Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[OH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[NH:13][OH:14].C(N(CC)CC)C.[CH3:22][O:23][C:24]([CH2:26][CH2:27][C:28](O)=[O:29])=[O:25].OS([O-])(=O)=O.[K+]>C1COCC1.O>[OH:14][N:13]([C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[OH:2])[C:28](=[O:29])[CH2:27][CH2:26][C:24]([O:23][CH3:22])=[O:25]
Reactant: ONc1ccc2ccccc2c1O
Reactant: COC(=O)CCC(=O)O
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)CCC(=O)N(O)c1ccc2ccccc2c1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of a 1.68 g (ca. 7.9 mmol) of 1-hydroxy-2-naphthylhydroxylamine hydrochloride in THF (10 ml) and water (2 ml) was added, 1.7 ml (12 mmol) of triethylamine, followed by addition of a solution of 300 mg (2 mmol) of acid chloride of 3-methoxycarbonylpropionic acid in THF (2 ml). The mixture was stirred at room temperature for 30 minutes, the reaction was completed by an addition of aqueous KHSO4, the mixture was extracted with methylene chloride, and the organic layer was dried over anhydrous magnesium sulfate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:8][C:7]([O:9][CH3:10])=[CH:6][CH2:5][CH:4]=1.C([Li])(C)(C)C.[I-].[Ba+2].[I-].[CH2:19](Cl)[CH:20]=[C:21]([CH3:23])[CH3:22]>C1COCC1.CCCCC>[CH3:1][O:2][C:3]1[CH:8]([CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])[C:7]([O:9][CH3:10])=[CH:6][CH2:5][CH:4]=1
Reactant: CC(C)=CCCl
Reactant: COC1=CCC=C(OC)C1
Agent: [Ba+2]
Agent: [I-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: COC1=CCC=C(OC)C1CC=C(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
A portion of barium iodide dihydrate was dried over 12 h at 150° C. under 6 mmHg vacuum in a 250-mL round-bottom flask to yield activated barium iodide (8.38 g, 21.4 mmol, 1.1 equiv.), which was taken up in THF (125 mL). Meanwhile, a THF (50 mL) solution of 1 (2.73 g, 19.5 mmol, 1 equiv.) was cooled to −78° C. in a 500-mL round-bottom flask, and a pentane solution of tert-butyllithium (1.63 M, 13.1 mL, 21.4 mmol, 1.1 equiv.) was added over 5 min. After stirring the resulting clear yellow solution at −78° C. for 1 h, the THF slurry of activated barium iodide was transferred via cannula to this solution over 15 min. After stirring the resulting yellow-tan slurry an additional 30 min at −78° C., a THF (2 mL) solution of 3 (2.4 mL, 21.4 mmol, 1.1 equiv.) was added, and the slurry was allowed to warm over 2.25 h. The reaction was then quenched with water and extracted thrice with EtOAc. The organic extracts were combined, washed twice with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting clear oil was slowly loaded onto a SiO2 plug and eluted with 98:2 hexane:EtOAc. The eluent was concentrated in vacuo to afford 2.90 g (13.3 mmol, 68% yield) of 11 as a clear, colorless oil. TLC Rf 0.77 (9:1 hexane:EtOAc). 1H NMR (600 MHz; CDCl3): δ 4.99 (t, J=7.4 Hz, 1H), 4.68 (dd, J=4.6, 3.0 Hz, 2H), 3.53 (s, 6H), 2.94-2.91 (m, 1H), 2.78 (ddt, J=20.7, 6.0, 3.0 Hz, 1H), 2.72 (dq, J=20.7, 4.6 Hz, 1H), 2.41 (dd, J=7.4, 4.7 Hz, 2H), 1.64 (s, 3H), 1.55 (s, 3H). 13C NMR (125 MHz; CDCl3): δ 154.5, 132.8, 120.6, 91.9, 54.4, 41.3, 28.5, 26.1, 24.7, 17.8.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([F:27])[CH:26]=1)[CH2:5][C@H:6]1[CH2:11][C@H:10]([C:12](=[O:19])[CH2:13][C:14](OCC)=[O:15])[CH2:9][CH2:8][N:7]1[C:20]([O:22][CH3:23])=[O:21].[OH-].[Na+].[NH2:30]O.Cl>CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([F:27])[CH:26]=1)[CH2:5][C@H:6]1[CH2:11][C@H:10]([C:12]2[O:19][NH:30][C:14](=[O:15])[CH:13]=2)[CH2:9][CH2:8][N:7]1[C:20]([O:22][CH3:23])=[O:21]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2cc(F)cc(F)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cc(F)cc(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 76 %

Procedure:
Trans-methyl 2-(3,5-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (0.927 g, 2.42 mmol) (from example 130, step 1) was dissolved in MeOH (8 mL) and cooled to −40° C. under nitrogen atmosphere. Sodium hydroxide (0.097 g, 2.42 mmol) dissolved in water (0.800 mL) was added over 7 min. After 20 min with stirring, hydroxylamine (50% by weight in water, 0.148 mL, 2.42 mmol) was added over 4.5 minutes and the solution was stirred for 3.5 hours at −40° C. The reaction mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (12.45 mL, 74.71 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and the crude mixture redissolved in DCM and washed with water. The organic phase was dried and concentrated. The compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-25% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Trans-methyl 2-(3,5-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.648 g, 76%) was isolated as a white solid. 1H NMR (400 MHz, cd3od) δ 1.45-2.12 (m, 4H), 2.80-3.35 (m, 4H), 3.35-3.70 (m, 3H), 4.12 (s, br., 1H), 4.62 (s, br., 1H), 5.71 (s, 1H), 6.77 (t, 1H), 6.87 (s, br., 2H). MS m/z 353 (M+H)+
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:6]2([CH2:10][CH2:9][N:8](C(OCC3C=CC=CC=3)=O)[CH2:7]2)[O:5][C:4](=[O:21])[NH:3]1.[H][H]>CO.[Pd]>[CH3:1][C:2]1([CH3:22])[C:6]2([CH2:10][CH2:9][NH:8][CH2:7]2)[O:5][C:4](=[O:21])[NH:3]1
Reactant: CC1(C)NC(=O)OC12CCN(C(=O)OCc1ccccc1)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1(C)NC(=O)OC12CCNC2

Procedure:
A mixture of benzyl 4,4-dimethyl-2-oxo-1-oxa-3,7-diazaspiro[4.4]nonane-7-carboxylate (0.50 g, 0.0016 mol) (2nd peak from chiral separation) in 20 mL of MeOH was hydrogenated in the presence of 10% Pd/C, under a balloon pressure of hydrogen, for 2 h. After filtering off the catalyst, the filtrate was concentrated to dryness and the resultant residue was used directly in next step. LCMS (M+H) 171.2.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[NH:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]1[O:20][CH:19]=[N:18][CH:17]=1.C([O-])(=O)C.[Na+]>ClCCCl.C(Cl)(Cl)Cl>[CH:3]([C:15]1[NH:11][C:12]([C:16]2[O:20][CH:19]=[N:18][CH:17]=2)=[CH:13][CH:14]=1)=[O:4]
Reactant: CN(C)C=O
Reactant: c1c[nH]c(-c2cnco2)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc(-c2cnco2)[nH]1
Temperature: 25 °C
Yield: 80 %

Procedure:
To an ice cooled 1 mL dimethylformamide was added 0.82 g (5.4 mmol) of phosphorus oxychloride while stirring under a nitrogen atmosphere. The mixture was stirred 20 minutes and then was added a solution of 0.60 g (4.5 mmol) of 5-(pyrrol-2-yl)oxazole in 15 mL of 1,2-dichloroethane while cooling in an ice bath. The reaction mixture was then heated under reflux for 20 minutes. After cooling to room temperature, 50 mL of chloroform was added followed by 60 mL of saturated aqueous sodium acetate. After heating under reflux for 20 minutes, the mixture was cooled to room temperature and the organic layer separated, washed with aqueous sodium carbonate and dried over anhydrous sodium sulfate. Following evaporation of the solvent at reduced pressure, the crude product was purified by column chromatography with chloroform elution to give 0.58 g (80%) of 5-(5-formylpyrrol-2-yl)oxazole as a white solid, m.p. 152°-153° C.; 1H-NMR (Acetone-d6) δ 6.68 (d, 1H, ArH), 7.09 (d, 1H, ArH), 7.61 (S, 1H, ArH), 8,22 (s, 1H, ArH), 9.57 (s, 1H, CHO).
Reaction SMILES: [F:1][C@H]1CCN(C(OC(C)(C)C)=O)C1.[C:14]([N:21]1[CH2:25][CH2:24][C@@H:23]([CH2:26]O)[CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].COCCN(S(F)(F)F)CCOC>ClCCl>[F:1][CH2:26][C@@H:23]1[CH2:24][CH2:25][N:21]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CO)C1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](F)C1
Agent: COCCN(CCOC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](CF)C1

Procedure:
Prepare using the method of Intermediate 48 with (R)-N-Boc-pyrrolidine-3-methanol (0.50 g, 2.48 mmol), [bis(2-methoxyethyl)amino]sulfur trifluoride (0.55 mL, 2.98 mmol) and anhydrous dichloromethane (2.5 mL) to give the title compound as a colourless oil (0.34 g): MS (m/e): 226 (M+23).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[CH2:18][N:19]2[C@@H:23]([CH3:24])[C@@H:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:21][C:20]2=[O:31])=[CH:6][C:5]([CH2:32][C:33]([OH:35])=[O:34])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:43][CH3:44].[CH3:45][C:46]#N>>[CH2:45]([O:34][C:33](=[O:35])[CH2:32][C:5]1[CH:6]=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][C:9]=2[CH2:18][N:19]2[C@@H:23]([CH3:24])[C@@H:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:21][C:20]2=[O:31])[C:2]([O:1][CH2:43][CH3:44])=[CH:3][CH:4]=1)[CH3:46]
Reactant: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1O
Reactant: CCI
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)Cc1ccc(OCC)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Temperature: 25 °C

Procedure:
To a suspension of [6-hydroxy-2′-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid (0.085 g, 0.18 mmol) and cesium carbonate (0.171 g, 0.53 mmol) in MeCN was added iodoethane (0.03 mL, 0.35 mmol), and the reaction was stirred at room temperature. The mixture was partitioned between EtOAc and H2O, and the aqueous layer was separated and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[CH3:11][O:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17][CH:16]=1)=[O:14]>C1COCC1.N1C=CC=CC=1.C(=O)(O)[O-].[Na+].CCOC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:21](=[O:22])[C:18]1[CH:17]=[CH:16][C:15]([C:13]([O:12][CH3:11])=[O:14])=[CH:20][CH:19]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(=O)Oc2ccccc2[N+](=O)[O-])cc1
Yield: 93.4 %

Procedure:
A solution of 2-nitrophenol (1.55 g, 11.2 mmol) and methyl 4-chlorocarbonyl benzoate (2.44 g, 12.2 mmol) in THF (14 mL) and pyridine (2.8 mL) was stirred for 2 h at room temperature. The reaction was diluted with saturated sodium bicarbonate (30 mL) and EtOAc (20 mL), the phases separated and the aqueous phase extracted with EtOAc (2×15 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to afford terephthalic acid 1-methyl ester 4-(2-nitrophenyl)ester (3.15 g, 94%). 1H NMR (CDCl3) δ 3.98 (s, 3H), 7.43 (d, 1H, J=7.8 Hz), 7.48 (t, 1H, J=7.8 Hz), 7.73 (t, 1H, J=7.8 Hz), 8.20 (m, 4H), 8.27 (m, 1H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18](C(=O)C)=[CH:17][CH:16]=3)[CH:11]=C(C3C=CC=CC=3)[N:9]=2)[CH2:4][CH2:3]1.[OH:30][CH:31]1CCNC[CH2:32]1.C(=O)([O-])[O-].[K+].[K+].[CH2:43]([Cl:45])Cl>CN(C=O)C>[Cl:45][C:43]1[N:9]=[C:8]([N:5]2[CH2:4][CH2:3][CH:2]([OH:1])[CH2:7][CH2:6]2)[CH:13]=[C:12]([NH:14][C:15]2[CH:16]=[C:17]([C:31](=[O:30])[CH3:32])[CH:18]=[CH:19][CH:20]=2)[CH:11]=1
Reactant: OC1CCNCC1
Reactant: ClCCl
Reactant: CC(=O)c1ccc(Nc2cc(-c3ccccc3)nc(N3CCC(O)CC3)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1cccc(Nc2cc(Cl)nc(N3CCC(O)CC3)c2)c1
Temperature: 100 °C

Procedure:
Samples of 1-[4-(4-hydroxy-6′-phenyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-ylamino)-phenyl]-ethanone (0.99 g, 3.5 mmol) and 4-hydroxypiperidine (0.7079 g, 7 mmol) were dissolved in DMF (10 mL) followed by the addition of potassium carbonate (0.5835 g, 4.2 mmol). The reaction mixture was stirred and refluxed for 12-18 hours at 100° C. under N2. The reaction mixture was diluted with CH2Cl2. The filtrate was washed two times with water and one time with brine. The organic phase was collected and dried over potassium carbonate. The filtered sample was concentrated, and the resulting solid was dried for 12-18 hours under vacuum.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][NH:2]1.C(N(C(C)C)C(C)C)C.Cl.Cl[C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1.C([O-])(O)=O.[Na+]>CC(O)C.C(OCC)(=O)C>[N:32]1[CH:33]=[CH:34][C:29]([N:2]2[CH2:3][CH2:4][C:5]3([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]3)[CH2:1]2)=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2)CC1
Reactant: Clc1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(c1ccncc1)C2
Temperature: 90 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
A mixture of tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (10.402 mmol, 1.0 eq.), N-ethyl-diisopropylamine (4.0 eq.) and 4-chloropyridine hydrochloride (3.0 eq.) in 2-propanol (20 ml) was stirred at 90° C. overnight. Ethyl acetate and sat. NaHCO3 solution were added and the aqueous phase was extracted with ethyl acetate a further 4×. The combined organic phases were washed 1× with sat. NaCl solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica, ethyl acetate/ethanol/ammonia (25% aq) 500:100:2). Yield: 45%
Reaction SMILES: [Ni:1].[C:2]1([CH3:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O-:12])(=[O:11])C>>[Ni:1].[CH2:2]([CH:7]([CH2:6][CH2:5][CH2:4][CH3:3])[C:9]([OH:12])=[O:11])[CH3:8]
Reactant: Cc1ccccc1
Reactant: CC(=O)[O-]
Agent: [Ni]
Product: CCCCC(CC)C(=O)O

Procedure:
The concentration of nickel in the acetate solution is practically 1 ppm or more, preferably, 10 ppm or higher. In case of using a nonpolar solvent such as toluene for obtaining a solution of 2-ethyl hexanoic acid nickel, the oxide 13 is unnecessary and the solution can be directly formed on the amorphous silicon film.
Reaction SMILES: [OH:1][C@H:2]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.N1C=CC=CC=1.[C:34](Cl)(=[O:36])[CH3:35]>C(Cl)Cl>[C:34]([O:1][C@H:2]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([C:21]#[N:22])[CH:23]=4)[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1)(=[O:36])[CH3:35]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4O)no2)cc1C#N
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)O[C@@H]1CCc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Temperature: 25 °C
Reaction time: 96 h
Yield: 91.7 %

Procedure:
To a flask containing (R)-5-(3-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 5 (36 mg, 0.10 mmol) in DCM (1 mL) was added pyridine (24 μL, 0.3 mmol) and acetyl chloride (21 μL, 0.3 mmol). The reaction was stirred at room temperature for 4 days. The crude reaction mixture was washed with saturated sodium bicarbonate, dried over magnesium sulfate, and purified by chromatography (EA/hexane) to give 37 mg (92%) of (R)-4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl acetate 13 as a white solid. LCMS-ESI (m/z) calculated for C23H21N3O4: 403.2; found 426.1 [M+Na]+, tR=4.19 min. 1H NMR (400 MHz, CDCl3) δ 8.37 (d, J=2.1, 1H), 8.27 (dd, J=8.9, 2.2, 1H), 8.10 (dd, J=7.7, 0.9, 1H), 7.53 (d, J=7.4, 1H), 7.35 (t, J=7.7, 1H), 7.06 (d, J=9.0, 1H), 6.21 (dd, J=7.2, 3.7, 1H), 4.73 (hept, J=6.1, 1H), 3.44 (ddd, J=17.5, 8.3, 6.3, 1H), 3.26 (ddd, J=17.6, 8.7, 4.8, 1H), 2.52 (tdd, J=14.9, 7.9, 6.3, 1H), 2.21-2.06 (m, 1H), 2.02 (s, 3H), 1.41 (d, J=6.1, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[NH:8][C:7](=O)[C:6]=2[CH:17]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19].O>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[NH:8][C:7](=[S:19])[C:6]=2[CH:17]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Nc1ccc2c(c1)C(=O)Nc1ccccc1S2
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1ccc2c(c1)C(=S)Nc1ccccc1S2

Procedure:
2-Amino-10,11-dihydrodibenzo[b,f][1,4]thiazepin-11-one (0.12 g was dissolved in toluene (20 ml). Phosphorus pentasulphide (0.11 g) was added to the solution and the whole was stirred under reflux for 16 hours and then cooled. Addition of water (40 ml) and separation of the phases gave, after evaporation of the dried organic layer, a yellow solid which was purified by column chromatography on silica gel and recrystallisation from ethanol to give the product as yellow needles (0.22 g, m/s. M- =258).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:17])[CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1.[CH2:18](Br)[C:19]#[CH:20].C(O)(=O)C>C1COCC1.O>[CH3:3][O:4][C:5](=[O:17])[CH:6]([CH2:20][C:19]#[CH:18])[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1
Reactant: C#CCBr
Reactant: COC(=O)Cc1ccc(C(=O)OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: C#CCC(C(=O)OC)c1ccc(C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
FIG. 4 shows a synthetic scheme useful in preparing 10-propargyl-10-dAM in accordance with the invention. A mixture of 60% NaH in oil dispersion (1.06 g, 26.5 mmol) in 18 mL of sieve-dried THF was cooled to 0° C. The cold mixture was treated with a solution of homoterephthalic acid dimethyl ester (5.0 g, 24 mmol. compound 1 in FIG. 4) in dry THF (7 mL), and the mixture was stirred for 1 hour at 0° C. Propargyl bromide (26.4 mmol) was added, and the mixture was stirred at 0° C. for an additional 1 hour, and then at room temperature for 16 hours. The resulting mixture was treated with 2.4 mL of 50% acetic acid and then poured into 240 mL of water. The mixture was extracted with ether (2×150 mL). The ether extracts were combined, dried over Na2SO4, and concentrated to an orange-yellow oil. Chromatography on silica gel (600 mL of 230-400 mesh) with elution by cyclohexane-EtOAc (8:1) gave the product α-propargylhomoterephthalic acid dimethyl ester (compound 2) as a white solid (4.66) which appeared by TLC (cyclohexane-EtOAc, 3:1) to be homogeneous. Mass spectral data on this product, however, showed it to be a mixture of the desired product 2, and the dipropargylated compound. No starting material 1 was detected. HPLC shows the ratio of mono- to di-propargylated products to be about 3:1. Since the dipropargylated product, unlike compound 1, cannot produce an unwanted coproduct in the next step of the reaction, this material was suitable for conversion to compound 3. Absence of starting compound 1 in the product used to proceed in the synthesis is very important in order to avoid the sequential formation of 10-dAM during the transformations lading to the final product, because complete removal from 10-dAM from 10-propargyl-1-dAM is very difficult.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]O)=[CH:4][C:3]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C([Br:34])C=C.O>C(#N)C.CCCCCC>[Br:34][CH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:4]=1
Reactant: C=CCBr
Reactant: OCCCc1ccc(F)c(Oc2ccccc2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CC#N
Solvent: CCCCCC
Product: Fc1ccc(CCCBr)cc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.2 %

Procedure:
To 5.30 g (0.0215 mole) of 3-(4-fluoro-3-phenoxyphenyl)-1-propanol in 18 ml of dry acetonitrile was added first 3.5 g (0.022 mole) of 1,1'-carbonyldiimidazole and then 13.0 g (0.107 mole) of allyl bromide. After stirring at room temperature for 1.5 hours the reaction mixture was heated at gentle reflux for two hours. The reaction mixture was poured into water, and this mixture was extracted twice with diethyl ether. The combined extracts were washed successively with 10% hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, an aqueous solution of sodium thiosulfate, water, and a saturated aqueous solution of sodium chloride. The organic solution was dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure, leaving an oil as a residue. The residue was dissolved in approximately 50 ml of hexane and the solution was filtered through a pad of silica gel. Evaporation of the solvent from the filtrate yielded 4.4 g of 1-bromo-3-(4-fluoro-3-phenoxyphenyl)propane as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[C:11]([O:13][CH3:14])=[O:12])=[O:5].[H][H]>CO.[Pd]>[NH2:19][C:18]1[C:2]([OH:1])=[C:3]([CH:15]=[CH:16][CH:17]=1)[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[C:11]([O:13][CH3:14])=[O:12])=[O:5]
Reactant: [H][H]
Reactant: COC(=O)[C@H]1CCCN1C(=O)c1cccc([N+](=O)[O-])c1O
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H]1CCCN1C(=O)c1cccc(N)c1O
Yield: 73.6 %

Procedure:
A solution of 4.03 g (13.63 mmol; 1.0 eq) of methyl (R)-1-(2-hydroxy-3-nitrobenzoyl)pyrrolidine-2-carboxylate in 50 ml of methanol was stirred at hydrogen atmospheric pressure in the presence of 390 mg (10% by weight) of palladium on carbon at 10% for 3 days. The reaction medium was filtered through celite, rinsed with methanol and evaporated. The residue was chromatographed on silica gel (200 g prepacked column) eluted with heptane/ethyl acetate (gradient). 2.65 g of methyl (R)-1-(3-amino-2-hydroxybenzoyl)pyrrolidine-2-carboxylate were obtained in the form of a yellow oil. Yield=74%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:17][CH:18]2[CH2:25][CH:21]3[CH2:22][NH:23][CH2:24][CH:20]3[CH2:19]2)=[N:4][C:5]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)=[N:6][CH:7]=1.CCN(CC)CC.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:17][CH:18]2[CH2:25][CH:21]3[CH2:22][N:23]([C:33](=[O:35])[CH3:34])[CH2:24][CH:20]3[CH2:19]2)=[N:4][C:5]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:15][CH2:16]3)[NH:11][N:10]=2)=[N:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Clc1cnc(Nc2cc(C3CC3)[nH]n2)nc1NC1CC2CNCC2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CC2CC(Nc3nc(Nc4cc(C5CC5)[nH]n4)ncc3Cl)CC2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45.7 %

Procedure:
To a solution of 5-chloro-N2-(5-cyclopropyl-1H-pyrazol-3-yl)-N4-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine (153.3 mg, 0.43 mmol) in DCM (10 mL) were added Et3N (82.3 mg, 0.81 mmol) and acetyl acetate (62.5 mg, 0.61 mmol). The reaction mixture was stirred at rt for 15 min, then quenched with H2O (30 mL) and extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/50) to give the title compound as a beige solid (79.0 mg, 46.1%).