N hydrogen chloride followed by extraction with methylene chloride (3 times 100 mL). The combined latter organic phase was dried over sodium sulfate, and concentrated to give 4-hydroxy-3,5-dimethylfuran-2(5H)-one. LCMS: (M+23)+: 151.10, 1HNMR (500 MHz, CDCl3), δ4.882-4.842 (dd, J=6.8 Hz, 1H), 3.744 (s, 1H), 1.759(s, 3H). 1.526-1.513 (d, J=6.8 Hz, 3H).
Reaction SMILES: CO[C:3]([C:5]1[C:17](=[O:18])[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[N:15]2[C:7](=[CH:8][C:9]3[C:14]2=[CH:13][C:12]([C:27]([F:30])([F:29])[F:28])=[CH:11][CH:10]=3)[C:6]=1[OH:31])=[O:4].[NH2:32][C@H:33]([C:35]([OH:37])=[O:36])[CH3:34].C[O-].[Na+]>COCCO>[F:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:16]2[N:15]3[C:7](=[CH:8][C:9]4[C:14]3=[CH:13][C:12]([C:27]([F:30])([F:28])[F:29])=[CH:11][CH:10]=4)[C:6]([OH:31])=[C:5]([C:3]([NH:32][C@@H:33]([CH3:34])[C:35]([OH:37])=[O:36])=[O:4])[C:17]2=[O:18])=[CH:25][CH:24]=1
Reactant: C[C@H](N)C(=O)O
Reactant: COC(=O)c1c(O)c2cc3ccc(C(F)(F)F)cc3n2n(Cc2ccc(F)cc2)c1=O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: C[C@H](NC(=O)c1c(O)c2cc3ccc(C(F)(F)F)cc3n2n(Cc2ccc(F)cc2)c1=O)C(=O)O
Yield: 30.1 %

Procedure:
A mixture of 4-(4-fluoro-benzyl)-1-hydroxy-3-oxo-6-trifluoromethyl-3,4-dihydro-4,4a-diaza-fluorene-2-carboxylic acid methyl ester (compound 43 d) (100 mg, 0.23 mmol), L-alanine (205 mg, 2.3 mmol) and sodium methoxide (99 mg, 1.84 mmol) in 2-methoxyethanol (3.5 mL) was microwaved at 150° C. for 2 h and concentrated. Residue was dissolved in water (80 mL), acidified to pH=3-4 using 1 N HCl solution and extracted with EtOAc. Organic layer was washed with brine, dried over MgSO4, filtered and concentrated. Crude product was purified by silica gel chromatography (15%-70% EtOAc (with 0.075% HOAc)/hexanes (with 0.1% HOAc)) to provide the title compound 34 mg. ESI (m/z): 490.03 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2Br)[CH:6]=1)[CH3:2].[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[C:24](B(O)O)[CH:25]=1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2[C:22]2[CH:21]=[C:20]([Cl:19])[CH:25]=[CH:24][C:23]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH:6]=1)[CH3:2]
Reactant: OB(O)c1cc(Cl)ccc1OCc1ccc(F)cc1
Reactant: CCOC(=O)c1cc(F)cc(C2=C(Br)CCC2)c1
Product: CCOC(=O)c1cc(F)cc(C2=C(c3cc(Cl)ccc3OCc3ccc(F)cc3)CCC2)c1

Procedure:
Prepared by general procedure B(iii) but using 3-(2-bromocyclopent-1-enyl)-5-fluorobenzoic acid ethyl ester instead of 3-(2-bromo-cyclopent-1-enyl)-6-methylbenzoic acid ethyl ester and using [5-chloro-2-(4-fluorobenzyloxy)phenyl]boronic acid instead of (5-chloro-2-benzyloxyphenyl)boronic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])[CH:5]=[C:6]([F:25])[C:7]=1[O:8][CH2:9][C:10]1[N:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]=[CH:13][C:14]=1[C:15]([F:18])([F:17])[F:16].O1CCCC1.[Li+].[OH-]>O>[F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH:5]=[C:6]([F:25])[C:7]=1[O:8][CH2:9][C:10]1[N:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]=[CH:13][C:14]=1[C:15]([F:18])([F:16])[F:17]
Reactant: CCOC(=O)CCc1cc(F)c(OCc2c(C(F)(F)F)ccn2-c2ccccc2)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCc1cc(F)c(OCc2c(C(F)(F)F)ccn2-c2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
Into a 25-mL round-bottom flask, was placed ethyl 3-(3,5-difluoro-4-[[1-phenyl-3-(trifluoromethyl)-1H-pyrrol-2-yl]methoxy]phenyl)propanoate (100 mg, 0.22 mmol, 1.00 equiv), tetrahydrofuran (1 mL) and a solution of LiOH (100 mg, 4.18 mmol, 18.93 equiv) in water (1 mL). The resulting solution was stirred overnight at 25° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting mixture was then concentrated under vacuum. The pH value of the solution was adjusted to pH5 with hydrogen chloride (2 mol/L). The resulting solution was extracted with ethyl acetate (3×5 mL) and the organic layers combined. The resulting residue was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, silica gel; mobile phase, ACN/H2O(0.05% CF3COOH)=1:1 increasing to ACN/H2O(0.05% CF3COOH)=9:1 within 10 min; Detector, UV 254 nm to yield 3-(3,5-difluoro-4-[[1-phenyl-3-(trifluoromethyl)-1H-pyrrol-2-yl]methoxy]phenyl)propanoic acid as a white solid (22.5 mg, 23%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:37])[NH:13][C:14](=[O:36])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26][CH2:27][NH:28][C:29](SC)=[CH:30][N+:31]([O-:33])=[O:32])[CH:17]=2)=[CH:3]1.[NH3:38]>C(O)C>[NH2:38][C:29]([NH:28][CH2:27][CH2:26][CH2:25][N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([C:15]2[C:14](=[O:36])[NH:13][C:12](=[O:37])[C:11]=2[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)=[CH:17]1)=[CH:30][N+:31]([O-:33])=[O:32]
Reactant: N
Reactant: CSC(=C[N+](=O)[O-])NCCCn1cc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c2ccccc21
Solvent: CCO
Product: Cn1cc(C2=C(c3cn(CCCNC(N)=C[N+](=O)[O-])c4ccccc34)C(=O)NC2=O)c2ccccc21
Temperature: 80 °C

Procedure:
A solution of 128 mg of the product of Example 51 in 30 ml of ethanol was treated with 10 ml of a saturated solution of ammonia in ethanol and the mixture was heated at 80° C. for 3 hours. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel with 10% methanol in dichloromethane to give 39 mg of 3-[1-[3-(1-amino-2-nitrovinylamino)propyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p. 206°-209° C. (decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[C:21]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)(=[O:23])[NH2:22]>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:28][C:27]3[CH:29]=[CH:30][C:24]([C:21](=[O:23])[NH2:22])=[CH:25][CH:26]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: NC(=O)c1ccc(N)cc1
Product: NC(=O)c1ccc(NC(=O)CC2CCc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)cc1
Yield: 56.9 %

Procedure:
A procedure similar to that described in Example 52 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (170 mg, 0.5 mmol) and p-carbamoylaniline (70 mg, 0.51 mmol) to give 130 mg of the title compound (57%): mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.05 (s, 1H), 10.23 (s, 1H), 7.85 (bs, 1H), 7.83 (d, 2H, J=8.6 Hz), 7.62 (d, 2H, J=8.6 Hz), 7.23 (bm, 2H), 7.17 (bs, 1H), 5.20~5.27 (m, 1H), 3.06 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.84 (dm, 1H, J=17.1 Hz), 2.63 (d, 2H, J=6.9 Hz), 2.12 (dm, 1H, J=13.5 Hz), 1.82~1.96 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[O:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30]1>>[O:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[C:31]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]4)[N:8]3[CH3:11])=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:3]=2)=[CH:30]1
Reactant: CC1(C)OB(c2coc3ccccc23)OC1(C)C
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-c3coc4ccccc34)nc21

Procedure:
Following the procedures for 140, 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol and 2-(benzofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was converted to 138. LCMS: M+H+=491.2. 1H-NMR (400 MHz, DMSO-d6): δ 8.75 (s, 1H), 8.58 (m, 1H), 7.66 (m, 1H), 7.40 (m, 2H), 4.66 (s, 2H), 4.31 (m, 4H), 3.90 (s, 3H), 3.80 (m, 4H), 3.68 (s, br, 1H), 3.12 (m, 2H), 2.90 (m, 2H), 1.90 (m, 2H), 1.56 (m, 3H), 1.06 (s, 6H)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[CH3:21]O>>[CH3:14][C:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)([CH3:15])[C:11]([O:13][CH3:21])=[O:12]
Reactant: CO
Reactant: CC(C)(C(=O)O)c1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)(C)c1ccc([N+](=O)[O-])cc1

Procedure:
To a solution of 5 g of 2-(4-nitrophenyl)-2-methylpropionic acid in 40 mL of methanol, under argon, are added 4 mL of sulphuric acid. The reaction medium is heated at reflux for 3 hours and concentrated under reduced pressure. The residue is taken up in a mixture of ice-water and dichloromethane, the phases are separated and the organic phase is dried over magnesium sulphate and filtered. The filtrate is concentrated under reduced pressure to give 5.18 g of methyl 2-methyl-2-(4-nitrophenyl)propanoate in the form of a pale yellow solid, the characteristics of which are as follows:
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH:15]2[CH2:19][CH:18]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]2[OH:28])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C[N+]1([O-])CCOCC1>ClCCl.C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH:15]2[CH2:19][CH:18]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][C:16]2=[O:28])[N:9]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CC2CC(NC(=O)OC(C)(C)C)CC2O)n1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cccc(CC2CC(NC(=O)OC(C)(C)C)CC2=O)n1
Yield: 67 %

Procedure:
Tetrapropylammonium perruthenate (0.07 mmol, 5 mol %) was added to a stirred solution of [6-(4-tert-butoxycarbonylamino-2-hydroxy-cyclopentylmethyl)-pyridin-2-yl]-carbamic acid tert-butyl ester IV-3 (0.14 mmol) and N-methylmorpholine-N-oxide (0.26 mmol) in dichloromethane (9 mL) and acteonitrile (1 mL) at room temperature, and was allowed to react overnight. When complete, the solvent was evaporated in vacuo and the residue was purified by column chromatography (silica gel, CH2Cl2:EtOAc, 8:2) to afford pure product as a white solid (67%).
Reaction SMILES: [C:1]([Si:5]([CH3:11])([CH3:10])[O:6][CH2:7][C:8]#[CH:9])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.B(F)(F)F.[CH3:21][CH2:22][O:23]CC.C(OC(=O)C)(=O)C>C1COCC1>[Si:5]([O:6][CH2:7][C:8]#[C:9][C:22](=[O:23])[CH3:21])([C:1]([CH3:3])([CH3:4])[CH3:2])([CH3:10])[CH3:11]
Reactant: CCOCC
Reactant: C#CCO[Si](C)(C)C(C)(C)C
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)C#CCO[Si](C)(C)C(C)(C)C
Temperature: 10 °C
Reaction time: 0.08 h
Yield: 48.9 %

Procedure:
To a solution of tert-butyldimethyl(prop-2-yn-1-yloxy)silane (15.1 g, 88.3%) in THF (300 mL), n-BuLi (67 mL, 105.9 mmol, 1.6 N in hexane) was added slowly at −78° C. After the addition was complete, the temperature was increased slowly to 10° C. over a period of 2 h. The reaction mixture was cooled again to −78° C. and BF3.OEt2 (14 mL, 105.9 mmol) added slowly and reaction mixture stirred at this temperature for 5 min. Acetic anhydride (11 mL, 115.6 mmol) was slowly added and the reaction was continued while temperature was allowed to rise to room temperature over a period of 2 h. After this time, reaction mass was quenched with 1N NaOH till pH 7-8 and biphasic solution was extracted with ethyl acetate. The organic layer was concentrated to obtain crude material which was further purified by column chromatography over silica gel to yield 5-((tert-butyldimethylsilyl)oxy)pent-3-yn-2-one (9.2 g, 52.6%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:31]([O:38][C:39](=[O:42])[CH2:40][NH2:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:10]([NH:41][CH2:40][C:39]([O:38][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:42])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccn1)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccn1)C(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
To a solution of (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-pyridyl)propanoic acid (55.0 g), glycine benzyl ester tosylate (69.7 g), and diphenylphosphoryl azide (46.7 ml) in N,N-dimethylformamide (550 ml) was added dropwise N,N-diisopropylethylamine (75.6 ml) at 4° C. The mixture was warmed to room temperature and stirred for 3 hours. The resulting mixture was poured into ice-cold saturated aqueous sodium hydrogencarbonate solution (700 ml). The mixture was extracted twice with ethyl acetate (total 1.3 L) and washed successively with water (400 ml×2), saturated aqueous ammonium chloride solution (200 ml), aqueous sodium hydrogencarbonate solution (300 ml×2), and brine (40 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated to give the title compound (77.4 g) as pale brown crystals.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C@:5]1([CH3:16])[O:9][C:8]2=[N:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][N:7]2[CH2:6]1.Cl[C:18]1[O:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1>CN(C=O)C>[CH3:16][C@@:5]1([CH2:4][O:3][C:18]2[O:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=3[N:22]=2)[O:9][C:8]2=[N:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][N:7]2[CH2:6]1
Reactant: C[C@]1(CO)Cn2cc([N+](=O)[O-])nc2O1
Reactant: Clc1nc2ccccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]1(COc2nc3ccccc3o2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 23.7 %

Procedure:
Sodium hydride (0.1 g, 2.4 mmol) was added to a solution of (R)-2-hydroxymethyl-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole prepared in Example 37 (0.40 g, 2.0 mmol) in DMF (4 ml) followed by stirring for 30 minutes with cooling on ice-bath. To the reaction mixture, 2-chlorobenzoxazole (0.38 g, 2.4 mmol) in DMF (4 ml) was added with cooling on ice-bath followed by stirring at room temperature for 48 hours. Ice-water was added to the reaction mixture. The precipitates were filtered off, washed with water, and then recrystallized from acetonitrile-isopropanol to afford (R)-2-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethoxy)benzoxazole (0.15 g, yield 24%) as a light yellow solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]([C:13]2[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[N:14]=2)[C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1.S(OC)(O[CH3:27])(=O)=O>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]([C:10]([C:13]2[N:14]=[C:15]([O:21][CH3:22])[CH:16]=[C:17]([O:19][CH3:20])[N:18]=2)([CH3:27])[C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cc(OC)nc(C(C#N)c2cccc(Cl)c2)n1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(C(C)(C#N)c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62 %

Procedure:
Sodium hydride (0.83 g of 80% in oil) was added to a stirred solution of the product of Example 48 (8.0 g) in dimethylformamide at room temperature. Dimethyl sulphate (3.5 g) was then added, and the mixture was stirred at room temperature for 4 hours. The mixture was poured onto water (250 ml), and the oil was extracted into ethyl acetate. The combined extracts were dried over magnesium sulphate, and evaporated to give an orange liquid, which was purified by chromatography to give 5.2 g of the desired product as a white solid, mp 89°-93° C.