Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][O:21][C:22]([C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[C:29](C=O)[CH:30]=2)[CH:25]=1)=[O:23].C(Cl)Cl.[H][H]>O1CCCC1>[CH3:20][O:21][C:22]([C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)=[O:23]
Reactant: COC(=O)c1ccc2cc(C=O)ccc2c1
Reactant: [H][H]
Agent: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1ccc2ccccc2c1

Procedure:
For example, 4'-alkoxy-4-bromobiphenyl (17) is reacted with triphenylphosphin to obtain triphenylphosphonium salt of 4'-alkoxybiphenyl (21). The thus obtained triphenylphosphonium salt of 4'-alkoxybiphenyl (21) is reacted with 6-formyl-2-naphthalenecarboxylic acid methyl ester as a solution in such as methylene chloride and then the resulting compound is reacted with hydrogen in the presence of the reducing catalyst such as paradium carbon in a solvent such as tetrahydrofuran (THF) to obtain 6-[4'-alkoxy-4-biphenyl)ethyl]-2-naphthalenecarboxylic acid methyl ester. The resulting 6-[4'-alkoxy-4-biphenyl)ethyl]-2-naphthalenecarboxylic acid methyl ester is hydrolysised to obtain 6-[4'-alkoxy-4-biphenyl)ethyl]-2-naphthalenecarboxylic acid (22).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([C@H:20]1[CH2:24][O:23][C:22](=[O:25])[N:21]1[C:26](=[O:35])[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Br[CH2:37][C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39].[Cl-].[Na+]>CCCCCC.O1CCCC1>[CH2:13]([C@H:20]1[CH2:24][O:23][C:22](=[O:25])[N:21]1[C:26](=[O:35])[C@H:27]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:37][C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(CCc1ccccc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: O=C(CBr)OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: O=C(C[C@@H](Cc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)OCc1ccccc1
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
2.91 ml (20.8 mmole) of diisopropylamine and 13.40 ml (21.4 mmole) of butyllithium (as a 1.6M solution in hexane) were added, at -78° C. and under an atmosphere of nitrogen, to 50 ml of anhydrous tetrahydrofuran, and the mixture was stirred for 30 minutes. A solution of 5.35 g (17.3 mmole) of (4S)-(-)-4-benzyl-N-(3-phenylpropionyl)-2-oxazolidinone in 20 ml of anhydrous tetrahydrofuran was added to the resulting mixture, and then the mixture was stirred at the same temperature for 1 hour. At the end of this time, a solution of 5.74 ml (36.2 mmole) of benzyl bromoacetate in 10 ml of anhydrous tetrahydrofuran was added dropwise to the mixture, and then the mixture was stirred for 3 hours. At the end of this time, a saturated aqueous solution of sodium chloride was added to the mixture, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated by distillation under reduced pressure. The residue was purified by medium pressure column chromatography through silica gel (using a 1:5 by volume mixture of ethyl acetate and hexane as the eluent) to afford 5.47 g (yield 69%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH3:9])[CH:8]=1)#[N:2].[CH3:10][O-].[Na+].[C:13]([OH:16])(=O)[CH3:14]>C(O)CC>[CH3:9][C:7]1[CH:8]=[C:3]([C:1](=[NH:2])[O:16][CH2:13][CH2:14][CH3:10])[CH:4]=[N:5][CH:6]=1
Reactant: CC(=O)O
Reactant: C[O-]
Reactant: Cc1cncc(C#N)c1
Agent: [Na+]
Solvent: CCCO
Product: CCCOC(=N)c1cncc(C)c1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
3-Cyano-5-methylpyridine (2 g, 16.9 mmol) was dissolved in 1-propanol (100 ml). Sodium methoxide (46 mg, 0.85 mmol) was added, and the resulting mixture was stirred at 0° C. for 20 hours. After the completion of the reaction, the reaction mixture was neutralized with acetic acid (56 mg, 0.93 mmol), and the resulting mixture was concentrated under reduced pressure. After concentration, ethyl ether (50 ml) was added to the residue, and insoluble sodium acetate was removed by filtration. The filtrate was concentrated under reduced pressure to give a crude product of propyl 5-methyl-3-pyridinecarboximidate.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][N:4]=1.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=1>CN(C=O)C>[F:26][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[F:25])[CH2:18][N:4]1[CH:5]=[C:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:8][C:3]1=[O:2]
Reactant: Fc1ccc(CBr)cc1F
Reactant: COc1ccc(COc2ccccc2)cn1
Solvent: CN(C)C=O
Product: O=c1ccc(COc2ccccc2)cn1Cc1ccc(F)c(F)c1
Yield: 30.4 %

Procedure:
According to Scheme 16 Method A: The title compound was prepared from 2-methoxy-5-(phenoxymethyl)pyridine (1 eq, 0.46 mmol, 0.10 g) and 4-(bromomethyl)-1,2-difluorobenzene (3 eq, 1.39 mmol, 0.18 mL) according to the procedure described for Example 1 Step 2. Reaction conditions: under reflux for 3 days in DMF (5 mL). The crude oil was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 25 g SiO2) using CH2Cl2/AcOEt 90/10 followed by recrystallization in diisopropyl ether to afford 1-(3,4-difluorobenzyl)-5-(phenoxymethyl)pyridin-2(1H)-one (0.14 mmol, 0.04 g, 29%) as a white solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][CH:9]([O:17][CH3:18])[CH2:10][CH2:11][CH2:12][C:13](OC)=[O:14].CCCCCC.C(OCC)(=O)C>O1CCCC1>[CH3:7][O:8][CH:9]([O:17][CH3:18])[CH2:10][CH2:11][CH2:12][CH2:13][OH:14]
Reactant: COC(=O)CCCC(OC)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(CCCCO)OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 34.4 %

Procedure:
To a suspension of LAH (0.4 g, 11 mmol) in tetrahydrofuran (20 ml) was added dropwise at 0° C. methyl 5,5-dimethoxyvalerate (3.5 g, 20 mmol) dissolved in tetrahydrofuran (30 ml), which was then stirred for 2 hours. After the reaction was completed, the mixture was poured into ice-water (50 ml) and then extracted with ether. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a crude product. This crude product thus obtained was subjected to silica gel column chromatography (n-hexane:ethyl acetate-2:1) to give 5,5-dimethoxypentanol (1.02 g, yield 34%). Methanesulfonylchloride (3.2 g, 28 mmol) and triethylamine (3.0 g, 30 mmol) dissolved in dichloromethane (50 ml) were added thereto, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was poured into water and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a crude product (2.36 g). While, 4,4,5,5,5-pentafluoropentyl thioacetate (5.7 g, 24 mmol) prepared in Step 1 was dissolved in methanol (10 ml), sodium methoxide (23 mg, 23 mmol, 11.0 mol/l) was added thereto, and the resulting mixture was stirred at room temperature for 1 hour. To this solution was added dropwise the crude product prepared above (0.90 g) dissolved in tetrahydrofuran (10 ml), which was then stirred at room temperature for 5 hours. After the reaction was completed, the reaction mixture was poured into water and extracted with ether. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a crude product. This crude product thus obtained was subjected to silica gel column chromatography (n-hexane:ethyl acetate=20:1) to give 5,5-dimethoxy-1-(4,4,5,5,5-pentafluoropentylthio)pentane (460 mg).
Reaction SMILES: O[Li].O.[Cl:4][C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][CH2:11][C:12]([O:14]CC)=[O:13])=[C:7]([CH3:19])[CH:6]=1>O.C1COCC1>[Cl:4][C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[C:7]([CH3:19])[CH:6]=1
Reactant: CCOC(=O)CCOc1ccc(Cl)cc1C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Cl)ccc1OCCC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
A solution of LiOH.H2O (0.50 g; 12 mmol) in water (10 mL) was added to a solution of ethyl 3-(4-chloro-2-methylphenoxy)propionate (1.98 g; 8.15 mmol; from step (i) above) in THF (20 mL). The reaction mixture was stirred at room temperature overnight, THF was evaporated and the water phase was washed with ether. The resultant solution was acidified with HCl (2M), whereafter a solid material precipitated. The product was filtered and air-dried yielding 0.62 g (35%) of the sub-title compound.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[O:15][N:14]=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.Cl>O1CCOCC1.C(O)C>[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]=2)[CH2:25][CH2:24]1
Reactant: BrCCOc1ccccc1-c1nc(-c2ccccc2)no1
Reactant: CN1CCNCC1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CN1CCN(CCOc2ccccc2-c2nc(-c3ccccc3)no2)CC1

Procedure:
1.72 g of 5-[2-(2-bromoethyl)oxy-phenyl]-3-phenyl-1,2,4-oxadiazole are dissolved in 50 ml of anhydrous dioxane and mixed with 2 g of N-methylpiperazine. The solution is refluxed for one hour and then concentrated by evaporation in vacuo. The residue is chromatographed on silica gel with dichloromethane/methanol (90/10). The base thus obtained is dissolved in anhydrous ethanol, acidified with ethereal HCl and precipitated with diethyl ether. The residue is recrystallised from anhydrous ethanol and diethylether. Yield: 1.7 g (78% of theory). m.p.: 251-253° C.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[CH:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1)=[C:2]=[S:3].[CH:26]([N:29]1[CH:33]=[N:32][N:31]=[C:30]1[C:34]1[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=1[NH2:36])([CH3:28])[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+]>C(O)(C)C.O>[CH:26]([N:29]1[CH:33]=[N:32][N:31]=[C:30]1[C:34]1[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=1[NH:36][C:2]([NH:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[CH:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1)=[S:3])([CH3:28])[CH3:27]
Reactant: CC(C)n1cnnc1-c1ccccc1N
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)n1cnnc1-c1ccccc1NC(=S)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Yield: 20.7 %

Procedure:
3-(4-Isothiocyanatophenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (WO 2011/017513) (0.088 g, 0.24 mmol), 2-(4-isopropyl-4H-1,2,4-triazol-3-yl)aniline (0.080 g, 0.40 mmol), and cesium carbonate (0.16 g, 0.50 mmol) in isopropyl alcohol (1.2 mL) was stirred at room temperature overnight. The reaction was diluted with water and extracted with ethyl acetate. The organic layers were dried over sodium sulfate, filtered and concentrated. The residue was loaded onto Celite® cartridge and purified by flash chromatography using 0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes as eluent to provide the title compound as a yellow solid (0.028 g, 20%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[H-].[Na+].[Cl:15][C:16]1[CH:21]=[C:20]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][OH:30])=[CH:25][C:24]=2[F:31])[CH:19]=[CH:18][N:17]=1>CN(C=O)C>[Cl:15][C:16]1[CH:21]=[C:20]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][O:30][C:2]3[CH:3]=[C:4]4[N:11]([CH3:12])[CH2:10][CH2:9][N:5]4[C:6](=[O:8])[N:7]=3)=[CH:25][C:24]=2[F:31])[CH:19]=[CH:18][N:17]=1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Oc2ccnc(Cl)c2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c1cc(OCc1ccc(Oc3ccnc(Cl)c3)c(F)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (50 mg, 0.269 mmol), sodium hydride (21.55 mg, 0.539 mmol) and (4-((2-chloropyridin-4-yl)oxy)-3-fluorophenyl)methanol (68.3 mg, 0.269 mmol) in DMF (2 mL).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][C@@H:15]2[CH2:17][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([NH:27][C@@H:28]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)[CH2:29][OH:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[CH2:20]([N:27]([C@@H:28]([CH2:31][C:32]1[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=1)[CH2:29][OH:30])[CH2:17][C@H:15]([OH:16])[CH2:14][O:13][C:12]1[CH:18]=[CH:19][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=[N+]([O-])c1ccc(C[C@@H](CO)NCc2ccccc2)cc1
Reactant: c1ccc(COc2ccc(OC[C@@H]3CO3)cc2)cc1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C[C@@H](CO)N(Cc2ccccc2)C[C@H](O)COc2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Yield: 81 %

Procedure:
A solution of (2S)-2-[(4-(benzyloxy)phenoxy)methyl]-oxirane (1.19 g) and (2S)-2-(benzylamino)-3-(4-nitrophenyl)-1-propanol (1.33 g) in ethanol (13 ml) was refluxed for 20 hours. After cooling to room temperature, the solvent was removed by evaporation and the residue was chromatographed on silica gel (eluent: chloroform/methanol=98/2) to give (2S)-2-[N-benzyl-N-[(2S)-3-[4-(benzyloxy)phenoxy]-2-hydroxypropyl]amino]-3-(4-nitrophenyl)-1-propanol (2.04 g) as a yellow gum.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].Cl.[CH3:31][N:32]([CH3:39])[C:33]([CH:35]1[CH2:38][NH:37][CH2:36]1)=[O:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:37]4[CH2:38][CH:35]([C:33]([N:32]([CH3:39])[CH3:31])=[O:34])[CH2:36]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CN(C)C(=O)C1CNC1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(C(=O)N(C)C)C3)n(C)c2n1
Reaction time: 3 h
Yield: 78.7 %

Procedure:
A solution of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (100 mg, 0.27 mmol) and azetidine-3-carboxylic acid dimethylamide hydrochloride salt (53 mg, 0.32 mmol) in DCE (4 mL) was stirred at ambient temperature for 1 h. Sodium triacetoxyborohydride (86 mg, 0.41 mmol) was added and the mixture stirred for 3 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, EtOAc:MeOH; gradient from 100:0 to 70:30) to afford 366 as a cream solid (107 mg, 83%). LCMS (Method G): RT=5.51 min, M+H+=504. 1H NMR (CDCl3, 400 MHz) δ 8.00 (m, 1 H); 7.75 (m, 1 H); 7.28 (m, 2 H); 4.34 (m, 4 H); 3.89-3.83 (m, 6 H); 3.83 (s, 3 H); 3.70-3.62 (m, 2 H); 3.57-3.46 (m, 3 H); 3.34 (q, J=7.5 Hz, 2 H); 2.96 (s, 3 H); 2.90 (s, 3 H) and 1.44 (t, J=7.5 Hz, 3 H)
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[CH:22][C:5]([NH:6][CH2:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:13][C:12]=2[Cl:21])=[O:9])=[CH:4][CH:3]=1.[CH2:24]=O>C(O)C.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:6]2[CH2:7][C:8](=[O:9])[N:10]([C:11]3[CH:16]=[CH:15][C:14]([S:17](=[O:19])(=[O:20])[NH2:18])=[CH:13][C:12]=3[Cl:21])[CH2:24]2)=[CH:22][CH:23]=1
Reactant: Cc1ccc(NCC(=O)Nc2ccc(S(N)(=O)=O)cc2Cl)cc1
Reactant: C=O
Solvent: CCO
Solvent: O
Product: Cc1ccc(N2CC(=O)N(c3ccc(S(N)(=O)=O)cc3Cl)C2)cc1
Temperature: 0 °C

Procedure:
2-(p-Methylanilino)-N-(2-chloro-4-sulphamoylphenyl)-acetamide (15g) was dissolved in ethanol (200 ml) and paraformaldehyde (2.5 g) in water (400ml) added thereto. The mixture was refluxed for 3 hours, cooled in ice/water and filtered to yield the title compound (6.45g), m.p. 223°-226° (ethanol).
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([N+:29]([O-])=O)[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[N:11](C(OC(C)(C)C)=O)[CH:12]=[C:13]([C:14]#[C:15][CH2:16][OH:17])[C:6]=12>C1COCC1.CO.[Pd]>[NH2:29][C:27]1[CH:26]=[CH:25][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[NH:11][CH:12]=[C:13]([CH2:14][CH2:15][CH2:16][OH:17])[C:6]=23)=[C:2]([F:1])[CH:28]=1
Reactant: CC(C)(C)OC(=O)n1cc(C#CCO)c2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(Oc2ccnc3[nH]cc(CCCO)c23)c(F)c1
Reaction time: 5 h
Yield: 13.3 %

Procedure:
A mixture of tert-butyl 4-(2-fluoro-4-nitrophenoxy)-3-(3-hydroxyprop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (50 mg, 0.15 mmol) and 10% Pd/C (containing 50% H2O, 120 mg) in THF (10 mL) and MeOH (2 mL) was hydrogenated at 1 atm for 5 h. The mixture was diluted with MeOH and filtered through a pad of Celite®. The crude mixture was purified by preparative HPLC to afford the desired product (6 mg, 13% yield) as a white solid. LC/MS ESI+) m/z 302 (M+H)+.
Reaction SMILES: [I-].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:3]1.[CH:31]([C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=1)=O.C(=O)([O-])[O-].[K+].[K+].O>CO>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:11]=[CH:31]/[C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)=[N:3]1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: c1ccc([P+](Cc2n[nH]c3ccccc23)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.3 %

Procedure:
(1H-indazol-3-ylmethyl)triphenylphosphonium iodide (3.20 g, 6.15 mmol) obtained in Step 4 was dissolved in methanol (60 mL), and the solution was added with methyl p-formylbenzoate (1.00 g, 6.09 mmol) and potassium carbonate (2.55 g, 18.5 mmol), followed by stirring at room temperature overnight. The reaction mixture was added with water, and was extracted with ethyl acetate, then the organic layer was washed with saturated brine, and was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by thin-layer chromatography (chloroform/methanol=15/1), was further triturated in mixed solvent of ethyl acetate/diisopropyl ether to obtain methyl (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoate (0.87 g, 51%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]3[CH2:24][CH2:23][NH:22][CH2:21][C:14]=3[N:15]=[C:16]([CH2:18][O:19][CH3:20])[N:17]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:25].[C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]2[C:13]3[CH2:24][CH2:23][N:22]([C:26]4[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][N:27]=4)[CH2:21][C:14]=3[N:15]=[C:16]([CH2:18][O:19][CH3:20])[N:17]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCc1nc2c(c(Nc3ccc(C(C)(C)C)cc3)n1)CCNC2
Reactant: Clc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCc1nc2c(c(Nc3ccc(C(C)(C)C)cc3)n1)CCN(c1ncccc1Cl)C2
Product: Cl

Procedure:
The title compound was prepared using the general procedure set forth in Example 3.B. using N-(4-tert-butylphenyl)-5,6,7,8-tetrahydro-2-(methoxymethyl)pyrido[3,4-d]pyrimidin-4-amine (0.105 g, 0.32 mmol), 2,3-dichloropyridine (0.071 g, 0.48 mmol), potassium carbonate (0.13 g, 0.96 mmol) and DMF (2 mL) and heating the reaction mixture for 1 h. The title compound was obtained as a light yellow solid (15 mg, 10%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.N1C=CC=CC=1.[C:26](Cl)(=[O:28])[CH3:27].O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([NH:19][C:26](=[O:28])[CH3:27])[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1
Reactant: CC(=O)Cl
Reactant: Nc1cc(Br)cc(Nc2nccc(C(F)(F)F)n2)c1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1cc(Br)cc(Nc2nccc(C(F)(F)F)n2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5-Bromo-N-[4-(trifluoromethyl)pyrimidin-2-yl]benzene-1,3-diamine (1.06 g, 3.19 mmol) was dissolved in dichloromethane (15.9 ml) and pyridine (0.28 ml, 3.51 mmol) was added. The solution was cooled to 0° C. and then, acetyl chloride (0.23 ml, 3.19 mmol) was added drop wise. The reaction mixture was stirred at 0° C. for 1 hour. Water and dichloromethane were added and the organic phase was separated, dried and concentrated under reduced pressure to afford N-(3-bromo-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)acetamide as a beige powder. 1H NMR (400 MHz, Acetone-d6) δ 9.37 (s, 1H), 9.32 (s, 1H), 8.83 (d, J=6 Hz, 1H), 7.97 (s, 1H), 7.95 (s, 1H), 7.74 (s, 1H), 7.27 (d, J=6 Hz, 1H), 2.10 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:16]=[CH:15][C:9]2[NH:10][C:11](=[O:14])[CH2:12][O:13][C:8]=2[CH:7]=1)=[O:4].[CH2:17]([CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(OCC)C>[CH2:17]([CH:25]1[CH2:26][CH2:27][N:28]([CH2:2][C:3]([NH:5][C:6]2[CH:16]=[CH:15][C:9]3[NH:10][C:11](=[O:14])[CH2:12][O:13][C:8]=3[CH:7]=2)=[O:4])[CH2:29][CH2:30]1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(CCl)Nc1ccc2c(c1)OCC(=O)N2
Reactant: c1ccc(CCC2CCNCC2)cc1
Solvent: CCOCC
Product: O=C(CN1CCC(CCc2ccccc2)CC1)Nc1ccc2c(c1)OCC(=O)N2

Procedure:
The title compound is prepared from 2-chloro-N-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-7-yl)-acetamide (Example 153a) and 4-phenethyl-piperidine according to the method described in Example 142b. Melting Point: 200-203° C. (diethylether)
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=4[C:27]([O:29]C)=[O:28])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:36]>CO.O1CCOCC1.Cl>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=4[C:27]([O-:29])=[O:28])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Na+:36]
Reactant: COC(=O)c1ccccc1CC1CCCC=C1c1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: O=C([O-])c1ccccc1CC1CCCC=C1c1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 2-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzoate (37 mg) in MeOH-1,4-dioxane (1:1, 3 ml) was added iN NaOH solution (1.0 ml) at 5° C. and the mixture was stirred at 80° C. for 3 hours. After cooling, the mixture was acidified with iN HCl and extracted with EtOAc. The organic layer was washed with water and brine, dried over magnesium sulfate, evaporated in vacuo. The residue was dissolved in MeOH-1,4-dioxane (1:1, 2 ml) and 1N NaOH solution (0.0824 ml) was added thereto. The mixture was evaporated and Et2 was added. The resulting solid was collected by filtration to give sodium 2-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl1methyl}benzoate (19.9 mg).