Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[I:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9]Br.C1CCN2C(=NCCC2)CC1>C1COCC1>[I:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: BrCc1ccccc1I
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Ic1ccccc1Cn1cncn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 34.4 %

Procedure:
To a stirring solution of 1,2,4-triazole (1.02 g, 14.8 mmol) and 2-iodobenzyl bromide (6.05 g, 20.3 mmol) in THF (10 mL) was added a solution of DBU (2.65 g, 17.4 mmol) in THF (2 mL) dropwise over a 1 hour period. The mixture was stirred at ambient temperature for 12 hours after which it was filtered. The filtrate was concentrated in vacuo and the resultant residue was dissolved in ethyl acetate. The organic layer was washed with water and brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 50-60% ethyl acetate/isohexane to give the title compound as a white solid (1.45 g). 1H NMR (360 MHz, CDCl3): δ 8.15 (1H, s), 8.00 (1H, s), 7.89 (1H, d, J=7.9 Hz), 7.36 (1H, t, J=7.6 Hz), 7.13 (1H, d, J=7.7 Hz), 7.08-7.04 (1H, m), 5.43 (2H, s).
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][N:8]=1.CN([CH:20]=[O:21])C.C1([Li])C2C(=CC=CC=2)C=CN=1.[NH4+].[Cl-]>CCOCC.C1COCC1.C(O)C.CCOC(C)=O>[CH:7]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:20]=[O:21])[C:11]=2[CH:10]=[CH:9][N:8]=1
Reactant: Brc1nccc2ccccc12
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Li]c1nccc2ccccc12
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCO
Product: O=Cc1cccc2cnccc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 62.5 %

Procedure:
To a solution of n-butyllithium (19.3 mL of 2.5M in hexanes, 48 mmol) in a mixture of ether (80 mL) and THF (80 mL) at −78° C. was added dropwise a solution of bromoisoquinoline (5.0 g, 24 mmol) in THF (10 mL). The reaction mixture was stirred at −78° C. under argon for 30 minutes. Following the general procedures described by Pearson, et al., in J. Heterocycl. Chem., Vol. 6 (2), pp. 243-245 (199), a solution of DMF (3.30 g, 45 mmol) in THF (10 mL) was cooled to −78° C. and quickly added to the isoquinolyllithium solution. The mixture was stirred at −78° C. for 15 minute. Ethanol (20 mL) was added followed by saturated NH4Cl solution. The resulting suspension was warmed to room temperature. The organic layer, combined with the ether extraction layer, was dried over Na2SO4. A pale yellow solid (2.4 g, 15 mmol, 64% yield) was obtained from chromatography (SiO2 Type-H, 50% EtOAc in hexanes) and recrystallization (ethanol): mp 114-116° C.;
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([CH2:10][NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:7]=[CH:6][C:5]=1[CH2:16][N:17]([CH2:26][C:27]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][N:28]=1)[CH2:18][C:19]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[CH3:33][C:32]1[C:27]([CH2:26][N:17]([CH2:16][C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:9][C:4]=2[CH2:3][OH:2])[CH2:18][C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=2)=[N:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)c1cc(CNS(C)(=O)=O)ccc1CN(Cc1ncccc1C)Cc1ncccc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccnc1CN(Cc1ccc(CNS(C)(=O)=O)cc1CO)Cc1ncccc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
Under N2, To a solution of 2-{[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-5-(methanesulfonylamino-methyl)-benzoic acid methyl ester (0.217 g, 0.450 mmol) in THF (20 mL) was added LiAlH4 (1.0 M in THF, 0.67 mL, 0.67 mmol) at −78° C. After the addition the reaction mixture was brought to room temperature and stirred at room temperature for 30 min. H2O (10 mL) was added, and THF removed. The aqueous residue was extracted with CH2Cl2 (3×20 mL), and the extracts were combined and dried over Na2SO4. After filtration the solvent was removed, and the residue was purified on silica gel column (500:25:1 CH2Cl2/MeOH/NH4OH), affording a white foam (0.165 g, 81%). 1H NMR (CDCl3) δ 2.13 (s, 6H), 2.87 (s, 3H), 3.71 (s, 4H), 3.90 (s, 2H), 4.25 (s, br, 2H), 4.28 (d, 2H, J=6.0 Hz), 4.59 (t, 1H, J=60 Hz), 6.65 (s, br, 1H), 7.06 (dd, 2H, J=4.8, 7.8 Hz), 7.21 (dd, 1H, J=1.5, 7.8 Hz), 7.26-7.31 (m, 2H), 7.38 (d, 2H, J=7.8 Hz), 8.35 (d, 2H, J=4.8 Hz); 13C NMR (CDCl3) δ 18.26, 41.00, 46.84, 57.30, 58.68, 62.79, 122.60, 127.04, 130.68, 131.99, 133.12, 136.72, 137.03, 138.30, 142.35, 146.18, 155.87. ES-MS m/z 455 (M+H). Anal. Calcd. for C24H30N4O3S.0.21CH2Cl2: C, 61.55; H, 6.49; N, 11.86; S, 6.79. Found: C, 61.62; H, 6.58; N, 11.64; S, 6.77.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]([CH2:16][OH:17])[CH2:11][N:12]([CH3:15])[CH2:13][CH:14]=2)=[CH:5][CH:4]=1.[H][H]>C(O)C.[Pd]>[ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][C@H:10]2[CH2:16][OH:17])=[CH:5][CH:4]=1
Reactant: CN1CC=C(c2ccc(F)cc2)C(CO)C1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CN1CC[C@H](c2ccc(F)cc2)[C@H](CO)C1

Procedure:
Thirty-five (35) g of (+)-4-(4-fluorophenyl)-3-hydroxymethyl-1-methyl-1,2,3,6-tetrahydropyridine hydrochoride and 5.5 g of Pd-catalyst (5% Pd on charcoal) are mixed in 2900 ml of 99% ethanol. The mixture is reduced at room temperature under one atmosphere of hydrogen pressure over a period of six hours, taking up 3250 ml of hydrogen. The reaction mixture is filtered and the filtrate is evaporated. The residue is washed with ether to give 33.5 g of the title compound. M.p. 158°-159° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:16][CH2:17][CH2:18][O:19][CH3:20])[C:5]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[C:6]([CH2:8][C:9]#[N:10])[CH:7]=1.[H-].[Na+].[C:23](N1C=CN=C1)(=[O:25])[CH3:24]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([O:16][CH2:17][CH2:18][O:19][CH3:20])[C:5]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[C:6]([CH:8]([C:23](=[O:25])[CH3:24])[C:9]#[N:10])[CH:7]=1
Reactant: COCCOc1cc(F)cc(CC#N)c1OCCOC
Reactant: CC(=O)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1cc(F)cc(C(C#N)C(C)=O)c1OCCOC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 90.9 %

Procedure:
A solution of (5-fluoro-2,3-bis{[2-(methyloxy)ethyl]oxy}phenyl)acetonitrile (250 mg, 0.88 mmol) in tetrahydrofuran (2 mL) was added to a suspension of sodium hydride (40% oil dispersion, 70 mg, 1.8 mmol) in tetrahydrofuran (5 mL), followed by the addition of 1-acetylimidazole (145 mg, 1.3 mmol). After five minutes at room temperature, stirring was continued at 60° C. for 20 minutes. After cooling to room temperature, the reaction mixture was quenched with hydrochloric acid (1M, 20 mL) and extracted with ethyl acetate (3×20 mL). The combined extract was washed with water and brine (20 mL each), dried over sodium sulfate, filtered and concentrated to give the crude 2-(5-fluoro-2,3-bis{[2-(methyloxy)ethyl]oxy}phenyl)-3-oxobutanenitrile (0.26 g, 0.80 mmol, 91% yield). 1H NMR (400 MHz, CDCl3): 6.73-6.69 (m, 2H), 4.29-4.21 (m, 2H), 4.15-4.13 (m, 2H), 3.79-3.76 (m 2H), 3.62-3.57 (m, 2H), 3.44 (s, 3H), 3.41 (s, 3H), 2.26 (s, 3H); MS (EI) for C16H20FNO5: 326 (MH+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH2:20][CH3:21])[N:8]=[C:9]2[C:18]=1[C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:11]=[C:10]2[NH2:19].[C:22]([O-:25])(=[O:24])[CH3:23].[K+].[I-].[Na+].CN(C=O)C>O>[C:22]([O:25][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH2:20][CH3:21])[N:8]=[C:9]2[C:18]=1[C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:11]=[C:10]2[NH2:19])(=[O:24])[CH3:23]
Reactant: CC(=O)[O-]
Reactant: CCn1nc2c(N)nc3ccccc3c2c1CCCCCl
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nc2c(N)nc3ccccc3c2c1CCCCOC(C)=O
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 1.3 %

Procedure:
1-(4-Chlorobutyl)-2-ethyl-2H-pyrazolo[3,4-c]quinolin-4-amine (3.8 g, 12.5 mmol, prepared as described in Example 19) was combined with potassium acetate (3.68 g, 37.5 mmol), sodium iodide (470 mg, 3.12 mmol), and DMF (21 mL). The mixture was heated at 90° C. for 2 hours, allowed to cool to ambient temperature, diluted with water (100 mL), stirred for 20 minutes, and then filtered to remove a black solid. The filtrate was allowed to stand for 1 week at which time crystals had formed. The crystals were isolated by filtration, purified by chromatography on a HORIZON HPFC system (25+M cartridge eluting with chloroform/CMA in a gradient from 100:0 to 70:30), and then recrystallized from acetonitrile to provide 55 mg of 4-(4-amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butyl acetate as a tan crystalline solid, mp 128-129° C. MS (APCI) m/z 327 (M+H)+;
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH:17][C:18]2[C:23]([N+:24]([O-])=O)=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:14]=[CH:15][CH:16]=1.C(O)(=O)C>C(O)C.C(Cl)(Cl)Cl.[Fe]>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH:17][C:18]2[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1cccnc1Nc1cccc(-c2ccc3ccccc3c2)c1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Nc1cccnc1Nc1cccc(-c2ccc3ccccc3c2)c1
Yield: 43.9 %

Procedure:
A mixture of 2-[3-(2-naphthyl)phenylamino]-3-nitropyridine (3.0 g), iron (2.46 g) and acetic acid (5.28 g) in ethanol (14 ml) was stirred under reflux for 6 hours. The reaction mixture was diluted with chloroform, filtered and treated with saturated sodium bicarbonate solution. The chloroform layer was separated, dried, evaporated and chromatographed on silica gel to give 2-[3-(2-naphthyl)phenylamino]-3-aminopyridine (1.2 g, 43.9%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl[C:13]1[N:18]=[CH:17][N:16]=[C:15]2[N:19]([CH:22]3[CH2:27][CH2:26][N:25]([C:28]4[O:32][N:31]=[C:30]([CH:33]([CH3:35])[CH3:34])[N:29]=4)[CH2:24][CH2:23]3)[N:20]=[CH:21][C:14]=12.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:21]2[C:14]3[C:15](=[N:16][CH:17]=[N:18][CH:13]=3)[N:19]([CH:22]3[CH2:23][CH2:24][N:25]([C:28]4[O:32][N:31]=[C:30]([CH:33]([CH3:35])[CH3:34])[N:29]=4)[CH2:26][CH2:27]3)[N:20]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: CC(C)c1noc(N2CCC(n3ncc4c(Cl)ncnc43)CC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1noc(N2CCC(n3nc(Oc4ccc(S(C)(=O)=O)cc4)c4cncnc43)CC2)n1
Temperature: 180 °C
Yield: 75.2 %

Procedure:
A mixture of 4-methanesulfonyl-phenol (available from Acros Organics, Geel, Belgium; 24 mg, 0.14 mmol), 4-chloro-1-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidine (Intermediate 22; 40 mg, 0.11 mmol) and potassium carbonate (19 mg, 0.14 mmol) in anhydrous DMF (2 mL) was heated in a Biotage Optimizer microwave at 180° C. for 10 min. The mixture was cooled and filtered through Celite, concentrated and held under vacuum. The residue was purified by flash column chromatography eluting with 0-3% methanol/dichloromethane to give 4-(4-methanesulfonyl-phenoxy-1-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidine (40 mg, 72%). Mass spectrum (ES) MH+=483.5.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=2)=[CH:4][C:3]=1[N+:18]([O-])=O.Cl[C:22]([O:24][CH2:25][CH2:26][CH3:27])=[O:23].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[NH2:18][C:3]1[CH:4]=[C:5]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=2)[CH:6]=[CH:7][C:2]=1[NH:1][C:22]([O:24][CH2:25][CH2:26][CH3:27])=[O:23]
Reactant: Nc1ccc(NCc2cc(Cl)cc(Cl)c2)cc1[N+](=O)[O-]
Reactant: CCCOC(=O)Cl
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CCCOC(=O)Nc1ccc(NCc2cc(Cl)cc(Cl)c2)cc1N
Yield: 58.7 %

Procedure:
A suspension of 15.5 g (50 mmol) 2-amino-5-(3,5-dichlorobenzylamino)-nitrobenzene is hydrogenated in a manner analogous with Example 1 (variant A) and worked up appropriately with 6.2 g (51 mmol) propyl chloroformate. 10.8 g of the end product are obtained in the form of the dihydrochloride. This forms colorless to pale pink crystals.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[CH:14][N:13]3[CH:24]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:26]1C=CC2N(C(C3C=CC=CN=3)=C(C(NC3C=CC=CC=3)=O)N=2)C=1C>>[CH3:26][C:14]1[N:13]2[CH:24]=[C:10]([C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:9])[N:11]=[C:12]2[CH:17]=[CH:16][C:15]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: O=C(Nc1ccccc1)c1cn2cc(-c3ccccn3)ccc2n1
Reactant: Cc1c(I)ccc2nc(C(=O)Nc3ccccc3)c(-c3ccccn3)n12
Product: Cc1c(-c2ccccn2)ccc2nc(C(=O)Nc3ccccc3)cn12

Procedure:
This product is obtained in a manner similar to that for the product of Example 3, replacing the 6-iodo-N-phenylimidazo[1,2-a]pyridine-2-carboxamide with 6-iodo-5-methyl-N-phenyl(pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:21])=[CH:5][C:6]=1[C:7]1[CH:8]=[C:9]([C:17]([O:19][CH3:20])=[O:18])[CH:10]=[C:11]([CH:16]=1)[C:12]([O:14]C)=[O:13].[OH-].[K+]>CO>[CH3:20][O:19][C:17]([C:9]1[CH:10]=[C:11]([CH:16]=[C:7]([C:6]2[CH:5]=[C:4]([Cl:21])[S:3][C:2]=2[Cl:1])[CH:8]=1)[C:12]([OH:14])=[O:13])=[O:18]
Reactant: COC(=O)c1cc(C(=O)OC)cc(-c2cc(Cl)sc2Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1cc(C(=O)O)cc(-c2cc(Cl)sc2Cl)c1
Temperature: 25 °C
Yield: 87.7 %

Procedure:
A mixture of dimethyl 5-(2,5-dichlorothiophen-3-yl)isophthalate (1.70 g) and potassium hydroxide (0.28 g) in methanol (50 ml) was heated to reflux for 48 hours. After being cooled to room temperature, the solvent was removed under reduced pressure. The residue was dissolved in water and was acidified with hydrochloric acid solution. The product was extracted with ethyl acetate and the organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (10:1) to afford 3-methoxycarbonyl-5-(2,5-dichlorothiophen-3-yl)benzoic acid (1.43 g).
Reaction SMILES: ClCCl.[Cl:4][C:5]1[CH:6]=[C:7]([CH2:21][CH2:22][OH:23])[CH:8]=[C:9]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C:10]=1[Cl:11].CCN(C(C)C)C(C)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>CCOCC>[CH3:33][S:34]([O:23][CH2:22][CH2:21][C:7]1[CH:8]=[C:9]([CH2:12][O:13][Si:14]([C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:15])[CH3:16])[C:10]([Cl:11])=[C:5]([Cl:4])[CH:6]=1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(CCO)cc(Cl)c1Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cc(CCOS(C)(=O)=O)cc(Cl)c1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a dichloromethane (0.11 M) solution of 2-[3,4-dichloro-5-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)phenyl]ethanol (1 eq.) from the previous step was added at 0° C. Hunig's base (1.5 eq.) and methanesulfonyl chloride (1.1 eq.). The resulting suspension was stirred at 0° C. for 30 min and at RT for 15 min. The reaction was then diluted with ether and quenched with 1N aq. HCl. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were washed further with 1 N aq. NaOH, water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo to give the title compound as a brown oil.
Reaction SMILES: Cl[CH:2]([C:7]1[CH:8]=[N:9][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:11][CH:12]=1)[C:3]([CH3:6])([CH3:5])[CH3:4].[C-:17]#[N:18].[Na+].C(=O)(O)[O-].[Na+].ClCCl>CS(C)=O.C(OCC)(=O)C>[CH3:4][C:3]([CH3:6])([CH3:5])[CH:2]([C:7]1[CH:8]=[N:9][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:11][CH:12]=1)[C:17]#[N:18]
Reactant: [C-]#N
Reactant: CC(C)(C)c1ncc(C(Cl)C(C)(C)C)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ncc(C(C#N)C(C)(C)C)cn1
Temperature: 25 °C
Yield: 155.7 %

Procedure:
A solution of 1-chloro-2,2-dimethyl-1-[2-(1,1-dimethylethyl)pyrimidin-5-yl]propane (5.08 g) and sodium cyanide (2.07 g) in dry dimethylsulphoxide (50 cm3) was heated to 60° C., under an atmosphere of dry nitrogen for a period of 17 hours. After cooling to the ambient temperature, the solution was poured into aqueous sodium bicarbonate solution and extracted with diethyl ether, washed with brine, dried over anhydrous magnesium sulphate, and concentrated by evaporation of the solvent under reduced pressure. The resulting brown oil was combined with the crude product from a similar reaction and subjected to column chromatography on silica gel using dichloromethane followed by dichloromethane containing 5% by volume ethyl acetate to give 3,3-dimethyl-2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]butyronitrile (7.6 g), identical in all respects to the material obtained in Example 15 (ii) above.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([C:24]([NH2:26])=[O:25])=[C:11]2[CH2:16][NH:15][CH2:14][CH2:13][N:12]2[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([N:42]=[C:43]=[S:44])=[CH:38][CH:37]=1>ClCCl>[Cl:8][C:9]1[C:10]([C:24]([NH2:26])=[O:25])=[C:11]2[CH2:16][N:15]([C:43](=[S:44])[NH:42][C:39]3[CH:38]=[CH:37][C:36]([O:35][CH3:34])=[CH:41][CH:40]=3)[CH2:14][CH2:13][N:12]2[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC(=O)c1c(Cl)c(-c2ccccc2)n2c1CNCC2
Reactant: COc1ccc(N=C=S)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=S)N2CCn3c(c(C(N)=O)c(Cl)c3-c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 7-chloro-6-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylic acid amide trifluoroacetic acid salt (50 mg, Reference Example 1) in dry dichloromethane (5 mL) was treated with dry triethylamine (54 μL), then with a solution of 4-methoxyphenyl isothiocyanate (18 μL) in dry dichloromethane (5 mL). After stirring at room temperature for a further 3 hours the reaction mixture was further treated with dichloromethane (10 mL) and then washed three times with water (5 mL). The organic phase was dried over magnesium sulfate and evaporated. The residue was subjected to column chromatography on silica eluting with a mixture of pentane and ethyl acetate (1:1, v/v) to give 7-chloro-2-(4-methoxyphenylthiocarbamoyl)-6-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylic acid amide (40 mg) as a white solid, m.p. 176–178° C. MS: 443 [MH]+, 441 [MH]+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]([NH:6][C:7]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])=[O:5].[C:22](#[N:25])[CH:23]=[CH2:24].Cl>C(OCC)C>[ClH:21].[C:22]([CH2:23][CH2:24][N:2]([CH3:1])[CH2:3][C:4]([NH:6][C:7]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])=[O:5])#[N:25]
Reactant: C=CC#N
Reactant: CNCC(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: Cl
Solvent: CCOCC
Product: CN(CCC#N)CC(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.0 g of 2-(methylamino-acetamido)-5-chloro-benzophenone were dissolved in 30 mls. of anhydrous alcohol and then mixed with 2.0 g of freshly distilled acrylonitrile. The mixture was stirred for 2 hours at room temperature and then heated under reflux for a further 8 hours. After being allowed to stand overnight at room temperature a further 2.0 g of freshly distilled acrylonitrile was added and the mixture heated under reflux with stirring for a further 4 hours. At this point a sample showed in a thin-layer chromatogram a uniform point which differed from that of the initial product. The turbid solution was filtered and concentrated in vacuo (approx. 0.1 mm Hg), 3.0 g of a colourless oil being obtained. This residue was dissolved in anhydrous diethyl ether. After passing dry hydrogen chloride into this solution, 3.6 g of 2-(5-cyano-3-methyl-3-aza-pentanamido)-5-chloro-benzophenone hydrochloride were obtained, corresponding to 92% of theory. The product had a melting point of 166°-168°. The RF value in a thin-layer chromatogram in methanol as flow medium was 0.85.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]([Br:24])(Br)Br.[F:25][C:26]1[CH:27]=[CH:28][C:29]([O:34][CH2:35][C:36]#[C:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=2)=[C:30](CO)[CH:31]=1>C1COCC1>[F:25][C:26]1[CH:27]=[CH:28][C:29]([O:34][CH2:35][C:36]#[C:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:45])([F:46])[F:47])=[CH:40][CH:39]=2)=[C:30]([CH:31]=1)[CH2:21][Br:24]
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cc(F)ccc1OCC#Cc1ccc(C(F)(F)F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(OCC#Cc2ccc(C(F)(F)F)cc2)c(CBr)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 23.6 %

Procedure:
834 mg (3.18 mmol) of triphenylphosphine and 1.05 g (3.18 mmol) of tetrabromomethane are dissolved in 2 ml of THF and stirred at room temperature for 10 min. Then 860 mg (2.63 mmol) of {5-fluoro-2-[3-(4-trifluoromethylphenyl)prop-2-ynyloxy]phenyl}methanol, dissolved in 2 ml of THF, are added dropwise, and the mixture is stirred at room temperature overnight. The solvent is distilled out in vacuo, and the residue is chromatographed on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1). 240 mg (0.62 mmol, 24% of theory) of 5-fluoro-2-[3-(4-trifluoromethylphenyl)prop-2-ynyloxy]benzyl bromide are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[C:9]([NH:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[CH:8][C:7]([CH3:16])=[N:6][C:5]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[O:25]C.B(Br)(Br)Br>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[C:4]1[C:9]([NH:10][CH:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[CH:8][C:7]([CH3:16])=[N:6][C:5]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[OH:25]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2ccc(Cl)cc2OC)c1C(=O)OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCC(CC)Nc1cc(C)nc(Oc2ccc(Cl)cc2O)c1C(=O)OC

Procedure:
The title compound was prepared by reacting 2-(4-chloro-2-methoxy-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-nicotinic acid methyl ester with BBr3 in methylene chloride at rt until all starting material was consumed. Standard work-up procedure gave the title compound.
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([CH3:23])[N:5]([P@:13]([CH2:21][CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])CC1C=CC=CC=1.[NH2:25][O:26][K].Cl>>[OH:26][NH:25][C:3](=[O:2])[C@H:4]([NH:5][P@:13]([CH2:21][CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])[CH3:23]
Reactant: NO[K]
Reactant: CC[P@](=O)(c1ccccc1)N(Cc1ccccc1)[C@H](C)C(=O)OC
Agent: Cl
Product: CC[P@@](=O)(N[C@H](C)C(=O)NO)c1ccccc1
Reaction time: 16 h

Procedure:
N-((S)-Ethylphenylphosphinyl)-N-benzyl-D-alanine methyl ester (105 mg, 0.30 mmol) is treated with a solution of NH2OK (1.0 mL, 1.76M in methanol) prepared as described in Fieser and Fieser, Vol. 1, p. 478. The reaction is stirred for 16 hours at which time TLC indicates completion. The reaction mixture is neutralized with 1M aqueous HCl and the volatiles are removed. The residue is purified by silica gel flash chromatography (95:5 ethyl acetate:methanol) to give N-hydroxy-2(R)-[[(S)-ethylphenylphosphinyl]amino]-propionamide as colorless solid: MS-IS m/z 347 [M+H]+, 369 [M+Na]+.