Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([C:5]2[N:10]=[CH:9][C:8]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([C:17]([OH:19])=O)[CH:12]=3)=[CH:7][CH:6]=2)[CH2:4][CH2:3]1.[CH3:20][O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[N:24]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[CH:2]1([C:5]2[N:10]=[CH:9][C:8]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([C:17]([NH:29][C:25]4[N:24]=[C:23]([C:22]([O:21][CH3:20])=[O:30])[CH:28]=[CH:27][CH:26]=4)=[O:19])[CH:12]=3)=[CH:7][CH:6]=2)[CH2:3][CH2:4]1
Reactant: O=C(O)c1cc(-c2ccc(C3CC3)nc2)ccn1
Reactant: COC(=O)c1cccc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)c1cccc(NC(=O)c2cc(-c3ccc(C4CC4)nc3)ccn2)n1

Procedure:
A solution of 6-cyclopropyl-3,4′-bipyridine-2′-carboxylic acid hydrochloride salt (1.73 g, 6.25 mmol), 6-aminopicolinate methyl ester (1.05 g, 6.87 mmol), (2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU, 2.85 g, 7.50 mmol), and N-methylmorpholine (1.51 mL, 13.8 mmol) in N,N-dimethylformamide was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure, and the residue suspended in acetonitrile. The solid thus obtained was isolated by filtration, washed with water (80 mL), acetonitrile (80 mL) and diethyl ether (80 mL) and dried under reduced pressure to afford methyl 6-(6-cyclopropyl-3,4′-bipyridine-2′-carboxamido)picolinate as a white powder, which was used directly in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:13])=[C:8](B(O)O)[CH:9]=1)[CH3:2].Br[C:15]1[C:20]([CH3:21])=[C:19]([CH3:22])[N:18]=[C:17]([C:23]#[N:24])[CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:13])=[C:8]([C:15]2[C:20]([CH3:21])=[C:19]([CH3:22])[N:18]=[C:17]([C:23]#[N:24])[CH:16]=2)[CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(F)c(B(O)O)c1
Reactant: Cc1nc(C#N)cc(Br)c1C
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOc1ccc(F)c(-c2cc(C#N)nc(C)c2C)c1
Yield: 74.4 %

Procedure:
(5-Ethoxy-2-fluoro-phenyl)boronic acid (1.71 g, 9.3 mmol) was added to a solution of 4-bromo-5,6-dimethyl-pyridine-2-carbonitrile (which may be prepared as described in Description 144) (1.96 g, 9.3 mmol) in monoglyme (50 mL). To this was added a hot solution of sodium carbonate (2.96 g, 27.9 mmol) in water (15 mL) under N2 at ambient temp. Bis(triphenylphosphine)palladium (II) dichloride (326.38 mg, 0.4700 mmol) was then added and the whole stirred mixture was degassed by bubbling N2 through it for 10 mins. The vigorously stirred mixture was then heated at reflux for 2 h. The solution was cooled and diluted with DCM (100 ml) and washed with water (75 ml), dried (Na2SO4) and evaporated to a black solid. This was dissolved in DCM (15 ml) and the solution applied to a 100 g SiO2 chromatography cartridge which was then eluted on a Biotage SP4 system with a gradient of EtOAc-isohexane (0-30%). Relevant fractions were pooled and evaporated to a colourless solid which was dried at RT for 3 h under vacuum to give 4-(5-ethoxy-2-fluoro-phenyl)-5,6-dimethyl-pyridine-2-carbonitrile (D51) (1.87 g):
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH2:13][CH2:12][CH:11]2/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([N:23]3[S:27](=[O:29])(=[O:28])[N:26](CC[Si](C)(C)C)[C:25](=[O:36])[CH2:24]3)=[C:19]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:18]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].Cl>C1COCC1>[C:1]1([S:7]([N:10]2[CH2:14][CH2:13][CH2:12][CH:11]2/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([N:23]3[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:36])[CH2:24]3)=[C:19]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:18]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/C3CCCN3S(=O)(=O)c3ccccc3)cc2OCc2ccccc2)S1(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1CN(c2ccc(/C=C/C3CCCN3S(=O)(=O)c3ccccc3)cc2OCc2ccccc2)S(=O)(=O)N1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 5-{4-[(E)-2-(1-benzenesulfonylpyrrolidin-2-yl)-vinyl]-2-benzyloxyphenyl}-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (53 mg) in THF (2 mL) is added 0.2 mL of a 1M solution of TBAF in THF. The mixture is stirred at 60° C. for 2 h then is allowed to cool to RT. The mixture is poured into 1N HCl (20 mL) and extracted with EtOAc. The organic phase is washed with 1N HCl and brine and is dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by reverse phase Biotage using a gradient of 0-100% EtOH/water as eluent to furnish the title compound as a blue oil: (M−1)−=548.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]([CH2:14][CH2:15][N:16]2C(=O)C3[C:18](=CC=CC=3)[C:17]2=[O:26])[CH2:4][CH:3]=1.[BH4-].[Na+].[OH-].[Na+].CN(C1C=CC=CN=1)C.C(OC(=O)C)(=O)C>C(O)(C)C.O.ClCCl.Cl.CC(C)=O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]([CH2:14][CH2:15][NH:16][C:17](=[O:26])[CH3:18])[CH2:4][CH:3]=1
Reactant: COc1ccc2c(c1)C(CCN1C(=O)c3ccccc3C1=O)CC=C2Br
Agent: CN(C)c1ccccn1
Agent: Cl
Agent: [BH4-]
Solvent: CC(C)=O
Solvent: O
Solvent: CC(C)O
Product: COc1ccc2c(c1)C(CCNC(C)=O)CC=C2Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To a solution of the compound obtained in Step B (390 mg, 0.95 mmol) in isopropanol (10 mL) at ambient temperature there is added sodium borohydride (179 mg, 4.7 mmol). The mixture is stirred for 3 hours under reflux, and then a solution of sodium hydroxide (76 mg, 1.9 mmol) in water (2.0 mL) is added dropwise. The mixture is maintained under reflux for 30 minutes, and then acetone (1.5 mL) is added. After 10 minutes, the mixture is cooled to ambient temperature before being concentrated under reduced pressure. The oil thereby obtained is dissolved in dichloromethane (10 mL). Dimethylaminopyridine (255 mg, 2.1 mmol) is then added, followed by acetic anhydride (200 μL, 2.1 mmol) dropwise. The solution is stirred at ambient temperature for 1 hour and then water is added. A few drops of hydrochloric acid (1N) are also added to obtain an acid pH. The aqueous phase is extracted with dichloromethane and the organic phases are washed with saturated NaCl solution, dried over magnesium sulphate, filtered and evaporated. The title compound is obtained after purification by flash column chromatography (ethyl acetate-petroleum ether: 90-10, then ethyl acetate-methanol: 90-10) in the form of an oil in a yield of 64%.
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][C:6]([NH2:8])=[NH:7].N[C:10]1[C:15]([C:16]#[N:17])=[N:14][C:13]([C:18]2[C:26]3[O:25][C:24]([CH3:28])([CH3:27])[CH:23]([OH:29])[C:22]=3[CH:21]=[CH:20][CH:19]=2)=[CH:12][N:11]=1>CO>[NH2:7][C:6]1[N:8]=[C:16]([NH2:17])[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:18]3[C:26]4[O:25][C:24]([CH3:27])([CH3:28])[CH:23]([OH:29])[C:22]=4[CH:21]=[CH:20][CH:19]=3)[N:14]=2)[N:5]=1
Reactant: CC1(C)Oc2c(-c3cnc(N)c(C#N)n3)cccc2C1O
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC1(C)Oc2c(-c3cnc4nc(N)nc(N)c4n3)cccc2C1O
Reaction time: 0.08 h

Procedure:
A solution of 2.8 grams (0.052 mole) of sodium methoxide in 100 mL of methanol is stirred, and 1.9 grams (0.019 mole) of guanidine hydrochloride is added. Upon completion of addition, the reaction mixture is stirred for about 5 minutes and then is filtered to remove sodium chloride. The filtrate is then added to 4.5 grams (0.01 6 mole) of 2-amino-3-cyano-5-(2,3-dihydro-3-hydroxy-2,2-dimethylbenzofuran-7-yl)pyrazine. The stirring reaction mixture is then heated to reflux where it is stirred for about 18 hours. After this time the reaction mixture is cooled and filtered. The filter cake is washed with water and dried, yielding 2,4-diamino-6-(2,3-dihydro-3-hydroxy-2,2-dimethylbenzofuran-7-yl)pteridine.
Reaction SMILES: B.CSC.[F:5][C:6]([F:18])([F:17])[C:7]([C:13]([F:16])([F:15])[F:14])([OH:12])[CH2:8][C:9]([CH3:11])=[CH2:10].[OH-:19].[Na+]>C1COCC1>[F:5][C:6]([F:17])([F:18])[C:7]([C:13]([F:14])([F:15])[F:16])([OH:12])[CH2:8][CH:9]([CH3:11])[CH2:10][OH:19]
Reactant: C=C(C)CC(O)(C(F)(F)F)C(F)(F)F
Reactant: [OH-]
Agent: B
Agent: [Na+]
Solvent: CSC
Solvent: C1CCOC1
Product: CC(CO)CC(O)(C(F)(F)F)C(F)(F)F
Yield: 83.3 %

Procedure:
To a 3-necked, 500 mL round bottomed flask equipped with an overhead stirrer, digital thermometer and a 125 mL constant-pressure addition funnel with a nitrogen inlet was added 27 mL (0.27 mol) of borane-dimethylsulfide complex (10.0M in THF). The addition funnel was charged with a solution of 50 g (0.23 mol) of 1,1,1-trifluoro-2-trifluoromethyl-4-methyl-pent-4-en-2-ol (1) in 140 mL of anhydrous THF. The flask was cooled and the olefin was added slowly with stirring while maintaining a temperature below 15° C. The mixture was stirred at room temperature overnight after which time it was recooled and 100 mL (0.3 mol) of 3M NaOH (aq) was added carefully. The reaction mixture was reduced in volume on a rotary evaporator and subsequently co-evaporated with two 500 mL portions of diethyl ether. The resulting heavy oil was taken up in 50 mL of THF and the solution transferred to a 250 mL 3-necked round bottomed flask equipped with a 125-mL addition funnel, a digital thermometer, and a magnetic stirbar. The addition funnel was charged with 70 mL of 30% hydrogen peroxide. The flask was cooled and the hydrogen peroxide added slowly with stirring. After stirring overnight at room temperature, the solution was diluted with 500 mL of diethyl ether and adjusted to pH 6 (wet litmus) with 5% HCl. The ether layer was separated and the aqueous layer was extracted with 2×250 mL of ether. The combined organic phases were washed with 2×500 mL of saturated ammonium chloride and brine, dried over MgSO4, and evaporated to a yellow oil. The oil was purified by distillation through a Vigreux column, bp 57° C.@1.0 mm Hg to yield 46 g (85%) of (2) as a low melting solid. The identity of the product was confirmed using 1H NMR spectroscopy and HRMS.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[N:8].[CH2:9]([OH:13])[CH2:10][CH:11]=[CH2:12].[OH-].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.ClCCl>[CH2:9]([O:13][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[N:8])[CH2:10][CH:11]=[CH2:12]
Reactant: N#CCCCCCBr
Reactant: C=CCCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: C=CCCOCCCCCC#N
Temperature: 25 °C
Reaction time: 96 h

Procedure:
6-Bromocapronitrile (1.19 ml, 9.00 mmol) and 3-buten-1-ol (946 ul, 11.0 mmol) were added to a stirred solution of potassium hydroxide (6.16 g, 110 mmol) and tetra-butylammonium bromide (434 mg, 1.35 mmol) in water (6 ml) and dichloromethane (2 ml). The reaction was stirred at room temperature for 4 days and then washed with diethyl ether (2×50 ml). The combined organics were washed with water (3×30 ml), dried (magnesium sulphate) and the solvent removed in vacuo to furnish the title compound as a colourless oil, 1.48 g.
Reaction SMILES: [I:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH2:4][S:5][C:6](=N)N.[OH-].[Na+].COS(OC)(=O)=O>O>[I:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH2:4][S:5][CH3:6]
Reactant: N=C(N)SCc1ccccc1I
Agent: [Na+]
Agent: [OH-]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: CSCc1ccccc1I
Temperature: 105 °C
Yield: 89 %

Procedure:
To a mixture of 2-(2-iodo-benzyl)-isothiourea (13.53 g, 36.2 mmol) from previous step and a solution of NaOH (22 mL) in water (15 mL) was added dropwise dimethylsulfate (4.1 mL, 43.4 mmol). The reaction mixture was heated to reflux (105° C.) for 2 h, cooled. The resulting oil was then extracted into diethyl oxyde, the organic layer was washed with water, dried over Na2SO4. On concentration the solution generated a yellow oil that was directly used in the next step without any further purification (8.5 g, yield=89%).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[I:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[S:23])=[CH:17][CH:16]=1>>[CH2:12]([O:11][C:9]([C:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[S:23][C:22]=1[NH:21][C:18]1[CH:19]=[CH:20][C:15]([I:14])=[CH:16][CH:17]=1)=[O:10])[CH3:13]
Reactant: CCOC(=O)Cc1cccnc1Cl
Reactant: S=C=Nc1ccc(I)cc1
Product: CCOC(=O)c1c(Nc2ccc(I)cc2)sc2ncccc12

Procedure:
Prepared from ethyl (2-chloropyridin-3-yl)acetate (D. H. Bremner et al., Synthesis, 1997, 949) (750 mg, 3.8 mmol) and 4-iodophenyl isothiocyanate (1.0 g, 3.8 mmol) by the method of Example 1. Title compound obtained as an off-white solid (800 mg, 50%). δH (DMSO-d6) 10.34 (1H, br s), 8.33-8.30 (2H, m), 7.79 (2H, dt, J 2.0, 6.7 Hz), 7.43-7.31 (3H, m), 4.40 (2H, q, J 7.1 Hz), 1.40 (3H, t, J 7.1 Hz). LCMS (ES+) RT 4.31 minutes, 425 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[C:8]([NH:14]CC2C=CC=CC=2)=[CH:7][C:6]=1[O:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH3:2]>[Pd].C1COCC1.CO>[CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([NH2:14])=[CH:7][C:6]=1[O:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH3:2]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(NCc2ccccc2)cc1OCCN(C)C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1cc(N)c(N)cc1OCCN(C)C

Procedure:
Prepared analogously to example 655d by hydrogenation of the product obtained from (687a) using palladium on charcoal in THF and methanol.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].[CH:11]1[CH:12]=[CH:13][C:14]([NH2:22])=[C:15]([C:17]([CH2:19][CH2:20][NH2:21])=[O:18])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:22][C:14]1[CH:13]=[CH:12][CH:11]=[CH:16][C:15]=1[C:17]([CH:19]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:20][NH2:21])=[O:18]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: NCCC(=O)c1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NCC(C(=O)c1ccccc1N)c1ccccc1[N+](=O)[O-]

Procedure:
2 ml of 2-nitro-fluorobenzene were reacted in 20 ml DMF, at room temperature, with 5 g of kynuramine and 3 g of potassium carbonate, to yield the desired product; reaction time was 2 h. The reaction mixture was placed in 250 ml of water and stirred. It was extracted into ethylacetate (2×100 ml), ethylacetate layer was washed twice with water (50 ml), dried with sodium sulphate and the solvent was distilled off. The crude material was purified by column chromatography run with ethylacetate and hexane mixture (1:9).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:43]=[CH:42][C:9]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:32])[C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=3)[C@H:13]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=3)[CH2:12]2)=[CH:8][CH:7]=1>O>[C:1]([NH:5][C:6]1[CH:43]=[CH:42][C:9]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:32])[C:18]3[CH:19]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:21]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:23]=3)[C@H:13]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=3)[CH2:12]2)=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: Nc1ccc(CN2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3ccc(Cl)c(Cl)c3)C2)cc1
Reactant: CC(=O)Cl
Solvent: O
Product: CC(=O)Nc1ccc(CN2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3ccc(Cl)c(Cl)c3)C2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Piridine (23 μl) and acetyl chloride (16 μl) were successively added to a solution of (2R)-4-(4-aminobenzyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)-piperazine (113 mg) and the whole was stirred at room temperature for 1.5 hours. The mixture was poured into water and the separated oil was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporate in vacuo. The residue was purified by column chromatography on silica gel with a mixture of toluene and ethyl acetate as an eluent to give (2R)-4-(4-acetylaminobenzyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)piperazine (98.3 mg). The obtained piperazine was dissolved in ethyl acetate. 4N Hydrogen chloride in ethyl acetate solution (43 μl) was added to the solution and the mixture was evaporated in vacuo. The residue was triturated with n-hexane to give (2R)-4-(4-acetylaminobenzyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)piperazine hydrochloride (92 mg).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[F:23][C:24]([F:36])([F:35])[O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1.O>ClCCl>[F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:30](=[O:31])[C:29]3[CH:33]=[CH:34][C:26]([O:25][C:24]([F:23])([F:35])[F:36])=[CH:27][CH:28]=3)[CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: O=C(NC1CCNCC1)c1ccc(F)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: O=C(NC1CCN(C(=O)c2ccc(OC(F)(F)F)cc2)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(4-fluorobenzoylamino)piperidine (0.15 g) in dichloromethane (5 ml) were added in turn pyridine (82 μl) and 4-trifluoromethoxybenzoyl chloride (106 μ) at 0° C. The mixture was allowed to warm to ambient temperature and stirred for 4 hours, which was taken up into a mixture of water and dichloromethane. The separated organic layer was washed in turn with hydrochloric acid (1N), aqueous sodium hydrogen carbonate, and brine, and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure gave 4-(4-fluorobenzoylamino)-1-(4-trifluoromethoxybenzoyl)piperidine (205 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[N:14]=[CH:13][N:12]([C:18]4[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=4)[C:21]#[N:22])[C:11]=3[N:10]=[C:9]2[C:26]2[CH:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)=[CH:4][CH:3]=1.[NH2:41][C:42]1[CH:43]=[CH:44][C:45](Br)=[N:46][CH:47]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:41][C:42]1[CH:43]=[CH:44][C:45]([C:29]2[CH:28]=[CH:27][C:26]([C:9]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[C:16](=[O:17])[C:15]4[N:14]=[CH:13][N:12]([C:18]5[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=5)[C:21]#[N:22])[C:11]=4[N:10]=3)=[CH:31][CH:30]=2)=[N:46][CH:47]=1
Reactant: Nc1ccc(Br)nc1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(ncn4-c4cccc(C#N)c4)c(=O)n3-c3ccc(Cl)cc3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: N#Cc1cccc(-n2cnc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccc(N)cn5)cc4)nc32)c1
Temperature: 100 °C

Procedure:
A solution of 3-{1-(4-chloro-phenyl)-6-oxo-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1,6-dihydro-purin-9-yl}-benzonitrile (7, 1.00 g, 1.81 mmol) in N,N-dimethylformamide (40 mL) is degassed with argon for 0.5 h. Then 5-amino-2-bromopyridine (0.47 g, 2.72 mmol), cesium carbonate (1.18 g, 3.62 mmol), Pd(dppf)2Cl2 (0.13 g, 0.181 mmol) is added and the resulted mixture is degassed with argon for 0.5 h. The reaction mixture is then heated at 100° C. for 4 h. The reaction mixture is cooled to it and diluted with water and extracted with ethyl acetate (3×). The combined organic layer is washed with brine, dried over Na2SO4, concentrated, and purified by column chromatography to afford 3-[2-[4-(5-amino-pyridin-2-yl)-phenyl]-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzonitrile. LC-MS calculated for C29H18ClN7O (M+H+) 516.1, found 516.0.
Reaction SMILES: [N+:1]([C:4]1[C:9]2[NH:10][C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)([C:14]#[N:15])[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[O-2].[Al+3].[O-2].[O-2].[Al+3].CS(O)(=O)=[O:29]>>[N+:1]([C:4]1[C:9]2[NH:10][C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)([C:14]([NH2:15])=[O:29])[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N#CC1(c2ccccn2)COc2cccc([N+](=O)[O-])c2N1
Reactant: CS(=O)(=O)O
Agent: [Al+3]
Agent: [O-2]
Product: NC(=O)C1(c2ccccn2)COc2cccc([N+](=O)[O-])c2N1
Temperature: 120 °C

Procedure:
5-Nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carbonitrile (100 mg, 0.4 mmol) was added to a vigorously stirring mixture of aluminum oxide (100 mg, 1 mmol) and methanesulfonic acid (2 mL, 30 mmol) at room temperature. The reaction mixture was then heated to 120° C. for 20 min, allowed to cool to room temperature, and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude product. The product was purified by FCC on silica gel eluting a hexane:ethyl acetate gradient to give 5-nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carboxamide as clear oil (0.040 g. 40%). LCMS calculated for C14H13N4O4 (M+H)+: m/z=301.1. found: 301.1.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][C:6]([C:13]2[NH:14][C:15](=[O:22])[C:16]([CH:19]([CH3:21])[CH3:20])([CH3:18])[N:17]=2)=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:2].[OH:23][CH:24]([CH3:29])[CH2:25][C:26](O)=[O:27].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[CH:19]([C:16]1([CH3:18])[C:15](=[O:22])[NH:14][C:13]([C:6]2[N:5]=[CH:4][C:3]([CH:1]3[O:23][CH:24]([CH3:29])[CH2:25][C:26](=[O:27])[O:2]3)=[CH:12][C:7]=2[C:8]([O:10][CH3:11])=[O:9])=[N:17]1)([CH3:20])[CH3:21]
Reactant: COC(=O)c1cc(C=O)cnc1C1=NC(C)(C(C)C)C(=O)N1
Reactant: CC(O)CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(C2OC(=O)CC(C)O2)cnc1C1=NC(C)(C(C)C)C(=O)N1
Yield: 20 %

Procedure:
A solution of methyl 5formyl-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinate (0.55 g, 0.0018 mol), 3-hydroxybutyric acid (0.28 g, 0 0027 mol) and a catalytic amount of para-toluenesulfonic acid in chloroform (25 mL) is heated at reflux temperature for 113 hours. During this time, water is removed by placement of an addition funnel containing 3 angstrom molecular sieves between the reaction flask and the reflux condensor. The reaction mixture is poured into aqueous saturated sodium bicarbonate and the layers are separated. The aqueous portion is extracted with additional methylene chloride and the combined organic extracts are dried over anhydrous magnesium sulfate and concentrated in vacuo to give a residue. The residue is purified by chromatography using silica gel and ethyl acetate in hexanes as eluant to yield the title compound (0.14 g, 20%) as a white solid, mp 65°-75° C., identified by IR and NMR spectral analyses.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[CH2:14][CH2:13]1)[N:8]([C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[O:36][CH3:37])[CH:7]2[CH2:38][C:39]([O:41]C)=[O:40].[OH-].[Na+].Cl>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[CH2:14][CH2:13]1)[N:8]([C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[O:36][CH3:37])[CH:7]2[CH2:38][C:39]([OH:41])=[O:40]
Reactant: COC(=O)CC1c2cccc(F)c2N=C(N2CCN(c3ccc(F)c(F)c3)CC2)N1c1cc(C(F)(F)F)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(C(F)(F)F)cc1N1C(N2CCN(c3ccc(F)c(F)c3)CC2)=Nc2c(F)cccc2C1CC(=O)O

Procedure:
In 40 ml of dioxane, 881 mg (1.49 mmol) of methyl {8-fluoro-2-[4-(3,4-difluorophenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetate (Example 32A) and 178 mg (4.46 mmol) of sodium hydroxide are stirred at 50° C. for 2 hours. Following acidification with 1N hydrochloric acid, the product is filtered off with suction, washed with water and dried under reduced pressure.