Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:17]([CH2:18][OH:19])[CH2:16][N:15]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:14]1>O1CCCC1.[Cl-].[Na+].O>[C:1]([NH:9][C:10]([NH:12][C:13]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:17]([CH2:18][OH:19])[CH2:16][N:15]([C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])[CH2:14]1)=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1(c2ccccc2)CN(C(=O)OCc2ccccc2)CC1CO
Reactant: O=C(N=C=S)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC(=S)NC1(c2ccccc2)CN(C(=O)OCc2ccccc2)CC1CO)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
Benzoyl isothiocyanate (15 mL, 112 mmol) is added to a 0° C. solution of benzyl 3-amino-4-(hydroxymethyl)-3-phenyl-pyrrolidine-1-carboxylate (34.7 g, 106 mmol) in tetrahydrofuran (347 mL). The mixture is warmed to room temperature and stirred for 1 hour. Brine (300 mL) is added, the aqueous layer is separated, the organic layer is dried over magnesium sulfate, and concentrated to give the title compound (51 g, 98%). ES/MS (m/e): 390 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][N:6]=1.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[C:23]1[N:28]=[C:27](NCCNC2C=CC([N+]([O-])=O)=CN=2)[CH:26]=[CH:25][C:24]=1[C:42]1[NH:43][CH:44]=[CH:45][N:46]=1>>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[C:23]1[N:28]=[C:27]([NH:1][CH2:2][CH2:3][NH:4][C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:12])[F:13])=[CH:7][N:6]=2)[CH:26]=[CH:25][C:24]=1[C:42]1[NH:46][CH:45]=[CH:44][N:43]=1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ccc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Reactant: NCCNc1ccc(C(F)(F)F)cn1
Product: FC(F)(F)c1ccc(NCCNc2ccc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1

Procedure:
[6-(2,4-dichlorophenyl)-5-imidazol-2-yl(2-pyridyl)](2-{[5-(trifluoromethyl)(2-pyridyl)]amino}ethyl)amine was prepared from (2-aminoethyl)[5-(trifluoromethyl)(2-pyridyl)]amine using the general method for [6-(2,4-dichlorophenyl)-5-imidazol-2-yl(2-pyridyl)]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:20]1([C:26]2[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[N:20]1([C:26]2[CH:33]=[CH:32][C:29]([CH2:30][N:4]3[CH2:3][CH2:2][N:1]([C:7]4[CH:8]=[CH:9][C:10]5[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=5)[N:12]=4)[CH2:6][CH2:5]3)=[CH:28][CH:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccc(N5CCOCC5)cc4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-morpholin-4-ylbenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-morpholin-4-ylphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([O:11]C)=[O:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[F:21].[CH3:22][C:23]([O-:26])([CH3:25])[CH3:24].[Na+].Cl>CN(C=O)C>[CH3:22][C:23]([O:26][CH2:2][C:3]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[F:21])([CH3:25])[CH3:24]
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(CBr)c1
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(F)c(-c2ccc(C(=O)O)cc2COC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.47 h
Yield: 20 %

Procedure:
A mixture of T31.2 (0.245 g, 0.69 mmol) and sodium 2-methylpropan-2-olate (0.20 g, 2.1 mmol) in DMF (6 mL) was stirred at room temperature for 28 minutes. The mixture was acidified with 1N HCl to pH 3-4 and then was extracted with EtOAc (100 mL). The organic phase was washed with brine and dried over anhydrous Na2SO4. After removing solvent, the residue was purified by flash chromatography (silica gel, 1:4 EtOAc/hexane) and gave T31.3 (49 mg) in 20% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[F:15][C:16]([F:40])([F:39])[CH2:17][NH:18][C:19]([C:21]1([CH2:34][CH2:35][CH2:36][CH2:37]Br)[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:20]>>[F:15][C:16]([F:39])([F:40])[CH2:17][NH:18][C:19]([C:21]1([CH2:34][CH2:35][CH2:36][CH2:37][N:12]2[CH2:13][CH2:14][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:10][CH2:11]2)[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:20]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: COc1ccccc1N1CCNCC1
Product: COc1ccccc1N1CCN(CCCCC2(C(=O)NCC(F)(F)F)c3ccccc3-c3ccccc32)CC1

Procedure:
Prepared analogously to Example 2 b from 1-(2-methoxy-phenyl)-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[C:4]([CH2:12][CH2:13][OH:14])=[CH:5][NH:6]2.N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[C:4]([CH2:12][CH2:13][O:14][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[CH:5][NH:6]2
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1ccc(Br)c2c(CCO)c[nH]c12
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(Br)c2c(CCO[Si](C)(C)C(C)(C)C)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
A mixture of 2-(4-bromo-7-methyl-1H-indol-3-yl)-ethanol (2.51 g, 9.89 mmol), imidazole (1.68 g, 24.7 mmol) and tert-butyldimethylsilyl chloride (1.79 g, 11.9 mmol) in DMF (30 mL) was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc (200 mL). The organic solution was washed with H2O (5×200 mL) and brine (200 mL), dried (Na2SO4), and concentrated to give 3.49 g (96%) of title compound as yellow oil. 1H NMR (CDCl3): 300 MHz δ 8.14 (bs, 1H), 7.11 (d, J=7.59 Hz, 1H), 6.99 (s, 1H), 6.72 (d, J=7.59 Hz, 1H), 3.90 (t, J=7.17 Hz, 2H), 3.19 (t, J=7.17 Hz, 2H), 2.31 (s, 3H), 0.87 (s, 9H), −0.08 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([NH2:16])[C:5](=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[CH:8]=1.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]=[C:25]=[O:26]>O>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]1[C:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[CH:8]=2)=[C:4]([C:3]([O:2][CH3:1])=[O:17])[NH:16][C:25]1=[O:26]
Reactant: O=C=NCCCCCBr
Reactant: COC(=O)C(N)C(=O)Cc1ccc(F)c(F)c1
Solvent: O
Product: COC(=O)c1[nH]c(=O)n(CCCCCBr)c1Cc1ccc(F)c(F)c1
Yield: 55 %

Procedure:
To 2-amino-4-(3,4-difluorophenyl)-3-oxobutyric acid methyl ester (0.100 g, 0.344 mmol) in 2 mL water was added 1-bromo-5-isocyanatopentane (0.3 mL), and the reaction mixture refluxed for 3 hours. The reaction mixture was concentrated and partitioned between EtOAc (30 mL) and 1N HCl (10 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (10 mL), dried over sodium sulfate, filtered and concentrated to give 0.080 g (55%) of the product as a syrup; 1H-NMR (CDCl3) δ1.36-1.81 (m, 6 H), 3.34 (t, J=6.6 Hz, 2 H), 3.32-3.37 (m, 2 H), 3.86 (s, 3 H), 4.21 (s, 2 H), 6.91-7.16 (m, 3 H), 9.53 (s, 1 H).
Reaction SMILES: Cl.O1CCOCC1.[Si]([O:15][CH2:16][C@H:17]([OH:39])[CH2:18][N:19]1[C:27]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)=[C:26]2[C:21]([N:22]([CH3:38])[C:23](=[O:37])[N:24]([CH3:36])[C:25]2=[O:35])=[CH:20]1)(C(C)(C)C)(C)C.[Cl:40][C:41]1[N:42]=[C:43]([CH:46]=O)[S:44][CH:45]=1.[O-]S(C(F)(F)F)(=O)=O.[Bi+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>C(O)C.CCOC(C)=O.O>[Cl:34][C:30]1[CH:29]=[C:28]([C:27]2[N:19]3[C:20]([CH:46]([C:43]4[S:44][CH:45]=[C:41]([Cl:40])[N:42]=4)[O:39][C@@H:17]([CH2:16][OH:15])[CH2:18]3)=[C:21]3[N:22]([CH3:38])[C:23](=[O:37])[N:24]([CH3:36])[C:25](=[O:35])[C:26]=23)[CH:33]=[CH:32][CH:31]=1
Reactant: Cn1c(=O)c2c(-c3cccc(Cl)c3)n(C[C@@H](O)CO[Si](C)(C)C(C)(C)C)cc2n(C)c1=O
Reactant: O=Cc1nc(Cl)cs1
Agent: Cl
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Bi+3]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cn1c(=O)c2c(-c3cccc(Cl)c3)n3c(c2n(C)c1=O)C(c1nc(Cl)cs1)O[C@@H](CO)C3
Temperature: 50 °C

Procedure:
HCl in dioxane (0.654 ml, 2.61 mmol) was added to a suspension of (R)-6-(3-((tert-butyldimethylsilyl)oxy)-2-hydroxypropyl)-5-(3-chlorophenyl)-1,3-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (250 mg, 0.523 mmol), 4-chlorothiazole-2-carbaldehyde (Intermediate H) (85 mg, 0.575 mmol) and bismuth triflate (103 mg, 0.157 mmol) in anhydrous ethanol (4 ml) and the mixture heated at 50° C. for 36 hours. Further portions of HCl in dioxane (0.654 ml, 2.61 mmol) were added as necessary to allow the reaction to run to completion. The mixture was cooled to room temperature and diluted with EtOAc (50 ml) and water (20 ml). The phases were separated and the aqueous phase extracted with EtOAc (3×30 ml). The combined organic extracts were washed with saturated NaHCO3(aq) (20 ml), water (20 ml) and brine (20 ml), dried over sodium sulfate and evaporated under vacuum. Purification by chromatography on silica, eluting with 10-70% EtOAc/hexane afforded the title compound as a mixture of diastereomers.
Reaction SMILES: Cl.CN([CH:5]([CH3:15])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1)=[O:7])C.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23]>C(O)C>[ClH:14].[OH:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[NH:16][CH2:15][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1)=[O:7]
Reactant: CC(C(=O)c1cccc(Cl)c1)N(C)C
Reactant: Nc1ccccc1O
Agent: Cl
Solvent: CCO
Product: O=C(CCNc1ccccc1O)c1cccc(Cl)c1
Temperature: 25 °C
Yield: 81.4 %

Procedure:
Dimethylamino-m-chloropropiophenone hydrochloride (74.9 g, 0.30 mol) was dissolved in 50% aqueous ethanol (700 ml) at reflux. 2-Aminophenol (32.9 g, 0.30 mol) was then added and the resulting red solution was refluxed for a further 2 hours. The reaction mixture was allowed to cool to room temperature and then extracted twice with ethyl acetate (2×100 ml). Note that brine was also added at this point to allow the two layers to separate effectively). The organic extracts were combined and an excess of concentrated hydrochloric acid (47 ml) was added. The solution was concentrated in vacuo and then allowed to cool. The precipitate that formed was filtered of, washed with diethyl ether and dried in vacuo to yield a cream powder (38.1 g, 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13](=O)[CH:14]([CH3:16])[CH3:15])[CH2:8][CH2:7]1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH:13]([NH2:28])[CH:14]([CH3:16])[CH3:15])[CH2:8][CH2:7]1
Reactant: [BH3-]C#N
Reactant: CC(C)C(=O)CC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: CC(C)C(N)CC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.2 %

Procedure:
To a solution of 1-[1-(3,4-dichlorobenzyl)piperidin-4-yl]-3-methyl-2-butanone (0.16 g, 0.49 mmol) in methanol (1.5 ml) was added ammonium acetate (0.38 g, 4.93 mmol), followed by sodium cyanoborohydride (31 mg, 0.5 mmol) and the resulting solution was stirred at room temperature. After 48 h, hydrochloric acid (conc.) was added until pH was 2 and the volatiles were removed under vacuum. The residue was dissolved in water and washed with ethyl acetate. The aqueous layer was then basified to pH>10 and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over sodium sulfate and concentrated to give 1(RS)-[1-(3,4-dichlorobenzyl)piperidin-4-ylmethyl]-2-methylpropylamine (0.16 g) as an oil which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH2:33][NH2:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH2:33][NH:34][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([C:15]2[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=2)=[CH:18][CH:19]=1
Reactant: CCCCCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Reactant: NCCc1ccccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCc1noc(-c2ccc(CNCCc3ccccc3F)cc2)n1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde (32.8 mg, 0.1 mmol) in anhydrous THF (0.6 mL) was added the 2-(2-fluorophenyl)ethylamine (11.8 mg, 0.1 mmol) and Ti(iPrO)4 (0.035 mL, 0.12 mmol). The mixture was stirred for 3 h at 60° C. then sodium triacetoxyborohydride (53 mg, 0.25 mmol) was added and the reaction mixture was stirred overnight at rt. THF (0.75 mL) was added followed by the PS-DEAM resin (Argonaut, 148 mg, 1.68 mmol/g), and the reaction mixture was stirred at rt overnight. The reaction mixture was filtered and the filtrates were eluted through a SCX column (Isolute, 1 g) with DCM (6 mL), then NH3 (2M in MeOH, 4 mL). The desired fractions (TLC monitoring) were concentrated under vacuum to give the title product.
Reaction SMILES: CO[C:3](=[O:30])[C:4]1[C:5](=[CH:10][C:11]([N:22]([CH3:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:12]([N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)C)[CH:13]=1)[C:6]([O:8]C)=O.COC(=O)C1C(=CC(N(C)C2C=CC=CC=2)=C([NH:44]C2C=CC=CC=2)C=1)C(OC)=O>>[CH3:29][N:22]([C:11]1[CH:10]=[C:5]2[C:6](=[O:8])[NH:44][C:3](=[O:30])[C:4]2=[CH:13][C:12]=1[NH:14][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1cc(N(C)c2ccccc2)c(N(C)c2ccccc2)cc1C(=O)OC
Reactant: COC(=O)c1cc(Nc2ccccc2)c(N(C)c2ccccc2)cc1C(=O)OC
Product: CN(c1ccccc1)c1cc2c(cc1Nc1ccccc1)C(=O)NC2=O

Procedure:
A solution of 564 mg (1.5 mmol) of 4,5-bis(anilino)phthalic acid dimethyl ester (Example 1) in 5 ml of acetonitrile is heated at 80° C. for 16 hours with 0.93 ml (15 mmol) of methyl iodide and 442 mg (3.2 mmol) of anhydrous potassium carbonate in a bomb tube. The reaction mixture is concentrated to dryness by evaporation, the residue is twice digested in dichloromethane and filtered, and the filtrate is concentrated by evaporation. Repeated chromatography on silica gel with hexane/ethyl acetate yields the title compounds in the form of slightly yellowish powders. (A): FAB-MS: 405 [M+ +H]; (B): FAB-MS: 391 [M+ +H].
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(OC)=O.CCCCCC.[C:45]([O:48]CC)(=[O:47])[CH3:46]>C(Cl)Cl>[C:45]([OH:48])(=[O:47])/[CH:46]=[CH:1]/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCC/C=C/C=O
Reactant: CCOC(C)=O
Agent: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCCCCCCCC/C=C/C=C/C(=O)O
Reaction time: 2 h

Procedure:
To the trans-2-tridecenal (1.7 g) dissolved in methylene chloride (80 ml) was added (carbomethoxymethylene)triphenyl phosphorane (4.0 g), and the mixture was stirred for 2 hours. The reaction mixture was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 100:1 to 20:1) to give the methyl ester of trans,trans-2,4-pentadecadienoic acid (2.1 g). Potassium hydroxide (2.0 g) was dissolved in a mixed solvent of ethanol-water (1:1), and the methyl ester of trans,trans-2,4-pentadecadienoic acid (2.1 g). After the mixture was stirred at 60° C. for 40 minutes, it was cooled, adjusted to a weak acidic range of pH with citric acid and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to give trans, trans-2,4-pentadecadienoic acid (1.9 g). The product was dissolved in N,N-dimethylformamide (DMF, 50 ml ), and para-nitrophenol (1.2 g) and N,N'-dicyclohexylcarbodiimide (1.7 g) were added. The mixture was stirred for 12 hours. After the reaction, precipitates produced were removed by filtration, DMF was removed by distillation, and the residue was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 200:1 to 50:1) to give the active ester of trans,trans-2,4-pentadecadienoic acid (1.3 g). To the active ester (600 mg) dissolved in DMF (30 ml) were added 6-(4'-N-glycyl-spicaminyl-amino)purine hydrochloride (750 mg) and triethylamine (1.2 ml). The mixture was stirred for 12 hours. After the solvent was removed by distillation, the residue was subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK285 in the yield of 530 mg.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])=[CH:11][C:10]=2[CH:22]=1)=[O:5].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Mg]Br>>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])=[CH:11][C:10]=2[CH:22]=1)=[O:5]
Reactant: COc1ccccc1[Mg]Br
Reactant: CON(C)C(=O)c1ccc2oc(CCN3CCC[C@H]3C)cc2c1
Product: COc1ccccc1C(=O)c1ccc2oc(CCN3CCC[C@H]3C)cc2c1

Procedure:
The product from Example 71E and 2-methoxyphenylmagnesium bromide were processed as described in Example 71F to provide the title compound. 1HNMR (300 MHz, CD3OD) δ 1.42 (d, 3H), 1.72 (m, 1H), 2.10 (m, 2H), 2.35 (m, 1H), 3.30 (m, 4H), 3.55 (m, 1H), 3.70 (s 3H), 3.80 (m, 2H), 6.80 (s, 1H), 7.1 (m, 2H), 7.30 (dd, 1H), 7.53 (m, 2H), 7.75 (dd, 1H), 7.95 (d, 1H); MS (ESI) m/z 364 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:20]=[C:21]([OH:26])[CH:22]=[C:23]([Cl:25])[CH:24]=1.[Cl-].[NH4+]>CN(C)C=O>[Cl:18][C:19]1[CH:20]=[C:21]([CH:22]=[C:23]([Cl:25])[CH:24]=1)[O:26][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=1
Reactant: Oc1cc(Cl)cc(Cl)c1
Reactant: C#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1cc(Oc2cc(Cl)cc(Cl)c2)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 68.5 %

Procedure:
To 5 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-propynyloxy)pyrimidine, 0.25 g of potassium carbonate, and 0.21 g of 3,5-dichlorophenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.24 g of 4-(3,5-dichlorophenoxy)-6-(2-propynyloxy)pyrimidine (the present compound (24)), m.p.: 136.5° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[C:14]2[C:19](=[CH:20][C:21]=1[CH3:22])[N:18]=[C:17]([CH3:23])[CH:16]=[CH:15]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:39])C=1>ClCCl>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[C:14]2[C:19](=[CH:20][C:21]=1[CH3:22])[N+:18]([O-:39])=[C:17]([CH3:23])[CH:16]=[CH:15]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(C)ccc2c1-c1ccc(Cl)cc1
Solvent: ClCCl
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2c(ccc(C)[n+]2[O-])c1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
To a stirred solution of (S)-ethyl 2-tert-butoxy-2-(5-(4-chlorophenyl)-2,7-dimethylquinolin-6-yl)acetate (100 mg, 0.25 mmol) in dichloromethane (5 mL) was added a solution of mCPBA (114 mg, 77%, 0.51 mmol) in DCM (2 mL) at 0° C. The mixture was stirred at 0° C. for 1 hour before quenched with NaHCO3 solution. The mixture was extracted with DCM (30 mL), washed with NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product (104 mg, 94%). LCMS-ESI+ (m/z): 442.2, 444.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]3[N:15]=[CH:16][C:17](I)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:19]([C:21]1[CH:22]=[CH:23][C:24]([NH2:27])=[N:25][CH:26]=1)#[CH:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]3[N:15]=[CH:16][C:17]([C:20]#[C:19][C:21]4[CH:22]=[CH:23][C:24]([NH2:27])=[N:25][CH:26]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(N)nc1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc2c(I)cnn12
Product: Cc1cc(-c2ccc(Cl)cc2)nc2c(C#Cc3ccc(N)nc3)cnn12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-3-iodo-7-methyl-pyrazolo[1,5-a]pyrimidine (example 292) (185 mg, 0.5 mmol) and 5-ethynyl-pyridin-2-ylamine (example D.1) (59 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (113 mg, 63%). MS (ISP) 360.0 [(M+H)+]; mp 244-246° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:24][CH2:23][C:14]3[NH:15][C:16]4[CH:17]=[C:18](Br)[CH:19]=[CH:20][C:21]=4[C:13]=3[CH2:12]2)=[N:9][CH:10]=1)=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].[CH:31]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)=[O:32]>C1COCC1.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>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:24][CH2:23][C:14]3[NH:15][C:16]4[CH:17]=[C:18]([C:37]5[CH:36]=[CH:35][CH:34]=[C:33]([CH:31]=[O:32])[CH:38]=5)[CH:19]=[CH:20][C:21]=4[C:13]=3[CH2:12]2)=[N:9][CH:10]=1)=[O:4]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: COC(=O)c1cnc(N2CCc3[nH]c4cc(Br)ccc4c3C2)nc1
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: [Cs+]
Solvent: C1CCOC1
Product: COC(=O)c1cnc(N2CCc3[nH]c4cc(-c5cccc(C=O)c5)ccc4c3C2)nc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 39.1 %

Procedure:
To a solution of methyl-2-(7-bromo-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)pyrimidine-5-carboxylate (0.360 g, 0.93 mmol) in THF:H20 (4:1) were added Cs2CO3 (2.42 g, 7.44 mmol) and 3-formylphenylboronic acid (0.27 g, 1.86 mmol). The reaction mixture was thoroughly degassed and freshly prepared tetrakis(triphenylphosphine)palladium(0) (0.268 g, 0.23 mmol) was added under nitrogen atmosphere at room temperature. The reaction mixture temperature was raised to 80° C. and continued stirring for 12 hr. The progress of the reaction was monitored by TLC and upon completion of the reaction the THF was removed under reduced pressure. The mixture was partitioned between ethyl acetate (100 ml) and water (15 mL). The organic layer was separated, dried over Na2SO4 filtered and the solvent was removed under reduced pressure to give crude residue, which was purified by column chromatography using silica gel to provide methyl-2-{7-[3-(formyl)phenyl]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl}pyrimidine-5-carboxylate (0.15 g, 39.13%).