Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][O:7][C@H:6]1Br)(=[O:3])[CH3:2].[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C)C=O>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][O:7][C@@H:6]1[N:20]=[N+:21]=[N-:22])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](OC(C)=O)CO[C@H]1Br
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](N=[N+]=[N-])OC[C@@H]1OC(C)=O
Yield: 80.2 %

Procedure:
4.88 g (12.2 mmol) of 2,3,4-tri-O-acetyl-α-L-xylopyranosyl bromide was dissolved in 40 ml of N,N-dimethylformamide, and 4.5 g (69.2 mmol) of sodium azide was added. The mixture was allowed to react at room temperature for 18 hours. The reaction mixture was then concentrated under reduced pressure and the residue extracted with chloroform (250 ml). The chloroform layer was washed with water (250 ml), dehydrated over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (Waggle C-200, 40 g) and eluted with chloroform-methanol (100:1). The eluate was crystallized from ethyl acetate-hexane to obtain 2.95 g (9.79 mmol, 68%) of 2,3,4-tri-O-acetyl-β-L-xylopyranosyl azide as a colorless needle crystal. The following are the physicochemical properties of this crystalline compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([CH:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:17]([O:19][CH3:20])=[O:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.S1C=CC=C1.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([CH:16]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:17]([O:19][CH3:20])=[O:18])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: COC(=O)C(c1ccccc1)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: c1ccsc1
Product: COC(=O)C(c1ccccc1)C1CCN(c2ccc(N)cc2)CC1
Yield: 98.1 %

Procedure:
A mixture of intermediate (17) (0.0022 mol) in methanol (100 ml) was hydrogenated at 50° C. with palladium on carbon (10%; 0.1 g) as a catalyst in the presence of a thiophene solution (4%; 0.1 ml). After uptake of hydrogen (3 equivalents), the catalyst was filtered off and the filtrate was evaporated. The residue was triturated in hexane. The precipitate was filtered off and dried, yielding 0.7 g (±)-methyl 1-(4-aminophenyl)-α-phenyl-4-piperidineacetate (intermediate 18, mp. 125° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14].[C:15](=O)([O:18]C)[O:16][CH3:17].[H-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:13][CH2:12][CH:11]([C:15]([O:16][CH3:17])=[O:18])[C:10]1=[O:14]
Reactant: COc1ccccc1C1CCCC1=O
Reactant: COC(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CCC(c2ccccc2OC)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
A mixture of 2-(2-methoxyphenyl)cyclopentanone (6.64 g, 34.9 mmol), dimethyl carbonate (58.8 ml, 698 mmol) and MeOH (4 drops) was stirred while sodium hydride (3.07 g, 60% wt, 77 mmol) was added slowly at 0° C. The mixture was wamed to RT and then heated to reflux for 2 hr and then stirred at RT overnight. The reaction was quenched with 1 N HCl (77 mL, 77 mmol) and extracted with ethyl acetate. The organic extracts were washed with water, dried with brine, and concentrated in vacuo. The crude product was purified by flash chromatography (SG, 0 to 75% EtOAc/Hexane) to get methyl 3-(2-methoxyphenyl)-2-oxocyclopentanecarboxylate (5.3 g, 21.35 mmol, 61.2% yield). LC-MS (M+Na)+=271.1. 1H NMR (500 MHz, CD3OD) δ 7.26-7.16 (m, 1H), 7.08 (d, J=7.3 Hz, 1H), 6.92-6.84 (m, 2H), 3.73-3.69 (m, 3H), 3.68 (s, 3H), 3.60-3.49 (m, 1H), 3.49-3.40 (m, 1H), 2.40-2.31 (m, 1H), 2.31-2.17 (m, 2H), 2.16-2.01 (m, 1H).
Reaction SMILES: C[C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+]([O-])=O.ClC1C=C(O)C=CC=1.[C:20]1(=[O:25])[O:24][CH:22]([CH3:23])[CH2:21]1>>[O:11]([CH:21]([CH2:22][CH3:23])[C:20]([OH:25])=[O:24])[C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=1
Reactant: CC1CC(=O)O1
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Agent: Oc1cccc(Cl)c1
Product: CCC(Oc1ccccc1)C(=O)O
Yield: 13 %

Procedure:
By the two-step method of Preparations G1/G2 and G3/G4, 3-methyl-4-nitrophenol and 3-chlorophenol were reacted with beta-butyrolactone and the intermediate phenoxybutyric acid derivative cyclized to form, respectively, 2,7-dimethyl-6-nitrochroman-4-one [overall yield 13.0%; m.p. 110°-113° C.;
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][C:4]=2[N:3]=[C:2]1[NH2:9].[CH3:10][C:11]1([CH3:19])[C:13]([CH3:15])([CH3:14])[CH:12]1[C:16](O)=[O:17].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C1COCC1>[S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][C:4]=2[N:3]=[C:2]1[NH:9][C:16]([CH:12]1[C:13]([CH3:15])([CH3:14])[C:11]1([CH3:19])[CH3:10])=[O:17]
Reactant: Nc1nc2c(s1)CCC2
Reactant: CC1(C)C(C(=O)O)C1(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)C(C(=O)Nc2nc3c(s2)CCC3)C1(C)C

Procedure:
A mixture of 5,6-dihydro-4H-cyclopentathiazole-2-ylamine (177 mg, 1.26 mmol), 2,2,3,3-tetramethylcyclopropanecarboxylic acid (244 mg, 1.52 mmol), 4-dimethylaminopyridine (50.0 mg, 0.41 mmol) and triethylamine (351 μL, 2.52 mmol) in 20 mL of THF was processed according to the method of Example 118A to provide the title compound: MS (DCI/NH3) m/z 265 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C@H:11]([C:17]([O:19][CH3:20])=[O:18])[CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:9])[N:6]=1.[CH3:21][C:22]1[CH:54]=[CH:53][C:25]2[CH:26]([C:36]3[C:37](=[S:52])[NH:38][C:39](=[O:51])[N:40]([CH2:42][C:43]4[O:47][C:46]([C:48](O)=[O:49])=[CH:45][CH:44]=4)[CH:41]=3)[C:27]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:28]=3[CH:29]=[CH:30][C:24]=2[CH:23]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH3:35][C:32]1[CH:33]=[CH:34][C:27]2[CH:26]([C:36]3[C:37](=[S:52])[NH:38][C:39](=[O:51])[N:40]([CH2:42][C:43]4[O:47][C:46]([C:48]([NH:1][C:2]5[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C@H:11]([C:17]([O:19][CH3:20])=[O:18])[CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:9])[N:6]=5)=[O:49])=[CH:45][CH:44]=4)[CH:41]=3)[C:25]3[CH:53]=[CH:54][C:22]([CH3:21])=[CH:23][C:24]=3[CH:30]=[CH:29][C:28]=2[CH:31]=1
Reactant: COC(=O)C[C@H](NC(=O)Cc1csc(N)n1)C(=O)OC
Reactant: Cc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(Cc2ccc(C(=O)O)o2)c(=O)[nH]c1=S
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C[C@H](NC(=O)Cc1csc(NC(=O)c2ccc(Cn3cc(C4c5ccc(C)cc5C=Cc5cc(C)ccc54)c(=S)[nH]c3=O)o2)n1)C(=O)OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of the product of step (ii) (0.22 g), product of example 11(0.2 g), bromo-tris(pyrrolidino)-phosphonium hexafluorophosphate (0.24 g), 4-dimethylaminopyridine (0.056 g) and N,N-diisopropylethylamine (0.2 ml) in dimethylformamide (5 ml) was stirred at room temperature for 24 hours. The mixture was partitioned between ethyl acetate and brine, washed with saturated aqueous sodium bicarbonate, dilute HCl and brine, dried (MgSO4) and evaporated. Purification was by chromatography eluting with ethyl acetate. Yield 0.24 g.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>CC(C)=O>[C:1]([Cl:12])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1
Solvent: CC(C)=O
Product: O=C(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
An amount of 500 g of benzoic acid was dissolved in 2000 ml of acetone, and 400 g of thionyl chloride was added dropwise over 3 hours. Thereafter, the mixture was stirred at a room temperature overnight under reflux. The solvent and unreacted thionyl chloride were removed to give 231 g of benzoyl chloride. Subsequently, the thus obtained benzoyl chloride was dissolved in 2000 ml of acetone and decompressed to 25 mmHg with an aspirator in a cooled state at 5° C. or less, and thereafter ammonia gas was purged therein. The reaction was stopped when the reaction system returned to normal pressure, and the reaction mixture was filtered under reduced pressure to obtain 169 g of ammonium benzoate. After the ammonium benzoate was washed with 1000 ml of water and then dissolved in 1N aqueous ice-cooled sodium hydroxide solution, bromine was added thereto. Thereby, the hydrolysis and decarboxylation was caused through the Hoffmann rearrangement to give the target 10.9 g of aniline.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([O:13][CH2:14][C:15]1[NH:24][C:23](=O)[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:26][CH3:27])[CH:21]=2)[N:16]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(#N)C>[CH2:6]([O:13][CH2:14][C:15]1[N:24]=[C:23]([Cl:3])[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:26][CH3:27])[CH:21]=2)[N:16]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COc1ccc2nc(COCc3ccccc3)[nH]c(=O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1ccc2nc(COCc3ccccc3)nc(Cl)c2c1
Reaction time: 1 h
Yield: 69 %

Procedure:
30 ml of phosphorus oxychloride was added to a suspension of 1.50 g (5.06 mmol) of 2-benzyloxymethyl-6-methoxyquinazolin-4(3H)-one in 75 ml of acetonitrile. The obtained mixture was heated under reflux. After one hour, the reaction mixture was distilled under a reduced pressure to remove the solvent and the obtained residue was dissolved in chloroform. The obtained solution was washed with a saturated aqueous solution of sodium hydrogen-carbonate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under a reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) to give 1.10 g of the title compound as a yellow crystal.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[CH2:21][CH2:22][NH2:23].[BH4-].[Na+]>CO.Cl>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:23][CH2:22][CH2:21][C:15]2[C:16]([Cl:20])=[CH:17][CH:18]=[CH:19][C:14]=2[Cl:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: NCCc1c(Cl)cccc1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCc2c(Cl)cccc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 105.7 %

Procedure:
0.38 ml of 4-tert-butylbenzaldehyde (2.25 mmol) and 288 mg 2-(2,6-dichloro-phenyl)-ethylamine (1.5 mmol) were dissolved in 4.5 ml methanol at rt, and after stirring for 30 min at rt, were refluxed for 2 h. After cooling down to rt, 85 mg (2.25 mmol) sodium borohydride were added and after stirring for 5 min at rt, the reaction mixture was then refluxed for 3 h. After cooling down to rt, the reaction mixture was treated with 4 drops 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:2) to give 533 mg colorless viscous oil (95%). MS (ISP) 336.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[C:24]([F:27])([F:26])[F:25])[CH2:19][NH2:20]>>[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[C:24]([F:25])([F:26])[F:27])[CH2:19][NH:20][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1
Reactant: COc1cccc2c(Cl)cc(C)nc12
Reactant: NCc1ccc(C(F)(F)F)c(Cl)c1
Product: COc1cccc2c(NCc3ccc(C(F)(F)F)c(Cl)c3)cc(C)nc12

Procedure:
Preparation was made using a similar procedure as described in example 1, method 1.3. Starting materials were 4-chloro-8-methoxy-2-methylquinoline and 3-chloro-4-trifluoromethylbenzylamine.
Reaction SMILES: O[C:2]1([CH3:11])[CH:6]([CH2:7][C:8]#[CH:9])[C:5](=[O:10])[CH:4]=[CH:3]1.[Cl-].[Na+].[OH2:14]>>[CH2:7]([C:6]1[C:5](=[O:10])[CH2:4][CH:3]([OH:14])[C:2]=1[CH3:11])[C:8]#[CH:9]
Reactant: O
Reactant: C#CCC1C(=O)C=CC1(C)O
Agent: [Cl-]
Agent: [Na+]
Product: C#CCC1=C(C)C(O)CC1=O

Procedure:
In an autoclave, 4-hydroxy-4-methyl-5-propargyl-2-cyclopentenone (3 g) and water (400 ml) were charged, and the resultant mixture was stirred at 150° C. for 6 hours in a nitrogen atmosphere. After cooling, sodium chloride (50 g) was added to the reaction mixture, the resulting mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and purified on column chromatography to give 2-propargyl-3-methyl-4-hydroxy-2-cyclopentenone (2.7 g). Yield, 90% nD21 1.5148.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:3]=1.C([O-])(O)=O.[Na+].[CH2:21]([O:23][C:24](=[O:38])[C:25]1[CH:30]=[C:29]([Cl:31])[C:28]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[N:27][CH:26]=1)[CH3:22]>CCO>[CH2:21]([O:23][C:24](=[O:38])[C:25]1[CH:30]=[C:29]([Cl:31])[C:28]([N:32]2[CH2:37][CH2:36][N:35]([C:6]3[CH:5]=[C:4]([C:9]4[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=4)[N:3]=[C:2]([Cl:1])[N:7]=3)[CH2:34][CH2:33]2)=[N:27][CH:26]=1)[CH3:22]
Reactant: CCOC(=O)c1cnc(N2CCNCC2)c(Cl)c1
Reactant: Fc1ccc(-c2cc(Cl)nc(Cl)n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc(N2CCN(c3cc(-c4ccc(F)cc4)nc(Cl)n3)CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 2,4-dichloro-6-(4-fluoro-phenyl)-pyrimidine (2.82 g, 0.12 mol) and NaHCO3 (1.95 g, 0.023 mol) in EtOH at 0° C., add 5-chloro-6-piperazin-1-yl-nicotinic acid ethyl ester (3.44 g, 0.013 mol). Remove the ice bath and stir at room temperature for 16 h. Concentrate under reduced pressure and partition between EtOAc and brine. Dry the organic layer (Na2SO4) and concentrate under reduced pressure to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([CH:9]=O)[CH:5]=[CH:4][N:3]=1.Cl.[NH2:12][OH:13].C([O-])(=O)C.[NH4+]>CO.O>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([CH:9]=[N:12][OH:13])[CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1ccnc(Cl)c1F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: ON=Cc1ccnc(Cl)c1F
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-3-fluoro-pyridine-4-carbaldehyde (1.20 g, 5.64 mmol) in MeOH (48 mL) and water (8 mL) were added hydroxylamine hydrochloride (0.59 g, 8.46 mmol) and ammonium acetate (1.30 g, 16.9 mmol), and stirring was continued at RT overnight. The reaction mixture was concentrated in vacuo, and the residue was suspended in CH2Cl2/MeOH 9:1. The precipitate was filtered off, washed with CH2Cl2 and dried to afford the title compound as a white solid. MS (LC/MS): 175.0 [M+H]+; tR (HPLC conditions b): 2.78 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[N:24][NH:25][C:26]2[N:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[C:11]2[C:12]([CH2:20][CH:21]([OH:23])[CH3:22])=[CH:13][C:14]3[O:18][CH2:17][O:16][C:15]=3[CH:19]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[S:40]([O:23][CH:21]([CH3:22])[CH2:20][C:12]1[C:11]([C:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[N:24][NH:25][C:26]2[N:27]=[CH:28][CH:29]=[CH:30][N:31]=2)=[CH:19][C:15]2[O:16][CH2:17][O:18][C:14]=2[CH:13]=1)(=[O:42])(=[O:41])[CH3:39]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)Cc1cc2c(cc1C(=NNc1ncccn1)c1ccc([N+](=O)[O-])cc1)OCO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Cc1cc2c(cc1C(=NNc1ncccn1)c1ccc([N+](=O)[O-])cc1)OCO2)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
2.35 g (5.58 mmol) of the compound prepared in Step A was dissolved in 50 ml of dry dichloromethane. The solution was cooled to 0° C. and after addition of 2.1 ml (15.07 mmol) of triethylamine 0.87 ml (11.22 mmol) of methanesulfonyl chloride was added over a period of 20 min, then the mixture was stirred at room temperature for 3 h. After washing with water it was dried and concentrated to yield 2.69 g (54%) of the title compound as an intermediate; Mp.: 122-124° C.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]([C:19]1[CH:24]=[C:23]([Cl:25])[C:22]([Cl:26])=[C:21]([Cl:27])[CH:20]=1)=[CH:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12]1([CH2:18][NH:17][CH2:16]1)[O:11][CH2:10]2)=[O:6].CCN(CC)CC.[C:37](O)(=[O:41])[CH:38]([CH3:40])[CH3:39].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[F:29][C:2]([F:1])([F:28])[C:3]([C:19]1[CH:20]=[C:21]([Cl:27])[C:22]([Cl:26])=[C:23]([Cl:25])[CH:24]=1)=[CH:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12]1([CH2:18][N:17]([C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH2:16]1)[O:11][CH2:10]2)=[O:6]
Reactant: O=C(C=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F)c1ccc2c(c1)COC21CNC1
Reactant: CC(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C(=O)N1CC2(C1)OCc1cc(C(=O)C=C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To the stirred solution of hydrochloride salt of 5′-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-2-enoyl)-3′H-spiro[azetidine-3,1′-isobenzofuran](Preparation 26, 1.0 g, 2.2 mmol, 1 eq) in DMF (10 mL) was added Et3N (2.4 mL, 17.3mmol, 8 eq) followed by addition of iso-butyric acid (0.38 g, 4.32mmol, 2 eq), HOBt (0.29 g, 2.16 mmol, 1 eq) and EDC.HCl (0.62 g, 3.24 mmol, 1.5 eq) at room temperature. Resulting reaction mixture was stirred at room temperature for 18 hours under nitrogen atmosphere. After consumption of starting material, reaction mixture was quenched by water (30 mL) and extracted with ethyl acetate (3×25 mL). Combined organic layer was washed with aqueous sodium bicarbonate (50 mL), aqueous LiCl solution (2×50 mL), brine (50 mL) and dried over sodium sulfate. Organic layer was concentrated in vacuo to get brown sticky oil (1.0 g, Crude). Purification was done by Combiflash chromatography using 40 g Redisep column. Compound was eluted in 40% ethyl acetate in n-hexane to get title compound as off white solid (0.5 g, 43%). 1H NMR (400 MHz, CDCl3) δ: 1.13-1.17 (m, 6H), 2.46-2.53 (m, 1H), 4.25 (d, J=10.64 Hz, 1H), 4.30-4.34 (m, 2H), 4.52 (d, J=9.32 Hz, 1H), 5.15 (s, 2H), 7.27 (s, 2H), 7.40 (d, J=1.36 Hz, 1H), 7.49 (d, J=8.04 Hz, 1H), 7.68 (s, 1H), 7.84 (d, J=7.92 Hz, 1H). LC-MS (m/z): 531.9 (M+H).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([O:32][CH2:33][CH3:34])([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[N:27]=[C:26](I)[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3[CH:29]([CH3:31])[CH3:30])=[CH:14][CH:13]=1)[PH2:10]=[O:11])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[Br-].[CH:36]1([Zn+])[CH2:40][CH2:39][CH2:38][CH2:37]1.O>CN(C=O)C>[CH2:1]([O:3][P:4]([C:9]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[N:27]=[C:26]([CH:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3[CH:29]([CH3:31])[CH3:30])=[CH:14][CH:13]=1)([O:32][CH2:33][CH3:34])[PH2:10]=[O:11])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOC([PH2]=O)(c1ccc(Nc2nc(I)nc3c2ncn3C(C)C)cc1)P(=O)(OCC)OCC
Reactant: [Zn+]C1CCCC1
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC([PH2]=O)(c1ccc(Nc2nc(C3CCCC3)nc3c2ncn3C(C)C)cc1)P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To {ethoxy-[4-(2-iodo-9-isopropyl-9H-purin-6-ylamino)-phenyl]-phosphinoylmethyl}-phosphonic acid diethyl ester (0.30 g, 0.48 mmol) in DMF (3.9 mL) was added PdCl2(PPh3)4 (17 mg, 0.024 mmol) followed by cyclopentylzinc bromide (0.5M THF, 3.9 mL, 1.9 mmol). The mixture was stirred at rt for 1 h, poured into water and extracted with EtOAc. The combined extracts, were washed with water, sat'd NaCl, then dried over MgSO4 and filtered. The material was used without purification in the next reaction.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[O:12][C:11](=[O:13])[NH:10][CH2:9]2)=[N:6][CH:7]=1.[H-].[Na+].I[CH3:17]>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[O:12][C:11](=[O:13])[N:10]([CH3:17])[CH2:9]2)=[N:6][CH:7]=1
Reactant: O=C1NCC(c2ccc(Br)cn2)O1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN1CC(c2ccc(Br)cn2)OC1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
Compound 14b (350 mg, 1.44 mmol) was dissolved in dried tetrahydrofuran, cooled to 0° C. NaH (86.4 mg, 2.16 mmol) was added, and iodomethane (0.18 mL, 2.88 mmol) was added dropwise. After the addition was completed, the reaction mixture was raised to room temperature for reacting overnight. The reaction was monitored by TLC (petroleum ether/ethyl acetate=5/1). After the reaction completed, the mixture was diluted with water, and extracted with ethyl acetate. The organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate. Column chromatography (petroleum ether/ethyl acetate=8/1) afforded 315 mg of white solid (compound 14c), yield 85%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=2)[CH:7]=1.[C:13]([O:17][C:18]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1B(O)O)=[O:19])([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>CCOC(C)=O>[CH:11]([C:8]1[N:6]2[CH:7]=[C:2]([C:21]3[N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[C:28]4[C:23]([CH:22]=3)=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)=[O:12]
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Reactant: O=Cc1cnc2ccc(Br)cn12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1c(-c2ccc3ncc(C=O)n3c2)cc2ccccc21
Yield: 51 %

Procedure:
6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde (step 1 of Intermediate 1, 150 mg, 0.6729 mmol), 1-(tert-butoxycarbonyl)-1H-indol-2-ylboronic acid (228 mg, 0.8742 mmol), dichlorobis(triphenylphosphine) palladium (II) (30 mg, 20% mmol) and 2M aqueous Na2CO3 (1 mL) were added to DMF (5 mL) and refluxed for 2 h. The reaction mixture was diluted with EtOAc and washed with water and brine. The solvent was evaporated to obtain solid residue, which was purified by column chromatography (silica gel, 1% methanol in chloroform) to obtain the title compound. Yield: 51%; 1H NMR (DMSO-d6; 300 MHz): δ 11.91 (s, 1H), 9.99 (s, 1H), 9.81 (s, 1H), 8.55 (s, 1H), 8.17 (dd, 1H, J=9.3, 1.8 Hz), 7.95 (d, 1H, J=9.3 Hz), 7.56 (d, 1H, J=7.8 Hz), 7.43 (d, 1H, J=8.4 Hz), 7.142 (t, 1H, J=7.2 Hz), 7.03 (m, 2H); MS: m/z 260 (M−1)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH2:13][OH:14]>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:11][CH2:12][CH2:13][OH:14])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: NCCO
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: O=[N+]([O-])c1ccc(NCCO)cc1

Procedure:
The title compound was prepared from 1-fluoro-4-nitrobenzene and 2-aminoethanol following the procedure described above. MS (ES+): m/z=183.0; 1H NMR (CDCl3, 500 MHz): δ 3.41 (t, 2H), 3.92 (t, 2H), 6.59 (d, 2H), 8.11 (d, 2H).
Reaction SMILES: [Li][CH2:2]CCC.CC1(C)CCCC(C)(C)N1.[Cl:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[F:23].CI>C1COCC1>[Cl:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([CH3:2])[C:18]=1[F:23]
Reactant: Fc1cnccc1Cl
Reactant: [Li]CCCC
Agent: CC1(C)CCCC(C)(C)N1
Solvent: C1CCOC1
Solvent: CI
Product: Cc1nccc(Cl)c1F
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 56 %

Procedure:
n-BuLi (8.5 ml of a 1.2 M soln in hexanes, 10.2 mmol) was added dropwise to a solution of 2,2,6,6-tetramethylpiperidine (1.73 ml, 10.2 mmol) in THF (30 ml) at 0° C. The mixture was then cooled to −78° C. and 4-chloro-3-fluoropyridine (1.0 ml, 10.2 mmol) was added dropwise over 15 minutes and then stirred for 25 minutes. MeI (0.64 ml, 10.2 mmol) was added dropwise at −78° C. and the resulting solution was left to warm to room temperature over several hours and quenched with saturated NaHCO3 (5 ml). The reaction was concentrated at reduced pressure, diluted with dichloromethane (50 ml), washed twice with saturated NaHCO3 (25 ml), dried (MgSO4), filtered and concentrated at reduced pressure. The residue was purified by FCC (pentane/diethyl ether with gradient, 9:1 to 8:2) to provide the title compound as colourless oil (833 mg, 56%).