Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][C:8]2([F:14])[F:13])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:21][N:22]1[CH:26]=[C:25]([C:27]2[CH:28]=[C:29]([C:33]3[N:38]=[CH:37][C:36](B4OC(C)(C)C(C)(C)O4)=[CH:35][N:34]=3)[CH:30]=[CH:31][CH:32]=2)[CH:24]=[N:23]1.ClCCl>C1OCCOC1.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[F:13][C:8]1([F:14])[CH:7]([N:5]2[CH:6]=[C:2]([C:36]3[CH:35]=[N:34][C:33]([C:29]4[CH:30]=[CH:31][CH:32]=[C:27]([C:25]5[CH:24]=[N:23][N:22]([CH3:21])[CH:26]=5)[CH:28]=4)=[N:38][CH:37]=3)[CH:3]=[N:4]2)[CH2:12][CH2:11][NH:10][CH2:9]1
Reactant: Cn1cc(-c2cccc(-c3ncc(B4OC(C)(C)C(C)(C)O4)cn3)c2)cn1
Reactant: FC1(F)CNCCC1n1cc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2cccc(-c3ncc(-c4cnn(C5CCNCC5(F)F)c4)cn3)c2)cn1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 11.4 %

Procedure:
To a solution of 4-(4-Bromo-pyrazol-1-yl)-3,3-difluoro-piperidine (intermediate 29; 150 mg; 0.50 mmol; 1.0 eq.) in Dioxane-1,4 (12 mL) and Water (3.0 mL) was added Potassium carbonate (141 mg; 0.99 mmol; 2.0 eq.) and 2-[3-(1-Methyl-1H-pyrazol-4-yl)-phenyl]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine (intermediate 30; 221 mg; 0.60 mmol; 1.2 eq.). The reaction mixture was degasified for 15 min and then 1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (20.88 mg; 0.02 mmol; 0.05 eq.) was added. The reaction mixture was then heated at 100° C. for 90 min. It was concentrated under reduced pressure, diluted with Water (15 mL) and extracted with ethylacetate (2×25 mL). Combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica (DCM: MeOH, 9:1) afforded the title compound as a brown solid (24 mg; 11%). 1H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 2H), 8.53-8.52 (m, 2H), 8.26 (s, 1H), 8.23-8.20 (m, 2H), 7.91 (s, 1H), 7.71 (d, J=8.1 Hz, 1H), 7.51 (t, J=7.8 Hz, 1H), 4.96-4.86 (m, 1H), 3.89 (s, 3H), 3.22-3.15 (m, 1H), 3.08-3.05 (m, 1H), 2.98-2.87 (m, 1H), 2.72-2.67 (m, 1H), 2.66-2.59 (m, 1H), 2.36-2.29 (m, 1H), 2.08-2.05 (m, 1H). HPLC (Condition A): Rt 3.00 min (purity 96.8%). MS (ESI+): 422.2.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[C:8]([I:11])=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1.[H-].[Na+].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[N:7]=[C:6]2[C:8]([I:11])=[CH:9][N:10]([S:20]([C:17]3[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=3)(=[O:22])=[O:21])[C:5]2=[N:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Brc1cnc2[nH]cc(I)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3nc(Br)cnc32)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 95.6 %

Procedure:
To a stirred solution of 2-bromo-7-iodo-5H-pyrrolo[3,2-b]pyrazine [Intermediate AT] (1.1 g, 3.5 mmol) in anhydrous THF (20 mL) cooled to 0° C. was added NaH [60% dispersion in mineral oil] (0.17 g, 4.3 mmol). The reaction mixture was stirred for 20 min at 0° C., after which p-toluenesulfonyl chloride (0.73 g, 3.8 mmol) in THF (8 mL) was added. The resulting mixture was stirred at rt for 3 hr, after which it was diluted with EtOAc and washed with H2O and brine. The organic layer was separated, dried over Na2SO4, filtered, and evaporated in vacuo to yield a residue that was triturated with hexanes to yield the title compound (1.6 g, 94%) as a light yellow powder. 1H NMR (DMSO-d6, 300 MHz) δ 8.62 (d, J=7.5 Hz, 2H), 8.03 (s, 1H), 8.00 (s, 1H), 7.47 (d, J=8.1 Hz, 2H), 2.37 (s, 3H). HPLC retention time: 2.84 minutes. MS ESI (m/z): 478.0/480.0 (M+H)+, calc. 477.
Reaction SMILES: C([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)(C)C.Br[CH2:13][C:14]1[CH:15]=[C:16]([CH2:22][CH:23]([O:27][CH:28]([CH3:30])[CH3:29])[C:24]([O-:26])=[O:25])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>>[CH:28]([O:27][CH:23]([CH2:22][C:16]1[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:14]([CH2:13][O:9][CH2:8][C:7]2[CH:6]=[CH:5][C:4]([O:20][CH:19]([CH3:18])[CH3:14])=[CH:11][CH:10]=2)[CH:15]=1)[C:24]([OH:26])=[O:25])([CH3:30])[CH3:29]
Reactant: CC(C)c1ccc(CO)cc1
Reactant: COc1ccc(CC(OC(C)C)C(=O)[O-])cc1CBr
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1COCc1ccc(OC(C)C)cc1

Procedure:
Using 4-isopropylbenzyl alcohol and 3-[3-(bromomethyl)-4-methoxyphenyl]-2-isopropoxypropanoate, 2-isopropoxy-3-(3-[(4-isopropoxybenzyl)oxy]methyl-4-methoxyphenyl)propanoic acid was obtained in the same method as in Example 247).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-:16].[Na+].II.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[I:16][C:11]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][NH:9][C:10]=1[C:12]([F:14])([F:15])[F:13]
Reactant: FC(F)(F)c1cc(-c2ccccc2)n[nH]1
Reactant: [I-]
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: FC(F)(F)c1[nH]nc(-c2ccccc2)c1I
Yield: 62.8 %

Procedure:
To a mixture of 3-phenyl-5-(trifluoromethyl)-1H-pyrazole (4.0 g, 18.85 mmol) in THF (50 mL) and water (50 mL) were added sodium iodide (2.83 g, 18.85 mmol), iodine (7.18 g, 28.3 mmol), and K2CO3 (2.61 g, 18.85 mmol) at room temperature. The reaction was refluxed for 16 h, quenched with sodium thiosulfite (2.0 M aq. 10 mL) and concentrated under reduced pressure. The reaction was extracted with ethyl acetate and washed with NaHCO3, brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as white solid (4.0 g). LCMS m/z=338.8 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.39-7.62 (m, 3H), 7.70-7.75 (m, 1H), 7.82-7.88 (m, 1H), 14.11 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4](Cl)[N:3]=1.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([NH:18][CH3:19])=[CH:16][CH:15]=1>>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([N:18]([CH3:19])[C:4]2[N:3]=[C:2]([NH2:1])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][NH:8]3)=[CH:16][CH:15]=1
Reactant: CNc1ccc(OC)cc1
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Product: COc1ccc(N(C)c2nc(N)nc3[nH]cnc23)cc1

Procedure:
The title compound was prepared from 2-amino-6-chloro-9H-purine (100 mg, 0.546 mmol) and 4-methoxy-N-methyl-aniline (127 mg, 0.656 mmol) by a procedure similar to Example 1b and was isolated as white powder (5 mg, 5%). 1H NMR (CDCl3): 7.54 (s, 1H), 7.25 (d, J=8.7 Hz, 2H), 6.98 (d, J=8.7 Hz, 2H), 3.86 (s, 3H), 3.66 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:19])[N:10]([CH2:20][C:21]([N:23]([CH3:34])[C:24]3[CH:33]=[CH:32][C:27]4[N:28]=[C:29]([CH3:31])[O:30][C:26]=4[CH:25]=3)=[O:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:41](I)[CH3:42]>CN(C=O)C.O>[CH2:41]([O:18][C:14]1[CH:13]=[C:12]2[C:17]([C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][N:10]([CH2:20][C:21]([N:23]([CH3:34])[C:24]3[CH:33]=[CH:32][C:27]4[N:28]=[C:29]([CH3:31])[O:30][C:26]=4[CH:25]=3)=[O:22])[C:11]2=[O:19])=[CH:16][CH:15]=1)[CH3:42]
Reactant: CCI
Reactant: Cc1nc2ccc(N(C)C(=O)Cn3nc(-c4cccc(F)c4)c4ccc(O)cc4c3=O)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc2c(-c3cccc(F)c3)nn(CC(=O)N(C)c3ccc4nc(C)oc4c3)c(=O)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
2-(4-(3-fluorophenyl)-7-hydroxy-1-oxophthalazin-2(1H)-yl)-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide (6.5 g, 14.19 mmol) was dissolved in DMF (60 mL), treated with K2CO3 (3.04 g, 21.2 mmol) and stirred at rt for 30 min. After cooling to 0° C., EtI (1.26 mL, 15.59 mmol) was added dropwise and the reaction was warmed to rt for 1 h. It was diluted with water (20 mL) and extracted with EtOAc (2×15 mL). The organics were washed with brine (300 mL), dried over Na2SO4, and concentrated to give crude material which was purified by chromatography (40% EtOAc/hexane) to yield 2-(7-ethoxy-4-(3-fluorophenyl)-1-oxophthalazin-2(1H)-yl)-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide (3.5 g) (487.52 [M+H]). 1H NMR: (400 MHz, DMSO) δ: 1.39-1.42 (t, 3H), 2.62 (s, 3H), 3.24 (s, 3H), 4.22-4.24 (d, J=7.2, 2H), 4.72 (s, 2H), 7.37-7.49 (m, 5H), 7.58-7.65 (m, 3H), 7.71-7.73 (d, J=8.4, 1H), 7.90 (s, 1H).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH2:30]([CH:33]1[CH2:38][CH2:37][CH:36]([CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([CH:47]3[CH2:52][CH2:51][C:50](=O)[CH2:49][CH2:48]3)=[CH:43][CH:42]=2)[CH2:35][CH2:34]1)[CH2:31][CH3:32]>C1COCC1>[CH3:2][O:3][CH:4]=[C:50]1[CH2:49][CH2:48][CH:47]([C:44]2[CH:43]=[CH:42][C:41]([CH2:40][CH2:39][CH:36]3[CH2:35][CH2:34][CH:33]([CH2:30][CH2:31][CH3:32])[CH2:38][CH2:37]3)=[CH:46][CH:45]=2)[CH2:52][CH2:51]1
Reactant: CCCC1CCC(CCc2ccc(C3CCC(=O)CC3)cc2)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCC1CCC(CCc2ccc(C3CCC(=COC)CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 75.2 %

Procedure:
THF solution (20 ml) including methoxymethyltriphenylphosphonium chloride (2 g, 5.9 mmol) was slowly added by in solid potassium tert-butoxide (0.6 g, 5.9 mmol) for 3 minutes in a flask filled with argon gas at −10° C. and then stirred for 20 minutes with maintaining the temperature. The temperature of reacting solution was adjusted to 0° C., added slowly dropwise by THF solution (15 ml) of 4-{4-[2-(4-propylcyclohexyl)ethyl]phenyl}cyclohexanone (1.5 g, 4.5 mmol) and then was stirred by warming to a room temperature. After the reaction termination, the resulting solution was diluted by distilled water (20 ml), extracted by ether (20 ml×3 times), washed by distilled water (10 ml×2 times) and then concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate:petroleum ether=1:40) to obtain 1-[4-(methoxymethylene)cyclohexyl]-4-[2-(4-propylcyclohexyl)ethyl]-benzene (1.2 g, 80%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[N:3]=[N:2]1.[C:14]([C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][C:24](O)=O)[CH:19]=[CH:20][CH:21]=1)#[N:15].P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>O>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][C:24]([CH2:23][CH2:22][C:18]4[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=4)[C:14]#[N:15])=[N:13][N:12]=3)=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: N#Cc1cccc(CCC(=O)O)c1
Reactant: NNC(=O)c1ccc2[nH]nnc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cccc(CCc2nnc(-c3ccc4[nH]nnc4c3)o2)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 16.4 %

Procedure:
A mixture of 1H-benzotriazole-5-carbohydrazide (354 mg, 2.00 mmol), 3-(3-cyanophenyl)propionic acid (350 mg, 2.00 mmol) and phosphorus oxychloride (5 mL) was stirred at 100° C. for 4 hr. After cooling, the reaction mixture was poured into water and neutralized with sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and recrystallized from methanol/water to give the title compound (104 mg, yield 16%) as colorless crystals.
Reaction SMILES: [NH3:1].[C:2]1([C:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]([O:29]C)=O)[CH:25]=4)[NH:20][CH:19]=3)[CH2:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CN(C)C=O>[C:2]1([C:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]([NH2:1])=[O:29])[CH:25]=4)[NH:20][CH:19]=3)[CH2:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: COC(=O)c1ccc2[nH]cc(CCCCN3CC=C(c4ccccc4)CC3)c2c1
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2[nH]cc(CCCCN3CC=C(c4ccccc4)CC3)c2c1

Procedure:
0.02 mol of concentrated ammonia (D=0.9) is added dropwise at 20° to a solution of 4.18 g of methyl 3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-indole-5-carboxylate in 30 ml of dimethylformamide. The mixture is stirred for a further hour at 20° and worked up in the customary manner to give 3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-indole-5-carboxamide, m.p. 207°-208°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:26])[CH:14]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([OH:26])[CH:14]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(C(=O)CCCCNC(=O)OC(C)(C)C)c1ccccc1
Solvent: CO
Product: CCOC(=O)C(c1ccccc1)C(O)CCCCNC(=O)OC(C)(C)C

Procedure:
The same procedures as in Example 14 were performed except that 0.1 g (0.28 mmol) of ethyl 7-(N-t-butoxycarbonylamino)-3-oxo-2-phenylheptanoate, 6.2 mg (0.0056 mmol) of [RuI(p-cymene)(S)-BINAP]I, 9.2 g (0.028 mol) of BSA, and 2 ml of methanol were used. The yield of the product was 65.3% and the ratio of the syn-form to the anti-form was 56.5:43.5.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:9]=[C:8]([Cl:10])[C:7]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:6][C:4]=1[NH2:5].[Cl:30][C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33]([Cl:38])[C:32]=1[N:39]1[C:43](=[O:44])[CH2:42][C:41](OCC)=[N:40]1.ClC1C=C(Cl)C(OCCCCCCCCCCCCCCCC)=CC=1N>>[Cl:38][C:33]1[CH:34]=[C:35]([Cl:37])[CH:36]=[C:31]([Cl:30])[C:32]=1[N:39]1[C:43](=[O:44])[CH2:42][C:41]([NH:5][C:4]2[CH:6]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:8]([Cl:10])=[CH:9][C:3]=2[Cl:2])=[N:40]1
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(N)c(Cl)cc1Cl
Reactant: CCOC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1
Agent: CCCCCCCCCCCCCCCCOc1cc(N)c(Cl)cc1Cl
Agent: Cl
Product: CCCCCCCCCCCCCCCCCCOc1cc(NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2)c(Cl)cc1Cl

Procedure:
Using 18 g of 2,4-dichloro-5-octadecyloxyaniline hydrochloride and 13 g of 1-(2,4,6-trichlorophenyl)-3-ethoxy-2-pyrazolin-5-one, which were prepared in a manner similar to Steps (1) and (2) of Synthesis Example 1, similar procedures to Step (3) of Synthesis Example 1, were carried out and recrystallization was performed from 100 ml of ethanol to obtain 15 g of the desired coupler. The melting point thereof was 98 to 99° C.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[S:14][C:13]3[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][C:7]=3[C:6]=2[CH:15]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[CH:30])=[N:27][CH:28]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[C:30][C:2]3[CH:3]=[CH:4][C:5]4[S:14][C:13]5[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][C:7]=5[C:6]=4[CH:15]=3)=[N:27][CH:28]=2)=[CH:21][CH:22]=1
Reactant: Ic1ccc2sc3c(c2c1)CCNCC3
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: Clc1ccc(-c2ccc(C#Cc3ccc4sc5c(c4c3)CCNCC5)nc2)cc1

Procedure:
Prepared according to general working method I from 3-iodo-6,7,8,9-tetrahydro-5H-10-thia-7-aza-benzo[a]azulene (770 mg, 2.34 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (500 mg, 2.34 mmol).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[CH:14][O:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11].[I-:17].[Na+]>CC(C)=O>[I:17][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[CH:14][O:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11]
Reactant: [I-]
Reactant: COC=C(C(=O)OC)c1ccccc1CCl
Agent: [Na+]
Solvent: CC(C)=O
Product: COC=C(C(=O)OC)c1ccccc1CI

Procedure:
A solution of methyl 2-[2-(chloromethyl)phenyl]-3-methoxypropenoate (1.0 equiv) and sodium iodide (1.5 equiv) in acetone was stirred at room temperature and monitored to completion by GC. The resulting mixture was filtered, concentrated under vacuum, then diluted with chloroform and filtered again to remove the remaining sodium salts. The filtrate was concentrated and purified by chromatography over silica gel eluted with ethyl acetate hexane mixtures to afford methyl 2-[2-(iodomethyl)phenyl]-3-methoxypropenoate as a yellow solid.
Reaction SMILES: [BH4-].[Na+].[OH:3][NH:4][C:5](=[O:34])[CH:6]([CH2:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CO>[OH:3][NH:4][C:5](=[O:34])[CH:6]([CH2:16][S:17]([C:20]1[CH:21]=[CH:22][C:23]([CH:26]([OH:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:24][CH:25]=1)(=[O:18])=[O:19])[CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(c1ccccc1)c1ccc(S(=O)(=O)CC(CCCc2ccccc2)C(=O)NO)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(NO)C(CCCc1ccccc1)CS(=O)(=O)c1ccc(C(O)c2ccccc2)cc1
Reaction time: 2 h
Yield: 95.1 %

Procedure:
Sodium borohydride (0.38 g) was added to a solution of example 58 (0.45 g) in MeOH (100 ml) and the solution was stirred for 2 h, then evaporated and the residue dissolved in water, acidified with citirc acid and extracted with ethyl acetate. The organic layer was washed with brine, dried and evaporated to give the crude product, which was purified by column chromatography, eluting with 7% MeOH in dichloromethane to give the title compound (0.43 g, 95%) as white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH2:11][CH2:12][CH3:13].[CH3:14][N:15](C)C=O>C(OCC)C.C(=O)(O)[O-].[Na+].[C-]#N.[Zn+2].[C-]#N.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>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]#[N:15])=[C:3]([O:10][CH2:11][CH2:12][CH3:13])[CH:4]=1
Reactant: CN(C)C=O
Reactant: CCCOc1cc(OC)ccc1Br
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: [C-]#N
Solvent: CCOCC
Product: CCCOc1cc(OC)ccc1C#N
Temperature: 95 °C
Yield: 74 %

Procedure:
To a solution of 1-bromo-4-methoxy-2-propoxy-benzene (500 mg, 2.04 mmol) in dimethylformamide (10 mL) at room temperature was added zinc cyanide (240 mg, 2.04 mmol). The reaction mixture was degassed by passing argon through for 2 h before tetrakis(triphenylphosphine)palladium (236 mg, 0.204 mmol) was added. The reaction mixture was heated at 90-100° C. under argon for 12 h. The reaction mixture was taken up in diethyl ether (10 mL) and sodium bicarbonate solution (2 mL). The product was extracted with diethyl ether (2×20 mL). The organic layers were washed with water (1×5 mL), brine (1×5 mL), and dried over anhydrous sodium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 15-20% ethyl acetate in hexanes yielded 4-methoxy-2-propoxy-benzonitrile (290 mg, 74%) as white solids.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].CN1CCOCC1.ClC1N=C(OC)N=C(OC)N=1.Cl.[NH2:24][CH2:25][C:26]1[CH:31]=[C:30]([C:32]2[N:37]=[C:36]([NH:38][S:39]([C:42]3[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][N:43]=3)(=[O:41])=[O:40])[C:35]([O:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=3[O:56][CH3:57])=[C:34]([O:58][CH3:59])[N:33]=2)[CH:29]=[CH:28][N:27]=1>CN(C=O)C>[CH3:59][O:58][C:34]1[C:35]([O:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[O:56][CH3:57])=[C:36]([NH:38][S:39]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][N:43]=2)(=[O:41])=[O:40])[N:37]=[C:32]([C:30]2[CH:29]=[CH:28][N:27]=[C:26]([CH2:25][NH:24][C:1](=[O:4])[CH3:2])[CH:31]=2)[N:33]=1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(CN)c2)nc1OC
Reactant: CC(=O)O
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(CNC(C)=O)c2)nc1OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6.6 mg of acetic acid and 22.3 mg of 4-methylmorpholin in DMF (5 ml) were added under ice-cooling 22.3 g of 2-Chloro-4,6-dimethoxy-1,3,5,-triazine and the solution was then stirred for 90 minutes at RT. Then 60 mg of 5-methyl-pyridine-2-sulfonic acid [2-(2-aminomethyl-pyridin-4-yl)-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide hydrochloride were added and stirring was continued for 12 h at RT. The mixture was partitioned between cold diluted HCl and EtOAc. The layers were separated the organic layer washed with water, dried over Na2SO4 and the solvent removed in vacuo to give N-{4-[4-methoxy-5-(2-methoxy-phenoxy)-6-(5-methyl-pyridine-2-sulfonylamino)-pyrimidin-2-yl]-pyridin-2-ylmethyl}-acetamide as a light yellow crystalline solid. ISN mass spectrum, m/e 549.1 (M−1 calculated for C26H26N6O6S: 549).
Reaction SMILES: B(Cl)(Cl)Cl.C(Cl)Cl.[Cl:8][C:9]1[N:14]2[N:15]=[CH:16][N:17]=[C:13]2[C:12]([CH2:18][CH2:19][O:20]CC)=[C:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:10]=1.O>C(Cl)(Cl)Cl>[Cl:8][C:9]1[N:14]2[N:15]=[CH:16][N:17]=[C:13]2[C:12]([CH2:18][CH2:19][OH:20])=[C:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:10]=1
Reactant: CCOCCc1c(-c2ccccc2)nc(Cl)n2ncnc12
Agent: ClB(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: OCCc1c(-c2ccccc2)nc(Cl)n2ncnc12

Procedure:
Under non-aqueous conditions 200 ml of a mixture of boron trichloride (0.2 mol) and methylene chloride (1 mol) is added over a period of 20 minutes with vigorous stirring to a solution containing 30 g of 5-chloro-8-(2-ethoxyethyl)-7-phenyl[1,2,4]triazolo[1,5-c]pyrimidine (0.1 moles) dissolved in 300 ml of chloroform. The resulting reaction mixture is stirred at room temperature for 3 hours. To the reaction mixture is added 400 ml of water and the resulting mixture is stirred for 1.5 hours and then allowed to stand at room temperature. The aqueous and organic layers are separated and the organic layer is dried over sodium sulfate, filtered and evaporated yielding a residue. The residue is chromatographed on silica gel and recrystallized from diethyl ether to yield 5-chloro-7-phenyl[1,2,4]triazolo[1,5-c]pyrimidine-8-ethanol having the structural formula ##STR21## and the azido tautomer thereof as a white solid having a melting point of 104°-105° C. and the following elemental analysis:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:16][CH2:17][CH3:18])=[C:9]([NH:12]C(=O)C)[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:19]#[N:20].[C:21]([C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26])#[CH:22].CS(O)(=O)=O.Cl>C(O)C>[NH2:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:16][CH2:17][CH3:18])[N:5]=[CH:4][C:3]([C:19]#[N:20])=[C:2]2[NH:26][C:25]1[CH:27]=[CH:28][CH:29]=[C:23]([C:21]#[CH:22])[CH:24]=1
Reactant: C#Cc1cccc(N)c1
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1NC(C)=O
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CCO
Product: C#Cc1cccc(Nc2c(C#N)cnc3cc(OCC)c(N)cc23)c1
Temperature: 80 °C
Reaction time: 19 h
Yield: 81.1 %

Procedure:
A mixture of N-(4-chloro-3-cyano-7-ethoxyquinolin-6-yl)acetamide (23.2 g, 0.08 mol, 1.00 equiv), 3-ethynyl aniline (10.1 g, 0.094 mol, 1.18 equiv), methanesulfonic acid (2.3 ml, 0.0355 mol) in ethanol (60 0 ml) was stirred under refluxed for 6 hours and then 0.6N hydrogen chloride (1000 ml, 0.6 mol) was added. The reaction mixture was heated to 80° C. and held for 19 hours, and then cooled to 0° C. to form precipitate. The precipitate was filtered and added to a solution of 1N potassium carbonate (400 ml) in methanol (600 ml) in which the mixture was stirred for 3 hours. The reaction mixture was filtered, washed with 1:1 methanol/water (500 ml) and dried to give 21.3 g of product. MS (ESI) m/z: 563 (M+1).