Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([Cl:37])[CH:35]=2)[C:10]2([CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[CH2:14][C:13](=[O:23])[NH:12][CH:11]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[C:9]1=[O:38])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Li+].I[CH2:42][CH3:43]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([Cl:37])[CH:35]=2)[C:10]2([CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[CH2:14][C:13](=[O:23])[N:12]([CH2:42][CH3:43])[CH:11]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[C:9]1=[O:38])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCI
Reactant: Cc1ccccc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)N(C(=O)OC(C)(C)C)c1cc(Cl)ccc12
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCN1C(=O)CC(c2cccc(Cl)c2)C2(C(=O)N(C(=O)OC(C)(C)C)c3cc(Cl)ccc32)C1c1ccccc1C
Yield: 63.9 %

Procedure:
In a manner similar to the method described in example 24c, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2′-(2-methylphenyl-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (0.3 g, 0.54 mmol) prepared in example 24b was reacted with LiH (86 mg, 10.9 mmol) (Aldrich) and iodoethane (2 mL, 25 mmol) in N,N-dimethyl-formamide to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-ethyl-2,3-dihydro-2′-(2-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester as a white foam (Yield: 0.2 g, 63%).
Reaction SMILES: [Br:1][C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:20][OH:21])[CH:3]=1.S(=O)(=O)=O>>[Br:1][C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:11]=2)(=[O:8])=[O:9])[CH:5]=[C:4]([CH:20]=[O:21])[CH:3]=1
Reactant: CS(=O)(=O)c1cccc(S(=O)(=O)n2cc(CO)cc2Br)c1
Agent: O=S(=O)=O
Product: CS(=O)(=O)c1cccc(S(=O)(=O)n2cc(C=O)cc2Br)c1
Yield: 57.7 %

Procedure:
Using {5-bromo-1-{[3-(methylsulfonyl)phenyl]sulfonyl}-1H-pyrrol-3-yl}methanol (4.88 g) and sulfur trioxide.pyridine complex (2.19 g), a procedure as in Reference Example 191 was performed to give the title compound as a white solid (yield 2.80 g, 58%).
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].Br[CH:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O>>[C:18]1([C:16]2[N:1]=[C:2]([C:3]3[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=3[CH3:8])[S:13][C:15]=2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(c1ccccc1)C(Br)c1ccccc1
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Product: COC(=S)c1cc(-c2nc(-c3ccccc3)c(-c3ccccc3)s2)c(C)s1

Procedure:
A solution of 75 mg (0.3 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge, Cornwall, UK) was reacted with 92 mg, 0.3 mmol) of 2-bromo-1,2-diphenylethan-1-one in a manner similar to Example 8, step (a) to give, after preparative thin-layer chromatrography purification, methyl 4-(4,5-diphenyl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate (9 mg, 7%) as a solid. 1H-NMR (DMSO-d6; 300 MHz) δ8.94 (br s, 0.4H), 8.66 (s, 1H), 8.60 (br s, 0.3 H), 8.08 (s, 1H), 7.93 and 7.20 (AB quartet, 2H, J=8.7 Hz), 7.68 and 7.35 (AB quartet, 2H, J=8.2 Hz), 2.77 (s, 3H), ), 2.33 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for C22H17NO2S3, 424.0 (M+H), found 424.3.
Reaction SMILES: C([O:8][CH2:9][CH:10]1[O:23][C:14]2=[C:15]3[C:20](=[CH:21][CH:22]=[C:13]2[O:12][CH2:11]1)[N:19]=[CH:18][CH:17]=[CH:16]3)C1C=CC=CC=1.Cl.[C:25]1(C)C=CC=CC=1>>[CH3:25][C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]3[O:12][CH2:11][C@H:10]([CH2:9][OH:8])[O:23][C:14]3=2)[N:19]=1
Reactant: Cc1ccccc1
Reactant: c1ccc(COCC2COc3ccc4ncccc4c3O2)cc1
Agent: Cl
Product: Cc1ccc2c3c(ccc2n1)OC[C@H](CO)O3
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
A mixture of crude (2S)-2[(benzyloxy)methyl-2,3-dihydro[1,4]dioxino[2,3-f]-quinoline product mixture (57.6 g, 0.179 mol) from example 7 in toluene (300 mL) was mixed with 20% HCl (436 g, 3.59 mol) and heated at 80° C. After 30 min, the reaction mixture was cooled to room temperature. The two layers were separated. A 30% NH4OH solution (400 mL) was added to the aqueous layer at 10–20° C. to pH 10. This was stirred for 30 min, the solid was filtered, washed with water and recrystallized from CH3OH (200 mL) to give 25.7 g (61.9%) of the title alcohol as an off-white solid.
Reaction SMILES: [NH:1]1[C:5]2[NH:6][CH:7]=[CH:8][C:9](=O)[C:4]=2[CH:3]=[N:2]1.O=P(Cl)(Cl)[Cl:13]>>[Cl:13][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:1][N:2]=[CH:3][C:4]=12
Reactant: O=c1cc[nH]c2[nH]ncc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccnc2[nH]ncc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
1,7-Dihydro-pyrazolo[3,4-b]pyridin4-one (1.2 g, 8.8 mmol) (Dorn, H. et al., Prakt. Chem., 324, 557-62 (1982)) in POCl3 (15 ml) at 0° C. was treated with PCd5 (2.5 mg, 0.01 mmol). The solution was allowed to warm to rt over 1 h, then heated to 90° C. and held 3h. The solution was concentrated under reduced pressure, then treated with ice and water (50 ml). The resulting mixture was extracted with ethyl acetate (100 ml), and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate (30 ml). The organic layer was dried over MgSO4, then evaporated under reduced pressure to give 4-chloro-1H-pyrazolo[3,4-b]pyridine as a yellow solid (820 mg, 60%). 1H NMR (300 MHz, CDCl3) δ 8.57 (d, 1H, J=5.2 Hz), 8.25 (s, 1H), 7.28 (d, 1H, J=5.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.Cl.[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH2:24])=[CH:19][CH:18]=1>>[CH3:6][O:8][C:9]([C:4]1[N:24]([CH2:23][C:20]2[CH:21]=[CH:22][C:17]([C:16]([O:15][CH3:14])=[O:25])=[CH:18][CH:19]=2)[C:6](=[O:8])[C:5]2[C:4]([C:9]=1[OH:10])=[CH:3][C:2]([Cl:1])=[CH:12][CH:11]=2)=[O:10]
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: O=C1OC(=O)c2cc(Cl)ccc21
Agent: Cl
Product: COC(=O)c1ccc(Cn2c(C(=O)OC)c(O)c3cc(Cl)ccc3c2=O)cc1

Procedure:
The present compound was synthesized according to the method shown in Reference Example 8 and using 4-chloro phthalic anhydride and 4-(aminomethyl)benzoic acid methyl ester hydrochloride.
Reaction SMILES: C[Si](C)(C)Br.[CH2:6]([O:8][C:9](=[O:28])[C@H:10]([NH:25]C=O)[CH:11]=[C:12]([CH3:24])[CH2:13][P:14]([O:20]C(C)C)([O:16]C(C)C)=[O:15])[CH3:7].C(O)C>ClCCl>[CH2:6]([O:8][C:9](=[O:28])[C@H:10]([NH2:25])[CH:11]=[C:12]([CH3:24])[CH2:13][P:14]([OH:16])([OH:20])=[O:15])[CH3:7]
Reactant: CCOC(=O)[C@@H](C=C(C)CP(=O)(OC(C)C)OC(C)C)NC=O
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)[C@H](N)C=C(C)CP(=O)(O)O
Reaction time: 20 h
Yield: 88.2 %

Procedure:
23 ml of trimethylbromosilane are added dropwise at room temperature withina period of 15 minutes to a solution of 10.3 g of 4 according to b) in 42 ml of dichloromethane. After 211/2 hours, 42 ml of ethanol are added whilecooling with ice, and the mixture is stirred for 20 hours. The whole is then concentrated by evaporation and the residue is dissolved three times in 70 ml of toluene each time and in each case is concentrated by evaporation again. The residue is dissolved in 42 ml of ethanol, and 42 mlof propylene oxide are added. After 11/2 hours, the mixture is filtered. Drying the filtration residue in a vacuum desiccator over P2O5 /KOH (3 hours/80°) yields 6.17 g of 5; [α]D =-78°(c=0.6, H2O); m.p. 194°-197° (decomp.), C8H16NO5P; calculated: C 40.51%, H 6.80%, N 5.91%, P 13.06%; found: C 39.4%, H 7.09%, N 5.73%, P 12.98%.
Reaction SMILES: [F:1][C:2]1[C:8]([CH3:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[F:11][B-:12]([F:15])([F:14])[F:13].[H+].[N:17]([O-])=O.[Na+]>O>[F:11][B-:12]([F:15])([F:14])[F:13].[F:1][C:2]1[C:8]([CH3:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[N+:4]#[N:17]
Reactant: O=N[O-]
Reactant: Cc1c(F)ccc(N)c1F
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: Cc1c(F)ccc([N+]#N)c1F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To 2,4-difluoro-3-methylaniline (20 g) are added 42% tetrafluoroboric acid (56 ml) and water (28 ml) under ice cooling and thereto a solution of sodium nitrite (10 g) in water (20 ml) is added dropwise at below 10° C. After dropwise addition, the mixture is stirred at 0° C. for 15 minutes and the formed crystals are filtered, which is washed with a mixture of ethanol--diethyl ether (1:2), then with diethyl ether, followed by drying under reduced pressure to give 2,4-difluoro-3-methylbenzene diazonium tetrafluoroborate (28.95 g), m.p. 114°-115° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:29])[NH:20][CH:21]3[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:30]([O:32]CC)=[O:31].[OH-].[Na+]>C1COCC1.CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:29])[NH:20][CH:21]3[CH2:22][CH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][CH2:26]3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:30]([OH:32])=[O:31]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CCC(C)(C)CC4)cc3)c(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CCC(NC(=O)c2ccc(Oc3cc4c(cc3Cl)C(C(=O)O)CCO4)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
To a solution of ethyl 6-chloro-7-(4-(4,4-dimethylcyclohexylcarbamoyl)phenoxy)chroman-4-carboxylate (0.056 g, 0.12 mmol) in 3:1 THF/EtOH (1 ml) was added 1M sodium hydroxide (0.24 ml, 0.24 mmol), and the reaction was stirred at ambient temperature overnight. The reaction was concentrated and the residue was diluted with water and 1M hydrochloric acid. The reaction was extracted twice with EtOAc, and the combined organic layers were washed with saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to yield 42 mg of the title compound (80% yield). MS (apci) m/z=458.1 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([CH3:29])[CH2:28][O:27]2)=[CH:22][N:21]=1>CN(C=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:29][C:26]([C:23]3[CH:22]=[N:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=3)([OH:27])[CH3:28])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: COc1ccc(C2(C)CO2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(C)(O)Cn2c3c(c4cc(C)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20.8 %

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (500 mg, 2.5 mmol) was dissolved in 5 mL DMF and stirred for 10 min at RT. Sodium hydride (300 mg, 7.5 mmol) was added portionwise at 0° C. and the reaction mixture was stirred for 10 min. 2-Methoxy-5-(2-methyl-oxiranyl)-pyridine (566 mg, 3.75 mmol) was diluted in DMF (2 mL) and added dropwise at the same temperature and stirred for 12 h. After consumption of starting material, the reaction mixture was quenched with ice water and extracted with EtOAc (3×30 mL). The combined organic layer was washed with water (7×30 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography over silica gel (eluent: 15% MeOH in DCM) and further crystallized in ether-hexane to obtain 190 mg of 1-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-(6-methoxy-pyridin-3-yl)-propan-2-ol. 1H NMR (CDCl3, freebase) δ (ppm): 8.22 (s, 1H), 7.5 (d, 1H), 7.1 (s, 1H), 7.0 (d, 1H), 6.83 (d, 1H), 6.5 (d, 1H), 4.1 (m, 2H), 3.91 (s, 3H), 3.5 (m, 2H), 2.63-2.81 (m, 4H), 2.41 (s, 3H), 2.39 (s, 3H), 1.58 (s, 3H). Separation by chiral HPLC provides enantiomers 64a and 64b.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][C:5]1([C:23](=[O:34])[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N+:31]([O-])=O)[NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH:2]=[CH2:3].[Cl-].[NH4+]>CO.C(OCC)(=O)C.[Zn]>[CH2:1]([CH:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][C:5]1([C:23](=[O:34])[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH2:31])[NH:16][C:17](=[O:22])[C:18]([F:20])([F:21])[F:19])[CH:2]=[CH2:3]
Reactant: C=CCC1CN(C(=O)OC(C)(C)C)CC1(NC(=O)C(F)(F)F)C(=O)Nc1ccccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: CCOC(C)=O
Product: C=CCC1CN(C(=O)OC(C)(C)C)CC1(NC(=O)C(F)(F)F)C(=O)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 99.1 %

Procedure:
A solution of tert-butyl 4-allyl-3-[(2-nitrophenyl)carbamoyl]-3-[(trifluoroacetyl)amino]pyrrolidine-1-carboxylate (0.816 g, 1.68 mmol) in methanol (30 mL) was treated with ammonium chloride (0.897 g, 16.8 mmol) and zinc (2.19 g, 33.5 mmol). After stirring at room temperature for 40 min, the mixture was diluted with ethyl acetate (30 mL) and filtered through a pad of Celite. The pad was washed with ethyl acetate and the filtrate was concentrated under reduced pressure. The residue was re-diluted with ethyl acetate (25 mL) and water (20 mL), and the layers were separated. The organic phase was washed with water (10 mL) and saturated aqueous sodium chloride (10 mL), dried over Na2SO4 and concentrated and dried under high vacuum for ˜2 h to give the tert-butyl 4-allyl-3-[(2-aminophenyl)carbamoyl]-3-[(trifluoroacetyl)amino]pyrrolidine-1-carboxylate intermediate (760 mg, 3:2 mixture of diastereomers) as a off-white foam that was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]2)[C:3]=1[CH3:21].[H-].[Na+].I[CH2:25][CH2:26][CH3:27]>C1COCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([CH2:25][CH2:26][CH3:27])[C:16](=[O:20])[CH2:15]2)[C:3]=1[CH3:21]
Reactant: CCCI
Reactant: Cc1c(N2CCNC(=O)C2)nc2cc(F)cc(F)c2c1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCN1CCN(c2nc3cc(F)cc(F)c3c(Br)c2C)CC1=O
Reaction time: 8 h

Procedure:
The 4-(4-bromo-5,7-difluoro-3-methylquinolin-2-yl)piperazin-2-one (70 mg, 0.200 mmol) was dissolved in THF (2.0 mL). To the solution was added sodium hydride (24.0 mg, 0.98 mmol) (60% dispersion) followed by addition of 1-iodopropane (230 μL, 2.40 mmol). The reaction was stirred overnight. The reaction was quenched with water and the mixture was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (1×25 mL) and dried over magnesium sulfate. The crude product was purified by medium pressure chromatography (silica gel, 0 to 80% EtOAc:hexanes) to give 4-(4-bromo-5,7-difluoro-3-methylquinolin-2-yl)-1-propylpiperazin-2-one. Mass Spectrum (ESI) m/e=400.1 (M+1).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[NH:13][N:12]=[C:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[C:10]=1[C:23]#[N:24]>C1COCC1>[C:5]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][NH:14][C:11]2[C:10]([C:23]#[N:24])=[C:9]([NH2:8])[NH:13][N:12]=2)=[CH:21][CH:20]=1)(=[O:7])[CH3:6]
Reactant: N#Cc1c(NCc2ccc(N)cc2)n[nH]c1N
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(CNc2n[nH]c(N)c2C#N)cc1

Procedure:
With stirring, a solution of 1.087 ml (11.5 mmol) of acetic anhydride in 20 ml of THF is added dropwise over a period of 15 minutes, to a suspension, cooled to 0° C., of 2.5 g (10.95 mmol) of 5-amino-3-(4-amino-benzylamino)-4-cyano-pyrazole in 50 ml of THF. The reaction mixture is stirred for a further 2 hours at RT, there initially being formed a solution from which crystalline product gradually precipitates. The reaction mixture is filtered and the filter residue is washed with THF and diethyl ether. Drying under a HV (8 hours, 110° C.) yields the title compound containing 21.06% THF; m.p. 124-126° C. (decomp.); FAB-MS: (M+H)+ 271 (C13H14N6O).
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=2)=[CH:16][CH:15]=1
Reactant: Oc1ccc(F)cc1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Oc2ccc(F)cc2)nc1
Temperature: 24 °C
Reaction time: 0.12 h
Yield: 98 %

Procedure:
To a 2-L, 3-necked, round-bottomed flask equipped with a mechanical stirrer, a thermo couple, and a condenser was added DMF (194 mL), ethyl 6-chloronicotinate (100.00 g, 0.522 mol), and 4-fluorophenol (65.09 g, 0.575 mol). A brown solution formed after stirring for 5-10 min. To the solution was then added Cs2CO3 (189.19 g, 0.575 mol) in one portion. The reaction temperature increased from 20° C. to 30° C. over 10 min without external heating and then started cooling down. The resulting suspension was stirred at rt for 2-3 h and the internal reaction temperature cooled back to 23-25° C. The reaction mixture was then heated to 60° C. and stirred for 18-20 h. HPLC analysis indicated that the reaction was complete. The heating mantle was removed and the reaction mixture was allowed to cool to 25-30° C. To the mixture was added deionized water (145.5 mL) in a steady stream over 5 min and a slight exotherm was observed. The resulting suspension was stirred at rt for 15-20 min. Two additional portions of deionized water (145.5 mL each) were added and the suspension was stirred at rt for 15-30 min. The pH of the suspension was around 9-10. The solid product was collected by vacuum filtration, rinsed thoroughly with deionized water in portions. The filter cake as dried in a filter funnel by pulling through air for 24 h. The product was isolated as a white solid (133.6 g). mp: 68.0° C. (by DSC). 1H NMR (CDCl3): δ 8.81 (d, J=2.6 Hz, 1H), 8.22 (dd, J=8.5, 2.6 Hz, 1H), 7.12 (br s, 2H), 7.10 (d, J=1.0 Hz, 2H), 6.94 (d, J=8.5 Hz, 1H), 4.38 (q, J=7.1 Hz, 2H), 4.38 (t, J=7.1 Hz, 3H). MS (ESI): M+H+=262.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[S:13][C:12]([CH2:20][CH2:21][C:22]#[N:23])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([C:24](=[O:29])[C@@H:25]([O:27][CH3:28])[CH3:26])[N:10]=1.Cl.Cl.[O:32]([NH2:34])[CH3:33].C(N(CC)CC)C>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[S:13][C:12]([CH2:20][CH2:21][C:22](=[N:34][O:32][CH3:33])[NH2:23])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([C:24](=[O:29])[C@@H:25]([O:27][CH3:28])[CH3:26])[N:10]=1
Reactant: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCC#N)c1ccccc1
Reactant: CON
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CON=C(N)CCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=O)[C@H](C)OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 25 %

Procedure:
To cooled (0° C.) solution of 3-(5-(2,5-difluorophenyl)-3-((S)-2-methoxypropanoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propanenitrile (0.052 g, 0.13 mmol, Example 14, Step C) in ethanol (0.5 mL) was added 9.8 M ethanolic HCl (0.5 mL, 4.9 mmol). After stirring at room temperature for 6 hours, the mixture was concentrated under reduced pressure. To the residue was added methoxylamine hydrochloride (0.021 g, 0.21 mmol), absolute ethanol (0.5 mL) and triethylamine (0.087 mL, 0.63 mmol). After stirring at room temperature for 16 hours, the mixture was concentrated under reduced pressure. The residue was diluted with 10% Na2CO3 (30 mL) and extracted with dichloromethane. The combined organics were dried, filtered and concentrated under reduced pressure. The residue was chromatographed (40% ethyl acetate in hexanes) to afford the product as a mixture of diastereomers (14 mg, 25% yield). MS ESI (+) m/z 463 (M+1) detected; 1H NMR (4001 MHz, CDCl3) δ 7.50 (m, 2H), 7.38 (m, 8H), 7.30 (m, 2H), 7.13 (m, 4H), 4.78 (q, 1H, J=6.3 Hz), 4.72 (q, 1H, J=6.3 Hz), 4.64 (br. s, 4H), 3.77 (s, 6H), 3.54 (m, 2H), 3.41 (s, 3H), 3.36 (s, 3H), 2.68 (m, 4H), 2.18 (m, 2H), 1.51 (d, 3H, J=6.3 Hz), 1.49 (d, 3H, J=7.0 Hz).
Reaction SMILES: [OH:1][CH2:2][C:3]12[CH2:10][O:9][P:6]([O:7][CH2:8]1)[O:5][CH2:4]2.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[P:6]12[O:9][CH2:10][C:3]([CH2:2][O:1][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)([CH2:8][O:7]1)[CH2:4][O:5]2
Reactant: O=C(Cl)c1ccccc1
Reactant: OCC12COP(OC1)OC2
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OCC12COP(OC1)OC2)c1ccccc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
16.4 g (0.1 mol) of 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2,2,2]octane are dissolved in 150 ml of toluene by warming. 19.6 g (0.1 mol) of benzoyl chloride are added dropwise at room temperature, followed by 10.1 g (0.1 mol) of triethylamine. The temperature is kept at 30 C by means of an ice bath. After the dropwise addition is complete, the mixture is stirred for 2 hours at 60°C and is then heated to the boil for a short time and filtered while hot from triethylamine hydrochloride. The filtrate is cooled, whereupon the product is precipitated. After filtering and drying, benzoic acid 1-phospha-2,6,7-trioxabicyclo[2,2,2]oct-4 -yl-methyl ester (Stabiliser No. 1) of melting point 160°C is obtained. After recrystallisation from ethanol or isopropanol the product forms long, snow-white needles. If in this example, the benzoyl chloride is replaced by an equivalent quantity of one of the substituted benzoic acid chlorides in Table 1 below, an otherwise identical procedure gives benzoic acid 1-phospha-2,6,7-trioxabicyclo[2,2,2]oct-4-yl methyl esters substituted at the nucleus, the melting points of which are shown.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:9]1[C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:11][C:12](Br)=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]([F:32])([F:31])[CH2:29][OH:30].C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>C(OCC)(=O)C>[CH3:19][O:18][C:16]([C:10]1[C:9]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:14][CH:13]=[C:12]([O:30][CH2:29][C:28]([F:32])([F:31])[F:27])[N:11]=1)=[O:17]
Reactant: OCC(F)(F)F
Reactant: COC(=O)c1nc(Br)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1nc(OCC(F)(F)F)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of methyl 3-(bis(tert-butoxycarbonyl)amino)-6-bromopyrazine-2-carboxylate (500 mg, 1.16 mmol), 2,2,2-trifluoroethanol (84 μl, 1.16 mmol), cesium carbonate (415 mg, 1.27 mmol) and dry DMSO (5 ml) was stirred at r.t. for 3 h. The reaction mixture was poured into ethyl acetate (100 ml) and extracted with saturated sodium bicarbonate (aqueous solution). The organic layer was washed with water and brine and the aqueous layers were back-extracted with ethyl acetate. The combined organic layers were dried, evaporated and the product was obtained after purification by silica gel chromatography using a heptane/ethyl acetate gradient as white solid (456 mg, 87%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl.[CH2:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][NH:10]1.[OH-].[Na+]>CCOC(C)=O.O>[N:5]1[CH:6]=[CH:7][C:2]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9]2)=[CH:3][CH:4]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Clc1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: c1ccc2c(c1)CCN(c1ccncc1)C2
Temperature: 150 °C

Procedure:
A mixture of 4-chloro-pyridine 1:1 hydrochloride (24.5 g, 163 mmol) and 1,2,3,4-tetrahydro-isoquinoline (65.3 g, 490 mmol) was slowly heated to 150° C. After 30 min the reaction mixture was cooled to rt, H2O (700 ml) and 2N NaOH (82 ml) was added followed by extraction with AcOEt (5 times 300 ml). The combined organic phases were dried (Na2SO4), and the solvent was evaporated. After trituration with pentane and recrystallization the title compound (30.2 g, 88%) was obtained as a light brown crystalline material. Mp. 95-96° C. (AcOEt), MS: m/e=210 (M+).