Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH:14]12[S:22][CH:18]([CH2:19][CH2:20][CH2:21]1)[CH2:17][CH:16]([CH:23]=[O:24])[CH2:15]2>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:23]([CH:16]2[CH2:17][CH:18]3[S:22][CH:14]([CH2:21][CH2:20][CH2:19]3)[CH2:15]2)[OH:24])=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: O=CC1CC2CCCC(C1)S2
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OC(c1ccc(Br)cc1)C1CC2CCCC(C1)S2
Temperature: -25 °C
Reaction time: 2 h
Yield: 61.3 %

Procedure:
To a solution of 1-bromo-4-iodobenzene (1.462 g, 5.17 mmol) in THF (13 ml) at −30° C. to −25° C. was added isopropylmagnesium chloride 2M in THF (2.82 ml, 5.64 mmol). The reaction mixture was stirred at −30 to −20° C. for 2 hrs, allowed to warm to −3° C. and 9-thia-bicyclo[3.3.1]nonane-3-carbaldehyde (800 mg, 4.70 mmol) was added, the syringe was rinsed with THF (1 ml) and the solution was stirred for 1.5 hrs while cooled in an ice bath. The reaction mixture was quenched at 0° C. with a solution of aqueous saturated NH4Cl and water 2/1 (15 ml), diluted with ethyl acetate and extracted with ethyl acetate. The organic phases were combined, washed with brine, dried using Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluting with a gradient of hexanes:MTBE 98:02 to 70:30) yielding the title intermediate (1.11 g, 2.88 mmol, 61%) as a colourless resin.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:15]([C:16](=[O:18])[CH:17]=2)=[C:14]([O:19]C)[CH:13]=[C:12]([O:21]C)[C:11]=3[C@@H:23]2[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]2[CH2:29][OH:30])[CH:5]=[CH:6][CH:7]=1.Cl.N1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:15]([C:16](=[O:18])[CH:17]=2)=[C:14]([OH:19])[CH:13]=[C:12]([OH:21])[C:11]=3[C@@H:23]2[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]2[CH2:29][OH:30])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(OC)c2c(=O)cc(-c3cccc(Cl)c3)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4cccc(Cl)c4)oc23)[C@@H]1CO
Temperature: 180 °C

Procedure:
A mixture of compound of example 32 (0.565 g, 1.31 mmol) and pyridine hydrochloride (1.2 g, 10.38 mmol) was heated at 180° C. for a period of 2.5 hours. The reaction mixture was diluted with methanol (60 mL) and basified with solid Na2CO3 to pH 10. The reaction mixture was filtered, and washed with methanol. The organic layer was concentrated and the residue purified by column chromatography using 0.01% ammonia and 4.5% methanol in chloroform as eluent to afford the title compound.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[CH:13][C:8]2[O:9][CH2:10][CH2:11][O:12][C:7]=2[CH:6]=1)(=O)C.[OH-].[Na+].CCOC(C)=O>CO>[O:9]1[C:8]2[CH:13]=[CH:14][C:5]([OH:4])=[CH:6][C:7]=2[O:12][CH2:11][CH2:10]1
Reactant: CC(=O)Oc1ccc2c(c1)OCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Oc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1 g of 2,3-dihydro-1,4-benzodioxin-6-yl acetate (5.149 mmol) is dissolved in a solution of methanol (7.5 ml) and, under an argon atmosphere, the mixture is made basic, dropwise, with a 10% sodium hydroxide solution. The mixture is stirred at ambient temperature for 4 hours. At the end of the reaction, the methanol is evaporated and the reaction medium is acidified (to pH=1) with a 2N HCl solution and then washed with ethyl acetate. After extraction, drying over MgSO4 is carried out and the product is concentrated in vacuo. Purification on a silica column allows an oil to be obtained (eluant:PE/AcOEt 8/2 then 7/3).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Br:7])[S:5][CH:6]=1.[Cl:8][CH2:9][C:10](Cl)=[O:11].N1C=CC=CC=1.C([O-])(=O)C.[Na+]>C(Cl)Cl>[Br:7][C:4]1[S:5][CH:6]=[C:2]([NH:1][C:10](=[O:11])[CH2:9][Cl:8])[N:3]=1
Reactant: Nc1csc(Br)n1
Reactant: O=C(Cl)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCl)Nc1csc(Br)n1
Yield: 29.7 %

Procedure:
The starting material was prepared as follows. 4-Amino-2-bromothiazole (15.6 g) and chloroacetyl chloride (7.6 g) were suspended in methylene chloride (100 ml) with stirring and treated with pyridine (16 ml) over 15 min., maintaining reaction temperature at 0° C. with an ice bath. After the addition was complete, the reaction mixture was stirred at room temperature for 3 hours, then poured onto 20% aqueous sodium acetate (500 ml) and stirred for 30 minutes. The mixture was separated and the organic layer washed with 2 N hydrochloric acid, water, sodium carbonate solution and water. The organic layer was dried (MgSO4) and the solvent removed in vacuo and the residue recrystallised twice from carbon tetrachloride to give 2-bromo-4-chloroacetamidothiazole (5.1 g). m.p. 146°-8° C. (Found: C, 24.1; H, 1.7; N, 11.2. C5H4ClBrN2OS requires C, 23.5; H, 1.6; N, 11.0%).
Reaction SMILES: Cl[CH:2]([CH3:4])[CH3:3].[Mg].[C:6]1([C:12]2[NH:13][C:14]([CH3:19])=[C:15]([CH:17]=[O:18])[N:16]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1COCC1>[C:6]1([C:12]2[NH:13][C:14]([CH3:19])=[C:15]([CH:17]([OH:18])[CH:2]([CH3:4])[CH3:3])[N:16]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Cc1[nH]c(-c2ccccc2)nc1C=O
Reactant: CC(C)Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1[nH]c(-c2ccccc2)nc1C(O)C(C)C
Yield: 57.9 %

Procedure:
35 Grams (0.45 mol) of 2-chloropropane was added to 10.8 g (0.45 mol) of magnesium in 100 ml of diethyloxyde. Then 55.8 g (0.3 mol) of 2-phenyl-4-formyl-5-methyl-1H-imidazole in 100 ml of THF were added. At the end of the addition, the mixture was refluxed for 30 minutes and then cooled and poured on ice water. The aqueous layer was extracted twice with 100 ml of diethyl ether. Evaporation of the solvent gave a residue which was recrystallized in ethanol to yield 40 grams of 2-phenyl-4-(1-hydroxy-2-methylpropyl)-5-methyl-1H-imidazole, which melted at 214° C.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:11])([CH2:9][CH3:10])[C:4](=[O:8])[CH:5](Cl)[Cl:6].C.C(O)C>C(OCC)(=O)C.[Pd]>[ClH:6].[NH2:2][C:3]([CH3:11])([CH2:9][CH3:10])[C:4](=[O:8])[CH2:5][Cl:6]
Reactant: CCC(C)(N)C(=O)C(Cl)Cl
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCC(C)(N)C(=O)CCl
Reaction time: 3 h
Yield: 196.6 %

Procedure:
In a 2 l Parr bottle were placed 41 g of 3-amino-1,1-dichloro-3-methyl-2-pentanone hydrochloride, 0.8 g of 10% palladium over charcoal and 400 ml of ethanol (200 proof). The resulting mixture was shaken in a Parr apparatus at 50 psi for 3 hours. The crude reaction mixture was filtered through Celite® filter agent and evaporated in vacuo. A viscous oil resulted, which was taken up in approximately 400 ml of ethyl acetate and stirred at room temperature for several hours. The expected 3-amino-1-chloro-3-methyl-2-pentanone hydrochloride crystallized as a white solid. To the resulting suspension were added 300 ml of hexane. Filtration yielded 34 g (98%) of the expected 3-amino-1-chloro-3-methyl-2-pentanone hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH:18]([N:20]1C(=O)C3C(=CC=CC=3)C1=O)[CH3:19])[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[N:7]2.O.NN>CCO>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH:18]([NH2:20])[CH3:19])[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[N:7]2
Reactant: CC(c1cc2c(Cl)cccc2nc1-c1ccccn1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(N)c1cc2c(Cl)cccc2nc1-c1ccccn1
Temperature: 80 °C
Yield: 68.2 %

Procedure:
2-(1-(5-Chloro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)isoindoline-1,3-dione (220 mg, 532 μmol) was added to EtOH. To the resulting slurry was added hydrazine hydrate (133 μl, 2658 μmol) and the mixture was heated in an oil bath at 80° C. for 3 h. The reaction mixture was cooled to room temperature, filtered, and rinsed with EtOH (10 mL). The filtrate was acidified with 1.0 N HCl (˜5 mL) and concentrated on the rotavap to remove ethanol. A minor amount of solid precipitated and was removed by filtration. The filtrate was neutralized with solid sodium carbonate and extracted (2×) with DCM:IPA (4:1). The organic extracts were dried with sodium sulfate, filtered and concentrated to obtain 103 mg (68%) of a solid/film. LC-MS (+esi, M+H+=284.0). 1H NMR (400 MHz, DICHLOROMETHANE-d2) δ ppm 1.42 (d, J=6.65 Hz, 3H) 4.71 (q, J=6.65 Hz, 1H) 7.38-7.42 (m, 1H) 7.60-7.68 (m, 2H) 7.88-7.97 (m, 2H) 8.02 (dq, J=7.78, 0.80 Hz, 1H) 8.68-8.71 (m, 1H) 8.82 (t, J=0.78 Hz, 1H). LC-MS (+esi, M+H+=284.0).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[O:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][NH2:29])[CH2:23][CH2:22]1>>[O:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][NH:29][C:2]2[N:3]=[C:4]([NH2:20])[C:5]3[N:6]=[CH:7][N:8]([C:18]=3[N:19]=2)[C@@H:9]2[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[CH2:23][CH2:22]1
Reactant: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: NCCC1CCOCC1
Product: Nc1nc(NCCC2CCOCC2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 6 h

Procedure:
A mixture of 2-chloroadenosine (0.3 g) and 2-(tetrahydropyran-4-yl)ethylamine (1.15 g) is stirred under nitrogen at 140° for 6 hours. The mixture is concentrated to dryness at reduced pressure, the residue is dissolved in ethanol, the solution is treated with propylene oxide (2 ml) and stirred overnight. It is concentrated to dryness and chromatographed through a 25×180 mm column of silica gel, with methylene chloride and ammonia-saturated methanol (9:1) as eluent. The fractions containing the desired product are combined and concentrated at reduced pressure. The residue is dissolved in absolute ethanol and treated with ethanolic hydrogen chloride to form the hydrochloride salt of 2-[2-(tetrahydropyran-4-yl)ethyl-amino]adenosine; [alpha]D25 -13.6° (DMSO); m.p. 120°-130° dec.
Reaction SMILES: Br[O:2][C:3]1[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:5]([OH:7])=[O:6].B([O-])([O-])O[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O.C(OCC)(=O)C>[C:14]1([C:9]2[CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]([OH:2])=[CH:11][CH:10]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [O-]B([O-])Oc1ccccc1
Reactant: O=C(O)c1ccccc1OBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(-c2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 87 %

Procedure:
In 400 ml of water, 21.7 g of bromosalicylic acid, 13.41 g of phenyl borate and 15.28 g of potassium carbonate were dissolved. The solution was stirred at room temperature for 40 minutes. The completion of the reaction was confirmed by TLC, and the reaction solution was poured into a mixture of diluted hydrochloric acid and ethyl acetate. The organic phase was extracted, separated, and washed with a saturated aqueous sodium chloride solution. The organic phase was dried with magnesium sulfate, and concentrated. The concentrate was recrystallized with acetonitrile to obtain 5-phenylsalicyclic acid as colorless crystals. The amount was 18.58 g (yield: 87%). The molecular structure was confirmed with a mass spectrum. Synthesis of ethyl 5-phenylsalicylate
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:12][CH:11]=2)[C:5]([C:21]#[N:22])=[C:4]([SH:23])[N:3]=1.C(=O)(O)[O-].[Na+].Cl[CH2:30][C:31]1[N:32]=[C:33]([NH2:36])[S:34][CH:35]=1.O>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:14][CH:15]=2)[C:5]([C:21]#[N:22])=[C:4]([S:23][CH2:30][C:31]2[N:32]=[C:33]([NH2:36])[S:34][CH:35]=2)[N:3]=1
Reactant: Nc1nc(CCl)cs1
Reactant: COCCOc1ccc(-c2c(C#N)c(N)nc(S)c2C#N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1ccc(-c2c(C#N)c(N)nc(SCc3csc(N)n3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.31 mmol) of 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-sulphanyl-pyridine-3,5-dicarbonitrile are dissolved in 1 ml of DMF. 103 mg (1.23 mmol) of sodium bicarbonate and 68.3 mg (0.46 mmol) of 4-chloromethyl-2-amino-1,3-thiazole are then added. The suspension is shaken at RT overnight, and water is added. The precipitate is filtered off with suction, washed with ethanol and diethyl ether and dried at 40° C. under reduced pressure. This gives 115.9 mg (86.2% of theory) of product.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:31]CCl>C(O)C.CC(C)=O>[ClH:31].[CH2:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCOc2ccccc2Cc2ccccc2)C1
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)=O
Product: O=C(O)[C@@H]1CCCN(CCOc2ccccc2Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The above ester (1.7 g, 4.6 mmol) was dissolved in ethanol (10 ml) and 4N sodium hydroxide (3.5 ml) was added. The mixture was stirred at ambient temperature for 5 h. Excess concentrated hydrochloric acid was added followed by dichloromethane (300 ml). The phases were separated and the organic phase was dried (Na2SO4). The solvent was evaporated in vacuo to give a foamy residue which was dissolved in acetone (15 ml). The solid which formed was isolated by filtration and dried to give 1.3 g of the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:3]=1[CH2:4][O:5][C:6]1[C:11](I)=[CH:10][CH:9]=[CH:8][C:7]=1[C:13]1[N:18]=[C:17]([N:19]2[C:23]([C:24]([F:27])([F:26])[F:25])=[C:22]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:21]=[N:20]2)[CH:16]=[CH:15][CH:14]=1.[CH3:38]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[CH3:1][C:2]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:3]=1[CH2:4][O:5][C:6]1[C:11]([CH3:38])=[CH:10][CH:9]=[CH:8][C:7]=1[C:13]1[N:18]=[C:17]([N:19]2[C:23]([C:24]([F:27])([F:26])[F:25])=[C:22]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:21]=[N:20]2)[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3cccc(I)c3OCc3ccc(C)cc3C)n2)c1C(F)(F)F
Reactant: CB1OB(C)OB(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(-c2cccc(-c3cccc(C)c3OCc3ccc(C)cc3C)n2)c1C(F)(F)F
Temperature: 65 °C
Reaction time: 18 h

Procedure:
A vial was charged with the product from Example 15 Step B (40 mg, 0.064 mmol), trimethyl boroxine (49 mg, 50 wt. %, 0.193 mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (5.3 mg, 0.006 mmol). Sodium carbonate (0.161 mL, 1.0 M aqueous, 0.161 mmol) and THF (0.25 mL) were added, and the resulting suspension was degassed by a nitrogen sparge. The vial was then capped and placed in a pre-heated (65° C.) oil bath. After 18 h, the reaction mixture was allowed to cool to ambient temperature, then was poured into water. The aqueous phase was extracted with EtOAc, and the organic phase was concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 20% EtOAc in hexanes, then 20 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 510.8 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:18]([Cl:19])=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[O:8])=[C:5]([OH:20])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].O.Br[CH2:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32]>CN(C=O)C>[NH2:2][C:3]1[C:18]([Cl:19])=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH2:11][N:12]([CH2:13][CH3:14])[CH2:15][CH3:16])=[O:8])=[C:5]([O:20][CH2:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:4]=1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Reactant: CC(C)C(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCC(=O)C(C)C
Reaction time: 20 h
Yield: 73 %

Procedure:
A mixture of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide hydrochloride (5.82 g, 18 mmoles), anhydrous potassium carbonate (12.48 g; 90 mmoles) in DMF (30 ml) and 1-bromo-3-methyl-2-butanone [4.5 g, 27 mmoles; prepared according to M. Gaudry and A. Marquet, Org. Syn. 55, 24 (1976)] was stirred for 20 hours under nitrogen. The mixture was poured into water (150 ml) and the solid collected, dried and crystallized from toluene to give the title compound (4.86 g, 73%), mp. 109°-110°. The NMR spectrum (90 MHz) gave the following resonances: δ8.56 (bt, 1H); 8.24 (s, 1H); 6.18 (s, 1H); 4.8 (s, 2H); 4.44 (s, 2H); 3.56 (m, 2H); 2.62 (m, 7H); 1.2 (d, 6H); 1.06 (t, 6H).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:6]=[N:7][C:8]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[C:9]([CH:12]=1)[C:10]#[N:11].Cl[C:25]1[CH:26]=[C:27]2[N:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:32][N:28]2[C:29](=[O:31])[N:30]=1>>[C:10]([C:9]1[CH:12]=[C:5]([CH2:4][O:3][C:25]2[CH:26]=[C:27]3[N:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:32][N:28]3[C:29](=[O:31])[N:30]=2)[CH:6]=[N:7][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=1)#[N:11]
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cc(CO)cnc1Oc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1cnc(Oc3cccc(C(F)(F)F)c3)c(C#N)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from NaH, 5-(hydroxymethyl)-2-(3-(trifluoromethyl)phenoxy)nicotinonitrile and tert-butyl 7-chloro-5-oxo-2,3-dihydroimidazo-[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[F:38][C:39]([F:49])([F:48])[C:40]1[CH:41]=[C:42]([CH:45]=[CH:46][CH:47]=1)[CH2:43][NH2:44]>>[CH3:35][O:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:44][CH2:43][C:42]4[CH:45]=[CH:46][CH:47]=[C:40]([C:39]([F:48])([F:49])[F:38])[CH:41]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NCc4cccc(C(F)(F)F)c4)n3Cc3ccccc32)ccc1-c1ccccc1C
Yield: 79 %

Procedure:
The title compound was prepared in 79% yield in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and 3-trifluoromethylbenzylamine, m.p. 176-177° C. MS [(+)ESI, m/z]: 610 [M+H]+ Anal. Calcd for C36H30F3N3O3: C, 70.93; H, 4.96; N, 6.89. Found: C, 70.89; H, 5.02; N, 6.80.
Reaction SMILES: [O:1]=[C:2]1[C:6](=O)[CH2:5][C:4](=[O:8])[CH:3]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16].S(=O)(=O)(O)O.[H][H]>[Pd].C(O)(=O)C>[O:1]=[C:2]1[CH2:6][CH2:5][C:4](=[O:8])[CH:3]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16]
Reactant: [H][H]
Reactant: O=C(O)CCCCCCC1C(=O)CC(=O)C1=O
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C(O)CCCCCCC1C(=O)CCC1=O

Procedure:
A mixture containing 45.7 parts of 2,3,5-trioxocyclopentaneheptanoic acid, 13 parts of 5% palladium-on-carbon catalyst, 453 parts of glacial acetic acid and 63.3 parts of concentrated sulfuric acid is shaken with hydrogen at a pressure of 3 atmospheres until 2 molecular equivalents of hydrogen are absorbed. The reaction mixture is then filtered and the resulting filtrate is mixed with 100 parts of solid sodium acetate. Evaporation of the mixture to dryness affords a solid residue which is extracted with water. The resulting extract is filtered and the filter cake is washed with water, dried, then recrystallized from acetone to afford white crystals of 2,5-dioxocyclopentaneheptanoic acid, melting at about 160°-161.5°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[NH:8][C:9](=[O:17])[N:10]([CH2:12][O:13][CH2:14][CH2:15][CH3:16])[CH:11]=1)=[O:5])[CH3:2].[CH3:25][Si](C)(C)N[Si](C)(C)C.[K].CI.[NH4+].[Cl-]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:8]([CH3:25])[C:9](=[O:17])[N:10]([CH2:12][O:13][CH2:14][CH2:15][CH3:16])[CH:11]=1)=[O:5])[CH3:2]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: CCCOCN1C=C(C(=O)OCC)C(c2ccc(F)cc2)NC1=O
Agent: [Cl-]
Agent: [K]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: CCCOCN1C=C(C(=O)OCC)C(c2ccc(F)cc2)N(C)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 104.6 %

Procedure:
To a solution of 4-(4-Fluoro-phenyl)-2-oxo-1-propoxymethyl-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid ethyl ester (152 mg, 0.39 mmol) in THF (3 mL) was added potassium hexamethyldisilazane (0.92 mL of 1M toluene solution, 0.46 mmol) at 0° C. under Ar. The mixture was stirred for 1 h at 0° C. Methyl iodide (0.23 mL of 2M solution in tert-butyl methyl ether) was added at 0° C., and the mixture was stirred at 0° C. overnight. Saturated aqueous NH4Cl was added, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried under Na2SO4, filtered and concentrated to dryness under reduced pressure. Purification of the residue by flash column (hexane/ethyl acetate gradient) gave 4-(4-fluoro-phenyl)-3-methyl-2-oxo-1-propoxymethyl-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid ethyl ester (143 mg, 91%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9]([O:21][CH3:22])[C:8]([Cl:23])=[C:7]([CH3:24])[C:6]=1[C:25](=[O:27])[CH3:26].Cl.[F:29][C:30]1([F:35])[CH2:34][CH2:33][NH:32][CH2:31]1>>[Cl:23][C:8]1[C:7]([CH3:24])=[C:6]([C:25](=[O:27])[CH3:26])[C:5]([O:4][CH2:3][CH2:2][N:32]2[CH2:33][CH2:34][C:30]([F:35])([F:29])[CH2:31]2)=[C:10]([O:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]=1[O:21][CH3:22]
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCCc1ccccc1
Reactant: FC1(F)CCNC1
Agent: Cl
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCN2CCC(F)(F)C2)c1OCCCc1ccccc1
Yield: 16 %

Procedure:
Example 34b (58 mg, 0.13 mmol) and 3,3-difluoropyrrolidine hydrochloride (2.5 eq.) were reacted as described under General Procedure J and the crude product was purified by flash chromatography (silica gel, hexane/Et2O 70:30) to afford the title compound as a pale yellow oil (10 mg, 16%). 1H NMR (300 MHz, CDCl3) δ 7.33-7.18 (m, 5H), 4.08 (t, J=6.2 Hz, 4H), 3.88 (s, 3H), 2.96 (t, J=13.4 Hz, 2H), 2.85-2.73 (m, 6H), 2.51 (s, 3H), 2.31-2.13 (m, 2H), 2.20-2.04 (m, 2H). MS (ES+) m/z 482.1 (M+H+).
Reaction SMILES: [N+:1]([O-:4])([OH:3])=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:16][C:15]([C:17]([F:20])([F:19])[F:18])=[C:14]([C:21]3[S:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=3)[CH:13]=2)=[CH:8][CH:7]=1.O>C(OC(=O)C)(=O)C>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[NH:16][C:15]([C:17]([F:19])([F:18])[F:20])=[C:14]([C:21]3[S:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=3)[C:13]=2[N+:1]([O-:4])=[O:3])=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])c1ccc(-c2cc(-c3ccc(Cl)cc3)[nH]c2C(F)(F)F)s1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2c(C(F)(F)F)[nH]c(-c3ccc(Cl)cc3)c2[N+](=O)[O-])s1
Temperature: 25 °C

Procedure:
A 90% nitric acid solution (0.02 g, 0.28 mmol) is added to a solution of 5-(p-chlorophenyl)-3-(5-nitro-2-thienyl)-2-(trifluoromethyl)pyrrole (0.13 g, 0.34 mmol) in acetic anhydride. The reaction mixture is stirred at room temperature for ten minutes, treated with additional 90% nitric acid solution (0.02 g, 0.28 mmol), stirred at room temperature for 15 minutes, poured into water, stirred at room temperature overnight and extracted with ether. The combined organic extracts are dried over MgSO4 and concentrated in vacuo to obtain the title product as a tan solid which is identified by 1HNMR spectral analysis.