Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[CH3:7])=[O:5].C([N-]C(C)C)(C)C.[Li+].[CH:24]([C:26]1[CH:42]=[CH:41][C:29]([CH2:30][CH2:31][C:32]2[N:37]3[CH:38]=[N:39][CH:40]=[C:36]3[CH:35]=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)=O>O1CCCC1>[CH2:2]([O:3][C:4]([C:6]([CH3:7])=[CH:24][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][CH2:31][C:32]2[N:37]3[CH:38]=[N:39][CH:40]=[C:36]3[CH:35]=[CH:34][CH:33]=2)=[CH:41][CH:42]=1)=[O:5])[CH3:1]
Reactant: O=Cc1ccc(CCc2cccc3cncn23)cc1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)=Cc1ccc(CCc2cccc3cncn23)cc1
Reaction time: 1 h

Procedure:
Triethyl 2-phosphonopropionate (0.61 g) is added to a solution of lithium diisopropylamide (from 0.32 g of diisopropylamine and 1.7 ml of 1.64M n-butyllithium) in 20 ml of dry tetrahydrofuran at 0° under nitrogen. After stirring at 0° for 15 minutes 5-(p-formylphenethyl)-imidazo[1,5-a]pyridine (0.55 g) is added in 5 ml of tetrahydrofuran and the reaction mixture is stirred for 1 hour at 0° and 1 hour at 25° before quenching with 25 ml of water. The layers are separated and the organic phase is dried and evaporated. The resulting oil is redissolved in ethyl acetate and passed through a column of silica gel to remove the excess phosphonate and to yield 5-[p-(2-ethoxycarbonylprop-1-enyl)phenethyl]imidazo[1,5-a]pyridine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=[CH:19][C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH2:30][O:31][CH:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:24][CH2:23]2)=[O:21])[CH:6]=[CH:7][C:8]=1[O:9]COCCOC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=[CH:19][C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH2:30][O:31][CH:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:24][CH2:23]2)=[O:21])[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: COCCOCOc1ccc(C=CC=CC(=O)N2CCN(CCCOC(c3ccccc3)c3ccccc3)CC2)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COc1cc(C=CC=CC(=O)N2CCN(CCCOC(c3ccccc3)c3ccccc3)CC2)ccc1O

Procedure:
To a solution of 650 mg (2.1 mmol) of N-(3-benzhydroxypropyl)piperazine in dry tetrahydrofuran (5 ml) was added a solution of 818 mg (2.1 mmol) of N-[5-[3methoxy-4-(β-methoxyethoxymethoxy)phenyl]-2,4-pentadienoyl]thiazolidihe-2-thione in dry tetrahydrofuran (6 ml) and the mixture was reacteed at room temperature for 14 hours. The reaction mixture was concentrated by evaporation under reduced pressure and the residue was diluted with chloroform. The mixture was washed, in turn, with 2N aqueous solution of sodium hydroxide and water and the organic layer was dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with 1% methanol in chloroform, to give 1.106 g (1.8 mmol) of N-[5-[3-methoxy-4-(β-methoxyethoxymethoxy)phenyl]-2,4-pentadienoyl]-N'-(3-benzhydroxypropyl)piperazine. To a solution of 1.064 (2.1 mmol) of the amide compound in methanol (10 ml) was added 370 mg (1.95 mmol) of p-toluenesulfonic acid monohydrate, and the mixture was refluxed for 1.5 hous under argon atmosphere. The mixture was concentrated by evaporation under reduced pressure, diluted with chloroform and washed, in turn, with a saturated aqueous solution of sodium hydrogencarbonate and water. The organic layer was dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with a 1 to 2% methanol in chloroform, to give 730 mg (1.42 mmol) of N-[5-(3-methoxy-4-hydroxyphenyl)-2,4-pentadienoyl]-N'-(3-benzhydroxypropyl)piperazine.
Reaction SMILES: [C:1]([N:6]1[CH2:10][CH2:9][O:8][C:7]1=[O:11])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CS(O)(=O)=O>C1(C)C=CC=CC=1>[C:13]1([NH:12][CH:3]([CH3:4])[CH2:2][C:1]([N:6]2[CH2:10][CH2:9][O:8][C:7]2=[O:11])=[O:5])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C/C=C/C(=O)N1CCOC1=O
Reactant: Nc1ccccc1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CC(CC(=O)N1CCOC1=O)Nc1ccccc1
Temperature: 0 °C
Yield: 23.4 %

Procedure:
To a solution of 3-crotonoyl-1,3-oxazolidin-2-one (155 mg, 1.0 mmol) in toluene (3 ml) in a stream of nitrogen was added Pd((R)-binap)(H2O)2(OTf)2 (26.6 mg, 0.025 mmol), and the resulting mixture was cooled to 0° C. Aniline (0.11 ml, 1.2 mmol) was added to the mixture, and to the solution was added slowly methanesulfonic acid (0.039 ml, 0.6 mmol). Then, the cooling ice-bath was removed and the reaction mixture was reacted at room temperature for 15 hours with stirring. After completion of the reaction, the solvent was evaporated off, and the crude product obtained was purified by a silica gel column chromatography (hexane:ethyl acetate=1:1) to give the objective compound 3-(3-phenylaminobutyryl)-oxazolidin-2-one (58 mg, 23% yield). Enantiomeric excess ratio of this product was determined by a liquid chromatography using a column for separation of optical isomers (column: AD-H) to be 78% e.e.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][NH:12][CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1.[F:24][CH:25]([F:29])[C:26](O)=[O:27]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:26](=[O:27])[CH:25]([F:29])[F:24])[CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1
Reactant: O=C(Nc1ncc(Cl)s1)N1CC2(CCNC2)c2cc(Cl)ccc21
Reactant: O=C(O)C(F)F
Product: O=C(C(F)F)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Cl)cc12

Procedure:
5-Chloro-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide and difluoroacetic acid
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Sn](CCCC)(CCCC)CCCC)=[CH:10][C:9]=1[O:27][CH3:28])(=[O:3])[CH3:2].[CH2:29]([N:31]1[CH2:36][CH2:35][N:34]([C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=[CH:39][N:38]=2)[CH2:33][CH2:32]1)[CH3:30]>C1(C)C(C)=CC=CC=1>[CH2:29]([N:31]1[CH2:32][CH2:33][N:34]([C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=[C:39]([C:11]3[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])=[C:9]([O:27][CH3:28])[CH:10]=3)[N:38]=2)[CH2:35][CH2:36]1)[CH3:30]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(CCCOC(C)=O)c(OC)c1
Reactant: CCN1CCN(c2nccc3ccccc23)CC1
Solvent: Cc1ccccc1C
Product: CCN1CCN(c2nc(-c3ccc(CCCOC(C)=O)c(OC)c3)cc3ccccc23)CC1
Yield: 40.8 %

Procedure:
2-(3-Acetoxypropyl)-5-tributylstannylanisole (0.92 g) and 3-bromo-1-((4-ethylpiperazin-1-yl)isoquinoline (0.37 g) were reacted in the presence of tetrakistriphenylphosphine (0.3 g) in xylene in nitrogen atmosphere for 4 hr. After cooling, the reaction solution was filtered and extracted with ethyl acetate. The resulting organic layer was washed with water and brine, dried and concentrated. The resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give 0.28 g of the title compound. (33-2) 1-(4-Ethylpiperazin-1-yl)-3-[4-(3-hydroxypropyl)-3-methoxyphenyl]isoquinoline hydrochloride
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.N12[CH2:23][CH2:22][CH2:21][N:20]=[C:19]1[CH2:18][CH2:17][CH2:16][CH2:15]C2.[CH3:24][N:25]([CH3:30])[S:26](N)(=[O:28])=[O:27]>O1CCCC1>[CH3:24][N:25]([CH3:30])[S:26]([C:19]1[NH:20][C:21]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:23][CH:22]=2)(=[O:28])=[O:27]
Reactant: CN(C)S(N)(=O)=O
Reactant: C1CCC2=NCCCN2CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1cc2ccccc2[nH]1
Temperature: 70 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
To 1.0 g of carboxylic acid 1 in a 100 mL round bottom flask equipped with a septa under nitrogen, was added 20 mL of dry dichloroethane (DCE). To this solution was then added 1.2 equivalents of Diphenylphosphorylazide (DPPA) in one portion followed by 3 equivalents of triethylamine. The solution was stirred overnight at room temperature. The reaction progress was followed by an analytical Shimadzu LC/MS. The crude mixture was passed through a 24 g SiliCycle/Isco silica gel cartridge with DCE to give acyl azide 2 as a light yellow foam after solvent evacuation (50-65% yield). The acyl azide was found to be stable at room temperature in a vacuum desiccator for up to one month. To 0.3 mmol of acyl azide 2 in 2 mL of dry toluene was added 1.2 equivalents of amine in a Biotage/Personal Chemistry microwave vial. The vial was capped and heated to 100° C. in a Biotage/Personal Chemistry Emrys Optomizer microwave for 25 minutes. The crude reaction mixture was then evacuated to near dryness, taken up in a 1:1 ethyl acetate/hexane mixture and purified by flash chromatography to yield urea 3 (50-55% yield). To 0.15 mmol of intermediate 3 was added 10 equivalents of potassium trimethylsilanolate (TMSOK) and 3 mL of dry tetrahydrofuran. The mixture was stirred at room temperature overnight. After the overnight treatment, the crude product was evacuated to near dryness, taken up in ethyl acetate, and neutralized with 0.5 M HCl. After extraction the solvent was removed to give a near quantitative yield of carboxylic acid 4 (purity >90%) which was used without further purification. To 0.14 mmol of carboxylic acid 4 in 1 mL of dry tetrahydrofuran was added 3 equivalents of carbonyldiimidazole. The solution was heated for 2-3 hours at 70° C. in a one dram vial equipped with a screw cap. At this point, 1.4 equivalents of neat 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) was dripped into the mixture followed by the addition of N,N-Dimethylsulfamide (as a solid). The vial was returned to the heating bath and shaken overnight. The crude reaction mixture was then evacuated to dryness and purified using a Shimadzu preparative HPLC to give dimethylamino sulfamide 5 as a yellow amorphous solid (35-50% yield).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:12])[C:2]#[CH:3].[CH3:13][O:14][CH2:15][C:16](Cl)=[O:17]>C1(C)C=CC=CC=1>[CH3:13][O:14][CH2:15][C:16]([N:4]([CH2:1][C:2]#[CH:3])[C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:12])=[O:17]
Reactant: COCC(=O)Cl
Reactant: C#CCNc1c(C)cccc1C
Solvent: Cc1ccccc1
Product: C#CCN(C(=O)COC)c1c(C)cccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
A mixture of 3.18 g (0.02 mole) of N-(2-propynyl)-2,6-dimethylbenzenamine, 2.4 g (0.022 mole) of methoxyacetyl chloride and 6 g of 4A molecular sieves in 100 ml of toluene is stirred at 60° overnight under a nitrogen atmosphere. The reaction mixture is cooled to room temperature and then filtered. The filtrate is combined with 200 ml of ether and washed with water, saturated sodium chloride solution, and dried over sodium sulfate. The drying agent is filtered and the solvent is evaporated under vacuum to give an orange-red oily material which is further purified by column chromatography (silica gel) using 20/80 ethyl acetate-n-hexane as solvent to give 2.57 g of pure product.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[NH:14][C:15]([C:17]1[CH:18]=[C:19]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[F:31])[CH:20]=[CH:21]C=1O)=[O:16].Cl>O1CCCC1.N1C=CC=CC=1>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[N:14]1[C:15](=[O:16])[C:17]2[CH:18]=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])[CH:20]=[CH:21][C:5]=2[O:4][C:2]1=[O:3]
Reactant: O=C(Nc1ccc(F)cc1F)c1cc(-c2ccc(F)cc2F)ccc1O
Reactant: COC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=c1oc2ccc(-c3ccc(F)cc3F)cc2c(=O)n1-c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 10 h
Yield: 61 %

Procedure:
A solution of methyl chloroformate (1.2 mL, 12 mmol) was added drop wised to a stirred solution of compound 2 (1.44 g, 4 mmol) in dry anhydrous tetrahydrofuran/pyridine (30 mL) at 0° C. The mixture was refluxed for 3 h. After 10 h stirring at room temperature, the pH value of the mixture was adjusted to pH=6 by 5% HCl(aq). The mixture was cooled to obtain crystalline compound on an ice bath for 2-3 h. After cooling, precipitated crystals were filtered off and washed with diluted HCl and water. The crude product was purified by crystallization from hot ethanol to afford compound 14.
Reaction SMILES: [CH3:1][C@H:2]1[N:7](CC2C=CC=CC=2)[C@@H:6]([CH3:15])[CH2:5][N:4]([C:16]2[CH:17]=[C:18]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]4[O:35][C:36]([CH3:39])=[CH:37][CH:38]=4)=[C:30]([F:40])[CH:29]=3)(=[O:27])=[O:26])[C:19]([O:22]C)=[N:20][CH:21]=2)[CH2:3]1.Cl>O1CCOCC1.O>[CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:15])[CH2:5][N:4]([C:16]2[CH:17]=[C:18]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]4[O:35][C:36]([CH3:39])=[CH:37][CH:38]=4)=[C:30]([F:40])[CH:29]=3)(=[O:27])=[O:26])[C:19](=[O:22])[NH:20][CH:21]=2)[CH2:3]1
Reactant: COc1ncc(N2C[C@@H](C)N(Cc3ccccc3)[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2ccc(C)o2)c(F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2ccc(S(=O)(=O)Nc3cc(N4C[C@@H](C)N[C@@H](C)C4)c[nH]c3=O)cc2F)o1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A solution of N-[5-[cis-3,5-dimethyl-4-(phenylmethyl)-1-piperazinyl]-2-(methyloxy)-3-pyridinyl]-3-fluoro-4-(5-methyl-2-furanyl)benzenesulfonamide (D31) 60 mg, 0.1 mmol) in dioxan (2 ml) was treated with 4.0M hydrogen chloride in dioxan (1 ml) and water (0.5 ml). The mixture was heated at 70° C. for 4 hours. The solvent was evaporated and the residue dissolved in ethanol (5 ml) and 2M hydrochloric acid (2 ml). 10% Palladium on carbon (10 mg) was added and the mixture stirred in a hydrogen atmosphere for 4 hours. The mixture was filtered through ‘celite’ and the solvent was evaporated. Purification by MDAP gave the title compound (E15). MS (ES+) m/e 461 [M+H]+.
Reaction SMILES: [NH:1]1C2(CCCCC2)[NH:4][CH2:3][C:2]1=[O:11].[O:12]1[CH2:22][CH:13]1[CH2:14][C:15]([O:17]CC(C)C)=O>C(O)(C)C.C(O)C>[CH2:14]1[C:15](=[O:17])[N:4]([CH2:3][C:2]([NH2:1])=[O:11])[CH2:22][CH:13]1[OH:12]
Reactant: CC(C)COC(=O)CC1CO1
Reactant: O=C1CNC2(CCCCC2)N1
Solvent: CCO
Solvent: CC(C)O
Product: NC(=O)CN1CC(O)CC1=O
Reaction time: 9 h

Procedure:
0.650 g 2,2-dimethyl-4-imidazolidinone ((5); R4 =R5 =CH3) (5.7 mmoles) is dissolved in 5 ml isopropanol. 1 g 2-methylpropyl 3,4-epoxybutanoate ((4); X=isobutyl) (6.32 mmoles) is added. The mixture is boiled for 9 h. A further 1 g of epoxyester is added and boiling is continued for a further 9 h. After cooling, the solvent is decanted and the dark mass obtained is taken up in ethanol. The solid obtained is filtered, to give oxiracetam, m.p. 167°-70° C.
Reaction SMILES: B(Br)(Br)Br.[NH2:5][C:6]([NH:8][C:9]1[NH:10][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23]C)=[CH:12][C:13]=1[C:14]([NH2:16])=[O:15])=[O:7].O>ClCCl>[NH2:5][C:6]([NH:8][C:9]1[NH:10][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[OH:23])=[CH:12][C:13]=1[C:14]([NH2:16])=[O:15])=[O:7]
Reactant: COc1ccccc1-c1cc(C(N)=O)c(NC(N)=O)[nH]1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: NC(=O)Nc1[nH]c(-c2ccccc2O)cc1C(N)=O
Reaction time: 0.5 h

Procedure:
Boron tribromide in dichloromethane solution (17%, 5.8 mL, 5.8 mmol) was added dropwise to a suspension of 2-aminocarbonylamino-5-(2-methoxyphenyl)pyrrole-3-carboxamide (Compound No. 1-9, 0.40 g, 1.5 mmol) in anhydrous dichloromethane (8 mL) for 7 minutes at −78° C., and the mixture was stirred for 30 minutes. Moreover, the mixture was stirred under ice-cooling for 5 hours, water (25 mL) was added thereto. The precipitated solid was filtered off with chloroform, dried under reduced pressure to give the target compound (0.39 g) quantitatively as a gray solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:10]=[C:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][CH:14]=1)=[O:6].[Cl:26][C:27]1[N:32]=[C:31](Cl)[C:30]([Cl:34])=[CH:29][N:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:26][C:27]1[N:32]=[C:31]([NH:1][C:2]2[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=2)[C:5]([NH:7][CH2:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19])[CH:12]=[CH:13][CH:14]=2)=[O:6])[C:30]([Cl:34])=[CH:29][N:28]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CNC(=O)c2cccc(N)c2)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(CNC(=O)c2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.7 %

Procedure:
To a solution of tert-butyl (3-{[(3-aminobenzoyl)amino]methyl}phenyl)carbamate (0.60 g, 1.8 mmol) and 2,4,5-trichloropyrimidine (0.183 mL, 1.6 mmol) in DMF (4.3 mL) was added potassium carbonate (0.331 g, 2.4 mmol). The resulting mixture was stirred overnight at room temperature. The reaction was quenched with sat'd NH4Cl and water. EtOAc was added and the layers separated. The aqueous layer was extracted with EtOAc twice. The combined organics were washed with water, dried, filtered and concentrated to give the crude, which was purified by silica gel column chromatography to give the desired product (138 mg, 18%). LCMS for C23H23Cl2N5O3 (M-tBu+H)+: m/z=432.0, 434.0, 436.0. 1H NMR (400 MHz, CD3OD): δ 8.23 (s, 1H), 8.04 (t, J=2.0 Hz, 1H), 7.96 (s, 1H), 7.83 (ddd, J=8.0, 2.0, 1.2 Hz, 1H), 7.67 (ddd, J=7.6, 2.4, 1.2 Hz, 1H), 7.48 (m, 2H), 7.21 (t, J=8.0 Hz, 1H), 7.00 (d, J=7.6 Hz, 1H), 4.54 (s, 2H), 1.49 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=2)[C:5]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)=[CH:4][N:3]=1.[H][H]>C(O)C.[Pd]>[NH2:14][C:10]1[CH:9]=[C:8]([C:6]2[C:5]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=[N+]([O-])c1cccc(-c2nc(Cl)ncc2Nc2cccc(F)c2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(-c2nc(Cl)ncc2Nc2cccc(F)c2)c1
Yield: 100 %

Procedure:
2-Chloro-N-(3-fluorophenyl)-4-(3-nitrophenyl)pyrimidin-5-amine (50 mg, 0.145 mmol) was added to the palladium/carbon (10 mg, 0.015 mmol) in ethanol (25 mL) and the applied hydrogen gas at 8 psi for 2 h at rt. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite; the solvent was removed by vacuum; and the crude material was purified by flash chromatography (2% CH3OH/DCM) to yield the title compound (35 mg, 0.145 mmol) as a solid. 1H NMR: (CDCl3, 400 MHz): δ 8.40 (s, 1H), 7.65 (m, 1H), 7.27-7.17 (m, 4H), 7.13-7.09 (m, 2H), 6.77 (m, 1H), 6.68 (m, 1H). ESI-MS: m/z 315.0 [M+H]+.
Reaction SMILES: Cl.C([O:9][P:10]([CH2:19][C@H:20]([OH:23])[CH2:21][NH2:22])([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])C1C=CC=CC=1.C([NH:34][C@H:35]([C:40](O)=[O:41])[C@H:36]([CH2:38][CH3:39])[CH3:37])(OCC1C=CC=CC=1)=O>>[NH2:34][C@@H:35]([CH:36]([CH3:37])[CH2:38][CH3:39])[C:40]([NH:22][CH2:21][C@@H:20]([OH:23])[CH2:19][P:10]([CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)(=[O:11])[OH:9])=[O:41]
Reactant: NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Product: CCC(C)[C@H](N)C(=O)NC[C@@H](O)CP(=O)(O)CC1CCCCC1

Procedure:
Step 4, Method B of Example 1 was substantially repeated in this Example 6 except for employing ((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride and N-Cbz-L-isoleucine as the starting materials. Subsequent hydrogenation of the resulting benzyl ester in accordance with the procedures of Step 5, Method A of Example 1 and RP-HPLC purification yielded the title compound. 1H NMR (CD3OD, 300 MHz): δ 4.18-4.03 (m, 1H), 3.72 (d, 1H), 3.40-3.35 (m, 2H), 2.01-1.85 (m, 5H), 1.80-1.50 (m, 7H), 1.42-1.18 (m, 4H), 1.17-0.95 (m, 8H). 31P NMR (CD3OD, 300 MHz): δ 53.18. LCMS m/z: [M+H]+=349.2.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:12][C:13]([F:20])([F:19])[C:14]([NH:16][CH2:17]O)=[O:15]>OS(O)(=O)=O>[F:12][C:13]([F:20])([F:19])[C:14]([NH:16][CH2:17][C:8]1[C:9]([F:11])=[CH:10][C:2]([Cl:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])=[O:15]
Reactant: O=C(O)c1ccc(F)cc1Cl
Reactant: O=C(NCO)C(F)(F)F
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(CNC(=O)C(F)(F)F)c(F)cc1Cl
Yield: 667543 %

Procedure:
The title compound was prepared according to the procedure described in step-1 of Intermediate-26 by using 2-chloro-4-fluorobenzoic acid (5.0 g, 0.002 mmol), 2,2,2-trifluoro-N-(hydroxymethyl)acetamide (4.0 g, 0.002 mmol) and conc. H2SO4 (50 mL) to afford 4.0 g of the desired product. 1H NMR (400 MHz, DMSO d6): δ 4.44 (d, J=12.0 Hz, 2H), 7.59 (m, 1H), 7.92 (m, 1H), 10.0 (br s, 1H), 13.5 (br s, 1H).
Reaction SMILES: [O:1]=[C:2]([C:6]1[N:14]2[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]2)=[CH:8][C:7]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3](Cl)=[O:4].C([N:23]([CH2:26][CH3:27])CC)C>ClCCl>[O:1]=[C:2]([C:6]1[N:14]2[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]2)=[CH:8][C:7]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]([NH:23][C:26]1[CH:27]=[CH:8][C:7]([CH3:15])=[CH:6][CH:2]=1)=[O:4]
Reactant: O=C(Cl)C(=O)c1c(-c2ccccc2)cc2ccccn12
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)C(=O)c2c(-c3ccccc3)cc3ccccn23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 128.3 %

Procedure:
To an ice-cold solution of oxo-(2-phenyl-indolizin-3-yl)-acetyl chloride (0.5 g, 1.76 mmol) and p-toludine (0.21 g, 1.94 mmol) in dichloromethane (10 ml) was added triethylamine (0.5 ml, 3.52 mmol). The reaction mixture was stirred at room temperature for 1 hr. The solvent was evaporated under vacuum. Column chromatography on silica gel afforded 2-oxo-2-(2-phenyl-indolizin-3-yl)-N-p-tolyl-acetamide (0.4 g, 65%).
Reaction SMILES: [F:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH2:4][CH2:3]1.[Li+].CC([N-]C(C)C)C.[Cl:22][C:23]1[CH:24]=[C:25]([O:36][S:37]([C:40]([F:43])([F:42])[F:41])(=[O:39])=[O:38])[CH:26]=[C:27]([Cl:35])[C:28]=1[CH2:29]OS(C)(=O)=O>C1COCC1>[Cl:22][C:23]1[CH:24]=[C:25]([O:36][S:37]([C:40]([F:42])([F:43])[F:41])(=[O:39])=[O:38])[CH:26]=[C:27]([Cl:35])[C:28]=1[CH2:29][CH:10]1[CH2:11][CH2:12][N:8]([C@H:5]2[CH2:6][CH2:7][C@@H:2]([F:1])[CH2:3][CH2:4]2)[C:9]1=[O:13]
Reactant: CS(=O)(=O)OCc1c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc1Cl
Reactant: O=C1CCCN1[C@H]1CC[C@@H](F)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1C(Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1[C@H]1CC[C@@H](F)CC1
Reaction time: 8 h

Procedure:
To a solution of cis-1-(4-fluoro-cyclohexyl)-pyrrolidin-2-one (252 mg, 1.36 mmol) in 13 mL dry THF, add 1.09 mL of 2M LDA (1.2 eq.) in THF dropwise at −78° C. Then, add 821 mg of trifluoro-methanesulfonic acid 3,5-dichloro-4-methanesulfonyloxymethyl-phenyl ester (1.5 eq) at −78° C. Allow the resulting solution to stand at room temp for overnight. Quench the mixture with saturated aqueous NH4Cl and extract with CH2Cl2. Wash the organic layer with water, then brine, and dry over Na2SO4, filter and concentrate. Purify the crude material by chromatography to afford the title compound: mass spectrum (m/z): 358 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([NH2:29])[C:23]=1[NH2:30]>>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH:7]=[CH:6][C:3]=1[C:4]1[NH:29][C:24]2[CH:25]=[C:26]([CH3:28])[CH:27]=[C:22]([CH3:21])[C:23]=2[N:30]=1
Reactant: CN1CCC(CCCOc2ccc(C=O)c(Cl)c2)CC1
Reactant: Cc1cc(C)c(N)c(N)c1
Product: Cc1cc(C)c2nc(-c3ccc(OCCCC4CCN(C)CC4)cc3Cl)[nH]c2c1
Yield: 86.3 %

Procedure:
This compound was prepared by the method described in Example 2, using 2-chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-benzaldehyde (106 mg, 0.36 mmol, 1.0 equiv), 3,5-dimethyl-benzene-1,2-diamine (49 mg, 0.36 mmol, 1.0 equiv), and Na2S2O5 (88 mg, 0.47 mmol, 1.3 equiv) in Step C. Purification by Method 2 afforded 128 mg (87%) of the title compound. MS (electrospray): mass calculated for C24H30ClN3O, 411.21; m/z found, 412.4 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.68 (d, J=8.5 Hz, 1H), 7.21 (br s, 1H), 7.12 (d, J=2.4 Hz, 1H), 7.01 (dd, J=8.7, 2.5 Hz, 1H), 6.90 (s, 1H), 4.05 (t, J=6.3 Hz, 2H), 2.92-2.88 (m, 2H), 2.54 (s, 3H), 2.43 (s, 3H), 2.29 (s, 3H), 2.09-2.03 (m, 2H), 1.85-1.76 (m, 4H), 1.47-1.11 (m, 5H).