Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[NH:1][N:2]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NNc1ccccn1
Reactant: O=Cc1ccccc1
Solvent: CCO
Product: C(=NNc1ccccn1)c1ccccc1
Temperature: 100 °C
Reaction time: 0.02 h
Yield: 83.9 %

Procedure:
In 20 ml of ethanol was dissolved 5.46 g of 2-hydrazinopyridine. With stirring, 5.32 g of benzaldehyde was added to the solution. With heat release, pale yellow crystals precipitated within about 30 seconds and the entire solution solidified after one minute. 10 ml of ethanol was added to the mass which was refluxed at 100° C. for 40 minutes. The reaction solution was allowed to cool at room temperature and further cooled down to 10° C. to cause crystals to precipitate. The crystals were collected by suction filtration, washed with ethanol and dried in vacuum at room temperature for one hour, obtaining 8.28 g (yield 83%) of pale yellow acicular crystals.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][CH2:4][Mg]I.ICCC(C)C.[Mg].BrCCBr.[C:19]([O:27][C@H:28]1[CH2:48][CH2:47][C@@:46]2([CH3:49])[C@@H:30]([CH2:31][CH2:32][C:33]3[C:34]4[C@:42]([CH3:50])([CH2:43][CH2:44][C:45]=32)[C@@H:37]([C@@H:38]([CH:40]=[O:41])[CH3:39])[CH2:36][CH:35]=4)[C:29]1([CH3:52])[CH3:51])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+]>C(OCC)C.C1COCC1>[C:19]([O:27][C@H:28]1[CH2:48][CH2:47][C@@:46]2([CH3:49])[C@@H:30]([CH2:31][CH2:32][C:33]3[C:34]4[C@:42]([CH3:50])([CH2:43][CH2:44][C:45]=32)[C@@H:37]([C@H:38]([CH3:39])[C@@H:40]([OH:41])[CH2:4][CH2:3][CH:2]([CH3:7])[CH3:1])[CH2:36][CH:35]=4)[C:29]1([CH3:51])[CH3:52])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)CC[Mg]I
Reactant: C[C@H](C=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](OC(=O)c2ccccc2)C(C)(C)[C@@H]1CC3
Agent: CC(C)CCI
Agent: [Cl-]
Agent: [Mg]
Solvent: BrCCBr
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)CC[C@H](O)[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](OC(=O)c2ccccc2)C(C)(C)[C@@H]1CC3
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
i)—A solution of 3-methylbutylmagnesium iodide (12 ml), prepared from 1-iodo-3-methylbutane (2.36 ml) and magnesium (0.48 g), activated with 1,2-dibromoethane (0.040 ml), in diethyl ether (10 ml and 10 ml, respectively) at reflux temperature, was added dropwise to (3β,5α,20S)-3-(benzoyloxy)-4,4-dimethylpregna-8,14-diene-20-carboxaldehyde (WO-09852965; 1.55 g) in THF (20 ml). The reaction mixture was stirred at room temperature for 45 min. and then poured into a saturated aqueous solution of ammonium chloride. The product was extracted into ethyl acetate; the combined organic phases were washed with a saturated aqueous solution of ammonium chloride and with brine, dried over magnesium sulfate and concentrated under reduced pressure. Column chromatography afforded (3β,5α,20S,22S)-4,4-dimethylcholesta-8,14-diene-3,22-diol 3-benzoate (1.1 g).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:15])=[CH2:5].[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Cl>CN(C)C=O>[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:6]([C:4]([CH3:3])=[CH2:5])[C:7]1=[O:15]
Reactant: ClCCCCCCCl
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)n1c(=O)n(CCCCCCCl)c2ccccc21
Reaction time: 8 h

Procedure:
To a stirred mixture of 3.2 parts of a sodium hydride dispersion 70% in 9 parts of N,N-dimethylformamide is added dropwise (slowly), during a 2 hours-period, a mixture of 17.4 parts of 1,3-dihydro-1-(1-methylethenyl)-2H-benzimidazol-2-one, 77.5 parts of 1,6-dichlorohexane and 36 parts of N,N-dimethylformamide. Upon completion, stirring is continued overnight at room temperature. The reaction mixture is filtered over hyflo and the N,N-dimethylformamide is evaporated in vacuo. The excess of 1,6-dichlorohexane is distilled off in an oil-bath with water-jet. The residue is dissolved in methylbenzene and the solution is stirred with activated charcoal. The latter is filtered off over hyflo and the filtrate is evaporated, yielding 1-(6-chlorohexyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one as an oily residue.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH2:14]Cl.[C:16]([O-:19])(=[O:18])[CH3:17].[K+].CN(C=O)C>O>[C:16]([O:19][CH2:14][C:3]1[N:4]=[C:5]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][N:6]2[C:7](=[O:8])[C:2]=1[Br:1])(=[O:18])[CH3:17]
Reactant: CC(=O)[O-]
Reactant: O=c1c(Br)c(CCl)nc2ccc(F)cn12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCc1nc2ccc(F)cn2c(=O)c1Br
Temperature: 40 °C
Reaction time: 3 h

Procedure:
A mixture of 3-bromo-2-(chloromethyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one (10.60 g, 36.36 mmol), potassium acetate (4.283 g, 43.64 mmol), and DMF (138.5 mL) was stirred at 40° C. After 3 h, the mixture was concd under reduced pressure. To the residue was added water (200 mL) and the resulting precipitate was collected by filtration, washed with water (300 mL), and dried to give (3-bromo-7-fluoro-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)methyl acetate as a brown solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.98 (1H, dd, J=4.9, 2.7 Hz), 8.18 (1 H, ddd, J=9.8, 7.1, 2.8 Hz), 7.86 (1 H, dd, J=9.7, 5.4 Hz), 5.21 (2 H, s), 2.16 (3 H, s); Mass Spectrum (ESI) m/e=315.0 [M+1 (79Br)] and 316.9 [M+1 (81Br)].
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:8]2)[O:4][N:3]=1.[CH2:31]([NH:33][CH2:34][CH2:35][OH:36])[CH3:32]>C(O)C>[CH2:31]([N:33]([CH2:34][CH2:35][OH:36])[C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:8]2)[O:4][N:3]=1)[CH3:32]
Reactant: CCNCCO
Reactant: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(Cl)no2)C1
Solvent: CCO
Product: CCN(CCO)c1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1
Reaction time: 2 h

Procedure:
To a solution of 150 mg (0.337 mmol) of the oxadiazole from Example 23A in 2.25 ml of ethanol were added 601 mg (6.74 mmol) of 2-(ethylamino)ethanol, and then the reaction mixture was stirred in the microwave at 80 for 2 h. Another 601 mg (6.74 mmol) of 2-(ethylamino)ethanol were added and the mixture was stirred in the microwave at 100 for a further 7 h. The solvent was removed under reduced pressure and the crude product was purified by means of preparative HPLC. Yield: 28.3 mg (17% of theory)
Reaction SMILES: C1(NS(=O)(=O)O)CCCCC1.[CH2:12]([N:16]1[CH2:20][CH2:19][CH2:18][C:17]1=[NH:21])[CH2:13][CH2:14][CH3:15].[Cl:22][C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1>>[CH2:12]([N:16]1[CH2:20][CH2:19][CH2:18][C:17]1=[N:21][C:30]([NH:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([Cl:22])[CH:24]=1)=[O:31])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCN1CCCC1=N
Reactant: O=C=Nc1cccc(Cl)c1
Agent: O=S(=O)(O)NC1CCCCC1
Product: CCCCN1CCCC1=NC(=O)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The cyclohexylsulfamic acid salt of 1-n-butyl-2-iminopyrrolidine (15.97 g.; 0.05 mole) is converted to free base (7.01 g.; 0.05 mole) in the usual manner. After drying over K2CO3, the benzene solution is filtered through diatomaceous earth and 7.68 g. (0.05 mole) of m-chlorophenylisocyanate is added. The reaction mixture is stirred at room temperature for 21/2 hours and then taken to dryness in vacuo leaving a solid residue, 1-(1 -n-butyl2-pyrrolidylidene)-3-(m-chlorophenyl)urea. Recrystallizations from ethyl acetate yields the pure product, m.p. = 94-96° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]([F:13])([F:12])[F:11])=[CH2:9])[CH:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.ClC1C=C(C(C(F)(F)F)=C)C=C(Cl)C=1.ClC1C=C(C2(C(F)(F)F)[O:44][N:43]=[C:42]([C:45]3[CH:56]=[CH:55][C:48]4[B:49]([OH:54])[O:50][C:51]([CH3:53])([CH3:52])[C:47]=4[CH:46]=3)C2)C=C(Cl)C=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2([C:10]([F:11])([F:12])[F:13])[O:44][N:43]=[C:42]([C:45]3[CH:56]=[CH:55][C:48]4[B:49]([OH:54])[O:50][C:51]([CH3:53])([CH3:52])[C:47]=4[CH:46]=3)[CH2:9]2)[CH:5]=[C:4]([C:14]([F:15])([F:16])[F:17])[CH:3]=1
Reactant: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc21
Reactant: C=C(c1cc(Cl)cc(C(F)(F)F)c1)C(F)(F)F
Agent: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(Cl)cc(C(F)(F)F)c4)(C(F)(F)F)C3)cc21

Procedure:
The title compound was prepared by using the same method as described in 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol with 1-chloro-3-(trifluoromethyl)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene to replace 1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene. It was obtained as a white solid. MS: m/z=478.1 [M+1]+.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC([N:36]1[CH:40]=[CH:39][CH:38]=[C:37]1[C:41]1[CH:46]=[CH:45][C:44]([F:47])=[C:43]([CH:48]=O)[CH:42]=1)=O)(C)(C)C>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:48][C:43]3[CH:42]=[C:41]([C:37]4[NH:36][CH:40]=[CH:39][CH:38]=4)[CH:46]=[CH:45][C:44]=3[F:47])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)NC(=O)n1cccc1-c1ccc(F)c(C=O)c1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Fc1ccc(-c2ccc[nH]2)cc1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2-(4-fluoro-3-formyl-phenyl)-pyrrole-1-carboxylic acid tert-butylamide according to the procedure of Example 66. MS (ES) m/z 552.0;
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=O)[CH2:2]1.Cl.[C:10]1([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24]N)=[CH:20][CH:19]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C.O>[C:10]1([CH2:16][O:17][C:18]2[CH:19]=[C:20]3[C:21](=[CH:22][CH:23]=2)[NH:24][C:3]2[CH2:4][CH2:5][CH2:6][C:1](=[O:8])[C:2]3=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NNc1ccc(OCc2ccccc2)cc1
Reactant: O=C1CCCC(=O)C1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C1CCCc2[nH]c3ccc(OCc4ccccc4)cc3c21
Yield: 38.4 %

Procedure:
1,3-Cyclohexanedione (3.1 g) and the product of Stage (i) (5.6 g) in ethanol (196 ml) and water (39 ml) was stirred at room temperature for 3 h and then heated to reflux for 14 h. The resulting solution was allowed to cool, poured into water (500 ml) and the precipitate filtered and washed with isopropyl acetate and ether to give a solid. Recrystallisation from methanol gave the title compound as a solid (2.5 g) m.p. 235°-237°.
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:20][NH:21][NH:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].O>CN(C1C=CN=CC=1)C.ClCCCl>[CH:1]1([C:4]([N:21]([CH3:20])[NH:22][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(O)C1CC1
Reactant: CNNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCCl
Product: CN(NC(=O)OCc1ccccc1)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.5 %

Procedure:
Cyclopropanecarboxylic acid (600 mg, 6.97 mmol), DMAP (170 mg, 1.39 mmol) and EDC.HCl (1.19 g, 7.67 mmol) were added in that order to a stirred solution of benzyl 2-methylhydrazinecarboxylate hydrochloride (JOC, 2013, 78, 3541-3552.) (1.80 g, 8.37 mmol) in DCE (10 mL) and the reaction mixture was stirred at 25° C. for 12 h. Water was added to the reaction mixture and the mixture extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), filtered, concentrated and the residue was purified by column chromatography on silica (100-200 mesh) eluting with 30% hexane in EtOAc to afford the title compound as a colourless gum (1.6 g, 80%): 1H NMR (300 MHz, DMSO-d6) δ10.01 (bs, 1H), 7.37 (s, 5H), 5.18 (s, 2H), 2.97 (s, 3H), 1.98-1.89 (m, 1H), 0.70-0.68 (m, 4H); ESIMS m/z 247.0 ([M−H]−); IR (thin film) 3502, 2928, 1736 cm−1.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26](OCC)=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:34][O:35][CH2:36][CH:37]([NH2:40])[CH2:38][CH3:39]>>[F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26]([NH:40][CH:37]([CH2:36][O:35][CH3:34])[CH2:38][CH3:39])=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O
Reactant: CCC(N)COC
Product: CCC(COC)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-(4-fluorobenzyl)-4-hydroxy-2-oxo-1-[2-(2-oxopyrrolidin-1-yl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 1-(methyloxy)-2-butanamine using conditions similar to those employed in Example 563 to provide a white solid: 1H NMR (d6-DMSO) δ 10.32 (1H, d, J=9 Hz), 8.53 (1H, s), 8.11 (1H, s), 7.38 (2H, dd, J=6, 9 Hz), 7.11 (2H, t, J=9 Hz), 4.37 (2H, b), 4.14 (2H, s), 4.05 (1H, b), 3.32-3.47 (6H, m), 3.26 (3H, s), 1.95 (2H, t, J=8 Hz), 1.69-1.80 (2H, m), 1.56-1.66 (1H, m), 1.42-1.56 (1H, m), 0.86 (3H, t, J=8 Hz); ES+ MS: 511 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)NN=C3)=[CH:6][CH:5]=[CH:4][N:3]=1.[F:17]C1C=CC(B(O)O)=CC=1.BrC1C(Cl)=NC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:14]([F:17])=[CH:15][CH:16]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1ncccc1-c1ccc2[nH]ncc2c1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Clc1ncccc1Br
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Fc1ccc(-c2cccnc2Cl)cc1

Procedure:
2-Chloro-3-(4-fluorophenyl)pyridine was synthesized analogous to the reaction conditions used in the preparation of 5-(2-chloropyridin-3-yl)-1H-indazole by heating the mixture of 4-fluorophenyl boronic acid (3.0 g, 21.4 mmol), 3-bromo-2-chloropyridine (4.9 g, 25.7 mmol), Pd(PPh3)4 (1.6 g, 1.3 mmol) and 2M aq. Na2CO3 (25 mL, 50 mmol) in 1,4-dioxane (125 mL) under argon atmosphere for 12 h. LC/MS indicated three products with MH+ 208, 254 and 268. Upon work-up of the reaction mixture, as discussed in the preparation of 5-(2-chloropyridin-3-yl)-1H-indazole, the crude concentrated was purified by flash silica gel column chromatography [Combiflash® companion System® with RediSep® silica gel column 120 g, 10-50% EtOAC/hexanes eluting solvent gradient upon liquid loading on to column]. Two fractions containing the desired product were identified and concentrated. 2-Chloro-3-(4-fluorophenyl)pyridine was isolated as a crystalline solid (888 mg, 16%) from the fraction containing 2,3-bis(4-fluorophenyl)pyridine by suspending the semi solid fraction mixture in 10% EtOAc/hexanes and filtered. 1H NMR (DMSO-d6): δ 8.41 (dd, 1H, J=1.8 and 4.7 Hz), 7.86 (dd, 1H, J=2.0 and 7.6 Hz), 7.54-7.48 (m, 3H), 7.34-7.31 (m, 2H). 19F NMR (DMSO-d6): δ −114.06 (s). LCMS: rt 7.50 min (A), purity 99%, MS (m/e) 208 (MH+).
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[CH:5]([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:6]([O:8][CH3:9])=[O:7]>CO>[CH3:1][O:2][CH:5]([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)CCCC(Br)C(=O)OC
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCCC(OC)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.2 %

Procedure:
12.2 g of sodium methoxide were added to a solution of 38.0 g of dimethyl α-bromoadipate (prepared as described in the following Preparation) in 100 ml of methanol, and the mixture was stirred overnight at room temperature. After this, methanol was evaporated from the reaction mixture under reduced pressure, and diethyl ether was added to the resulting residue. The solution thus obtained was washed with water and dried over anhydrous sodium sulfate. The diethyl ether was evaporated off under reduced pressure, and the residue was distilled, to give 11.4 g of the title compound, boiling at 74°-79° C./1 mm Hg (133 Pa).
Reaction SMILES: [N:1]1([CH2:5][CH2:6][C:7]2[N:11]([CH3:12])[N:10]=[N:9][C:8]=2[CH2:13][OH:14])[CH2:4][CH2:3][CH2:2]1.Cl[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]2=[N:26][N:27]=[C:28]([C:29]3[CH:33]=[C:32]([CH3:34])[O:31][N:30]=3)[N:18]2[N:17]=1>>[N:1]1([CH2:5][CH2:6][C:7]2[N:11]([CH3:12])[N:10]=[N:9][C:8]=2[CH2:13][O:14][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]3=[N:26][N:27]=[C:28]([C:29]4[CH:33]=[C:32]([CH3:34])[O:31][N:30]=4)[N:18]3[N:17]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(Cl)nn23)no1
Reactant: Cn1nnc(CO)c1CCN1CCC1
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4nnn(C)c4CCN4CCC4)nn23)no1

Procedure:
The reaction was carried out according to Example 1 step 4 using [5-(2-(azetidin-1-yl)ethyl)-1-methyl-1H-[1,2,3]triazol-4-yl]methanol (103 mg, 0.53 mmol) and 6-chloro-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[3,4-α]phthalazine (150 mg, 0.53 mmol). The crude residue was purified by column chromatography on silica using 2% MeOH/CH2Cl2 containing 1% NH3 to yield, after recrystallisation from CH2Cl2/iso-hexanes, the desired phthalazine (104 mg, 44%). 1H NMR (360 MHz, CDCl3) δ 8.68 (1H, d, J=7.9 Hz), 8.19 (1H, d, J=7.9 Hz), 7.95 (1H, t, J=7.9 Hz), 7.78 (1H, t, J=7.9 Hz), 6.95 (1H, s), 5.75 (2H, s), 4.07 (3H, s), 3.11 (4H, t, J=6.9 Hz), 2.84 (2H, t, J=7.1 Hz), 2.65-2.50 (5H, m), 1.99 (2H, quintet, J=6.9 Hz). m/z (ES+) 446 (M+H+).
Reaction SMILES: C([C:3]1[N:8]=[C:7]([C:9]#[N:10])[C:6]([C:11]([O:13][CH3:14])=[O:12])=[C:5]([NH:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[N:4]=1)#N.C(N(CC)C(C)C)(C)C.[CH:32]1([NH2:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:9]([C:7]1[C:6]([C:11]([O:13][CH3:14])=[O:12])=[C:5]([NH:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[N:4]=[C:3]([NH:38][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[N:8]=1)#[N:10]
Reactant: COC(=O)c1c(C#N)nc(C#N)nc1Nc1cccc(C)c1
Reactant: NC1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1c(C#N)nc(NC2CCCCC2)nc1Nc1cccc(C)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 89.9 %

Procedure:
A mixture of methyl 2,4-dicyano-6-(m-tolylamino)pyrimidine-5-carboxylate (102.3 mg, 0.349 mmol), N,N-diisopropylethylamine (0.075 mL, 0.429 mmol) and cyclohexylamine (0.05 mL, 0.437 mmol) in DMF (2 mL) was stirred at RT for 14 h. Saturated aq NaHCO3 was added and the mixture was extracted with EtOAc. The organic layers were washed with aq NaHCO3, water, and brine, and were filtered through SiO2. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (SiO2, hexanes/EtOAc=4/1) to give the title compound as a yellow oil (114.7 mg, 90%). 1H NMR (500 MHz, CDCl3) δ ppm 1.19-1.45 (m, 5H), 1.64-1.67 (m, 1H), 1.73-1.80 (m, 2H), 2.00-2.05 (m, 2H), 2.38 (s, 3H), 3.75-3.82 (m, 1H), 3.98 (s, 3H), 5.57-5.58 (br d, J=7.9 Hz, 1H), 6.97-6.98 (m, 1H), 7.27-7.29 (m, 1H), 7.46-7.51 (m, 2H), 10.62 (br s, 1H). [M+H] calc'd for C20H24N5O2, 366. found, 366.
Reaction SMILES: I[C:2]1[C:7]([CH:8]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:18])[N:5]=[C:4]2[S:19][C:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:3]=12.C(=O)([O-])[O-].[K+].[K+].[CH3:32][C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][N:34]=1.C(OCC)(=O)C>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][C:6]1[N:5]=[C:4]2[S:19][C:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:3]2=[C:2]([C:36]2[CH:35]=[N:34][C:33]([CH3:32])=[CH:38][CH:37]=2)[C:7]=1[CH:8]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1I)CCCC3
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1ccc(C)nc1)CCCC3
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
To a solution of methyl 2-[4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate (0.050 g; 0.106 mmol) in a mixture of DME-water (3:1) (0.480 mL) were added potassium carbonate (0.044 g; 0.317 mmol), tetrakis(triphenylphosphine)palladium(0) (0.012 g; 0.010 mmol) and 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.046 g; 0.211 mmol). The solution was stirred for 30 min at 140° C. under a microwave irradiation. Ethyl acetate was added to the reaction mixture and the solution was washed with brine. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethylacetate (10-80%) in heptane furnished 0.025 g (54%) of the title compound as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N+:3]=1[O-:10].[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][N+:3]=1[O-:10]
Reactant: [O-][n+]1cc(CCl)ccc1Cl
Reactant: C1CCNC1
Solvent: CC#N
Product: [O-][n+]1cc(CN2CCCC2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
To a solution of 2-chloro-5-(chloromethyl)pyridine 1-oxide (477 mg, 2.68 mmol; described in: Tilley, J. W. et al, J. Heterocyclic Chem. 1979, 16, 333) in acetonitrile (10 mL) was added pyrrolidine (381 mg, 5.36 mmol), and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was dissolved in 2 M HCl(aq) and washed with ethyl acetate. The aqueous layer was alkalized to pH 8 with NaHCO3 (s), and the mixture was extracted four times with ethyl acetate. The combined organic layers were dried (Na2SO4), and the solvent was evaporated to give 0.43 g (75% yield) of the title compound as a red oil: 1H NMR (CDCl3, 400 MHz) δ 8.37 (d, J=1 Hz, 1 H), 7.44 (d, J=8 Hz, 1 H), 7.23 (dd, J=8, 2 Hz, 1 H), 3.57 (s, 2 H), 2.51 (m, 4 H), 1.80 (m, 4 H); 13C NMR (CDCl3, 100 MHz) δ 140.1, 139.9, 137.2, 126.4, 126.4, 56.4, 54.0, 23.5; MS (ES) m/z 213 (M++1).