Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([C:16]1[C:21]([O:22]C)=[C:20]([NH:24][C:25]2[C:30](=[O:31])[N:29]3[C:32]4([CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)[NH:33][C:34](=[O:35])[C:28]3=[C:27]([CH3:41])[CH:26]=2)[N:19]=[CH:18][N:17]=1)C(=O)OC(C)(C)C)=O)(C)(C)C.ClCCl.B(Br)(Br)Br>O>[NH2:8][C:16]1[N:17]=[CH:18][N:19]=[C:20]([NH:24][C:25]2[C:30](=[O:31])[N:29]3[C:32]4([CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)[NH:33][C:34](=[O:35])[C:28]3=[C:27]([CH3:41])[CH:26]=2)[C:21]=1[OH:22]
Reactant: COc1c(Nc2cc(C)c3n(c2=O)C2(CCCCC2)NC3=O)ncnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1cc(Nc2ncnc(N)c2O)c(=O)n2c1C(=O)NC21CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A flask was charged with tert-butyl N-tert-butoxycarbonyl-N-(5-methoxy-6-((8′-methyl-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidin-4-yl)carbamate (3, 0.40 g, 0.70 mmol) and dichloromethane (20 mL) was added and mixture was cooled to −20° C. boron tribromide (0.87 g, 3.50 mmol) was then added to the mixture drop wise. The reaction mass was stirred at room temperature overnight. After completion, water was added to the reaction mixture and quenched with saturated aqueous solution of sodium bicarbonate till pH 8. Yellow solid was precipitated out, filtered and washed with water (20 mL) followed by diethyl ether then finally dried under high vacuum to afford 6′-((6-amino-5-hydroxypyrimidin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (Cpd. No. 202) as yellow solid. Yield: 0.085 g, 34%; MS (ESI) m/z 357.16 [M+1]+; 1H NMR: (400 MHz, DMSO-d6) δ 10.06 (s, 1H), 9.15 (brs, 1H), 8.50 (s, 1H), 8.40 (m, 1H), 8.08 (s, 1H), 6.65 (brs, 2H), 3.00-2.94 (m, 2H), 2.44 (s, 3H), 1.73-1.62 (m, 5H), 1.46-1.43 (m, 2H), 1.24-1.21 (m, 1H).
Reaction SMILES: CO.B(F)(F)F.[CH3:7]COCC.[CH3:12][N:13]1[C:17](=[O:18])[CH2:16][CH:15]([C:19]([OH:21])=[O:20])[CH:14]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)(Cl)Cl>[CH3:12][N:13]1[C:17](=[O:18])[CH2:16][CH:15]([C:19]([O:21][CH3:7])=[O:20])[CH:14]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOCC
Reactant: CN1C(=O)CC(C(=O)O)C1c1ccccc1
Agent: FB(F)F
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)C1CC(=O)N(C)C1c1ccccc1

Procedure:
To 400 ml. of methanol containing 25 ml. of boron trifluoride etherate was added 60 g of 1-methyl-5-oxo-2-phenylpyrrolidin-3-carboxylic acid and the solution refluxed for 8 hours. Concentration in vacuo provided an oil which was dissolved in chloroform. The chloroform solution was washed with a saturated sodium carbonate solution, a saturated sodium bicarbonate solution, water, a saturated sodium chloride solution and dried (Na2SO4). Titration and concentration in vacuo provided 63 g. of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[N:7]([C:12]1[CH:17]=[C:16]([NH:18][CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[N:15]=[C:14]([CH3:24])[N:13]=1)[CH2:6][CH2:5]2.[Br-:25].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[Br:25][C:17]1[C:12]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][C:9]=3[Cl:11])[CH2:5][CH2:6]2)=[N:13][C:14]([CH3:24])=[N:15][C:16]=1[NH:18][CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21]
Reactant: [Br-]
Reactant: CCC(CC)Nc1cc(N2CCc3cc(Cl)cc(Cl)c32)nc(C)n1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCC(CC)Nc1nc(C)nc(N2CCc3cc(Cl)cc(Cl)c32)c1Br
Yield: 93.2 %

Procedure:
4-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-6-(1-ethylpropylamino)-2-methylpyrimidine (1.15 g, 3.14 mmol) and pyridinium tribromide (1.16 g, 3.63 mmol) were stirred in dry dichloromethane (20 mL) at 20° C. for 16 h. The reaction mixture was quenched with saturated aqueous Na2S2O5 (6 mL) and diluted with EtOAc (200 mL). The EtOAc was washed with water, brine, dried and stripped in vacuo. The residue was chromatographed on silica gel using 20% EtOAc/hexanes to give the product, 5-bromo-4-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-6-(1-ethylpropylamino)-2-methylpyrimidine (1.30 g, 93% yield).
Reaction SMILES: Br[CH:2]([CH:4]1[O:19][C:7]2=[C:8]3[C:13](=[C:14]([CH3:16])[CH:15]=[C:6]2[CH:5]1[CH3:20])[NH:12][C:11](=[O:17])[C:10]([CH3:18])=[CH:9]3)[CH3:3].[N-:21]=[N+:22]=[N-:23].[Na+].CN(C)C=O>O>[N:21]([CH:2]([CH:4]1[O:19][C:7]2=[C:8]3[C:13](=[C:14]([CH3:16])[CH:15]=[C:6]2[CH:5]1[CH3:20])[NH:12][C:11](=[O:17])[C:10]([CH3:18])=[CH:9]3)[CH3:3])=[N+:22]=[N-:23]
Reactant: Cc1cc2c3c(cc(C)c2[nH]c1=O)C(C)C(C(C)Br)O3
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c3c(cc(C)c2[nH]c1=O)C(C)C(C(C)N=[N+]=[N-])O3
Yield: 72.1 %

Procedure:
A mixture of the compound obtained in Example 289 (3.30 g, 9.9 mmol), sodium azide (3.84 g, 59 mmol) and dimethylformamide (30 ml) was allowed to react at 120° C. for 4 hours. The reaction mixture was poured into water to obtain 2.13 g of the title compound as a pale brown solid (72.7%).
Reaction SMILES: [OH:1][CH:2]([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3]/[CH:4]=[CH:5]/[I:6].O.O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].O.S(=O)(=O)(O)O>CCOCC>[I:6]/[CH:5]=[CH:4]/[CH2:3][C:2](=[O:1])[CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCC(O)C/C=C/I
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCCCC(=O)C/C=C/I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6.4 g. of 4-hydroxy-1-iodo-trans-1-octene (U.S. Pat. No. 4,061,671, Ex. 4) in 25 ml. of ether, cooled in an ice-bath under argon, is added dropwise over 15 minutes, 25 ml. of a solution prepared by dissolving 100 g. of sodium dichromate dihydrate in 300 ml. of water, followed by 136 g. of sulfuric acid with ice-bath cooling and subsequent dilution to 500 ml. After addition, the mixture is stirred at room temperature for 2 hours and diluted with ether. The ether phase is separated and saved. The aqueous phase is extracted with ether. The ether solutions are combined, washed with saturated sodium chloride solution, 5% sodium thiosulfate solution, twice with saturated sodium chloride solution, dried over magnesium sulfate and taken to dryness, giving the product as an orange oil.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][O:6][CH2:5][C@H:4]1[OH:8].S=[C:10]1[CH2:14][S:13][C:12](=[O:15])[NH:11]1.C(N(C(C)C)C(C)C)C>C(O)C>[OH:8][C@@H:4]1[CH2:5][O:6][CH2:7][C@H:3]1[NH:2][C:10]1[CH2:14][S:13][C:12](=[O:15])[N:11]=1
Reactant: N[C@@H]1COC[C@H]1O
Reactant: O=C1NC(=S)CS1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(N[C@@H]2COC[C@H]2O)CS1
Yield: 40.8 %

Procedure:
To a solution of trans-4-aminotetrahydrofuran-3-ol hydrochloride (1.00 g) in ethanol (30 mL) were added 4-thioxo-1,3-thiazolidin-2-one (954 mg) and N-ethyl-N-(1-methylethyl)propan-2-amine (3.87 mL), and the mixture was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (591 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[C:24]([C:25]([OH:27])=O)=[CH:23][N:22]=[CH:21][CH:20]=3)[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[N:9]=2)[CH:7]=1.C(N(CC)CC)C.[CH:36]1([NH2:39])[CH2:38][CH2:37]1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[C:24]([C:25]([NH:39][CH:36]4[CH2:38][CH2:37]4)=[O:27])=[CH:23][N:22]=[CH:21][CH:20]=3)[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[N:9]=2)[CH:7]=1
Reactant: NC1CC1
Reactant: O=C(O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1CCCC2
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1CCCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.3 %

Procedure:
To a suspension of 4-[2-(5-chloro-2-fluorophenyl)-5,6,7,8-tetrahydroquinazolin-4-yl-amino]-nicotinic acid (40 mg, 0.10 mmol, 1 eq) in dry DMF (1 ml) was added triethylamine (15 μl, 0.11 mmol, 1.1 eq) followed by cyclopropylamine (70 μl, 0.10 mmol, 10 eq). To the suspension was added a solution of PyBrOP (56 mg, 0.21 mmol, 1.2 eq) in DMF (500 μl) dropwise. The reaction mixture was stirred at room temperature for 16 h. The reaction was concentrated in vacuo and the residue was triturated with ether (2×20 ml). The crude residue was purified by flash column chromatography (0-5% MeOH in CHCl3) to give 4-[2-(5-Chloro-2-fluorophenyl)-5,6,7,8-tetrahydroquinazolin-4-ylamino]-N-cyclopropyl nicotinamide, compound of formula (45), (15 mg, 34%) as a white solid.
Reaction SMILES: C(OP([C:9]([O:25][CH3:26])([O:23][CH3:24])[CH2:10][CH2:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=1)(OCC)=O)C.[Li]CCCC.[CH3:32][C:33]1[S:37][C:36]([C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[C:45]([CH:48]=O)[CH:46]=3)[C:41]([CH3:51])([CH3:50])[CH2:40][CH:39]=2)=[CH:35][CH:34]=1>C1COCC1.CCOCC>[CH3:26][O:25][CH:9]([O:23][CH3:24])[CH2:10]/[C:11](/[C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:21][CH:22]=1)=[CH:48]\[C:45]1[CH:46]=[C:47]2[C:42]([C:41]([CH3:51])([CH3:50])[CH2:40][CH:39]=[C:38]2[C:36]2[S:37][C:33]([CH3:32])=[CH:34][CH:35]=2)=[CH:43][CH:44]=1
Reactant: Cc1ccc(C2=CCC(C)(C)c3ccc(C=O)cc32)s1
Reactant: CCOC(=O)c1ccc(CCC(OC)(OC)P(=O)(OCC)OCC)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)c1ccc(/C(=C/c2ccc3c(c2)C(c2ccc(C)s2)=CCC3(C)C)CC(OC)OC)cc1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
To a cold (-78° C.) solution of ethyl 4-(diethoxyphosphoryl-3,3-dimethoxypropyl)benzoate (Compound D, 1.4 g, 3.6 mmol), in THF (20 mL) was added n-BuLi (1.6M solution in hexane, 2.5 mL, 4 mmol). The mixture was stirred for 20 minutes at -78° C. and 10 min. at -10° C. The reaction mixture was recooled to -78° C. and 1(5-methyl-thien-2-yl)3,4-dihydro-4,4-dimethyl-7-naphthaldehyde (Compound G, 650 mg, 2.3 mmol) in THF (4 mL) was added to it. The mixture was stirred for 2 hours at -10° C. and diluted with ether (100 mL), washed with brine (10 mL) dried with MgSO4 and the solvent was removed by distillation to to afford a cis and trans (E and Z) isomeric mixture. Purification by chromatography on silica gel of the crude material afforded the title compound as an off (~ 90% purity).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:27])[N:10]([CH2:18][C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=3)[C:22]#[N:23])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:29][C:30]1[CH:39]=[C:38]2[C:33]([CH:34]=[CH:35][C:36]([C:40]#[N:41])=[CH:37]2)=[CH:32][CH:31]=1>>[C:22]([C:21]1[CH:20]=[C:19]([CH2:18][N:10]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]([CH2:29][C:30]3[CH:39]=[C:38]4[C:33]([CH:34]=[CH:35][C:36]([C:40]#[N:41])=[CH:37]4)=[CH:32][CH:31]=3)[C:9]2=[O:27])[CH:26]=[CH:25][CH:24]=1)#[N:23]
Reactant: N#Cc1cccc(Cn2c(-c3ccccc3)c(-c3ccccc3)[nH]c2=O)c1
Reactant: N#Cc1ccc2ccc(CBr)cc2c1
Product: N#Cc1cccc(Cn2c(-c3ccccc3)c(-c3ccccc3)n(Cc3ccc4ccc(C#N)cc4c3)c2=O)c1

Procedure:
In a manner similar to Preparation 2 above, 3-[(2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1-yl) methyl]benzonitrile was reacted with 7-(bromomethyl)-naphthalene-2-carbonitrile to give 7-[[3-(3-cyanophenyl)methyl-2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1-yl]methyl]naphthalene-2-carbonitrile; NMR (CDCl3) 8.05 (s,1), 7.9 (d,1), 7.85 (d,1), 7.55 (m,3), 7.4 (m,2), 7.2 (m,9), 7.0 (m,3), 5.1 (s,2), 4.95 (s,2) ppm.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[CH:6]=1.[C:8]([C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18])#[N:9].C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.O>[Br:7][C:5]1[CH:6]=[C:2]([C:12]2[CH:13]=[CH:14][C:15]([O:16][CH:17]([CH3:19])[CH3:18])=[C:10]([CH:11]=2)[C:8]#[N:9])[S:3][CH:4]=1
Reactant: Brc1csc(Br)c1
Reactant: CC(C)Oc1ccc(B(O)O)cc1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)Oc1ccc(-c2cc(Br)cs2)cc1C#N

Procedure:
A 2 mL microwave vial was charged with 2,4-dibromothiophene (20 mg, 0.08 mmol), (3-cyano-4-isopropoxyphenyl)boronic acid (17 mg, 0.08 mmol), potassium carbonate (35 mg, 0.25 mmol) and 3:1 mixture of DME/H2O (4 mL). The reaction mixture was degassed by bubbling N2 through the stirred solution for 10 min. Pd(PPh3)4 (7 mg, 0.006 mmol) was added and the solution degassed for an additional 2 min. The vial was subjected to microwave irradiation at 70° C. for 30 min or until starting material consumed. 5-(4-bromothiophen-2-yl)-2-isopropoxybenzonitrile THIO INT-3 was used in the next experiment without purification. LCMS-ESI (m/z) calculated for C14H12BrNOS: 320.9; no M+ observed, tR=4.15 min.
Reaction SMILES: [CH3:1]C1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.C([O:21][CH2:22][CH2:23][C:24]1([C:30]([O:32][CH3:33])=[O:31])[CH2:28][CH2:27][CH2:26][C:25]1=[O:29])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][O:29][C:25]12[CH2:26][CH2:27][CH2:28][C:24]1([C:30]([O:32][CH3:33])=[O:31])[CH2:23][CH2:22][O:21]2
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: COC(=O)C1(CCOC(C)=O)CCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1cc[nH+]cc1
Solvent: CO
Product: COC(=O)C12CCCC1(OC)OCC2
Temperature: 25 °C
Yield: 85 %

Procedure:
A reaction vessel was charged with 1,580 parts of methanol, 25 parts of PPTS, 228 parts of 2-(2-acetoxyethyl)-2-methoxycarbonylcyclopentanone (12) obtained in Preparation Example 2 at room temperature. The mixture was refluxed for three hours with stirring. After cooling the reaction solution to room temperature, 30 parts of potassium carbonate was added and the mixture was stirred for one hour at room temperature. Insoluble matters were removed by filtration, the filtrate was washed with a brine, and the solvent was evaporated. The residue was distilled under reduced pressure to obtain 167 parts of the target compound (13) (yield: 85%). Boiling point: 68° C./3.5 mmHg
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][CH:6]=1.[OH-].[Na+]>O1CCCC1.CO>[C:11]([C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:15])=[O:2])=[CH:6][CH:7]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: COC(=O)Cc1ccc(C(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 4-tert-butylphenyl acetic acid methyl ester (10.0 g, 48.5 mmol) in a mixture of tetrahydrofuran (50 mL) and methanol (50 mL) was added 6 mol/L aqueous sodium hydroxide solution (16.2 mL, 97.0 mmol), and the mixture was stirred at room temperature for 3 hr. The mixture was concentrated under reduced pressure and 6 mol/L hydrochloric acid was added thereto while cooling in ice, to adjust the pH to 4 to 5. A precipitated solid was collected by filtration to afford (4-tert-butylphenyl)acetic acid as a colorless powder (9.32 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.[O:25]1[C:29]2[CH:30]=[C:31]([NH2:34])[CH:32]=[CH:33][C:28]=2[CH2:27][CH2:26]1>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14]([NH:34][C:31]3[CH:32]=[CH:33][C:28]4[CH2:27][CH2:26][O:25][C:29]=4[CH:30]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Reactant: Nc1ccc2c(c1)OCC2
Solvent: CC(=O)O
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(Nc3ccc4c(c3)OCC4)nc21

Procedure:
1 g of compound of formula (II), 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one, and 352 mg of the compound of formula (III), (2,3-dihydro-6-benzofuranyl)amine, are heated at 80° C. in 10 ml of acetic acid for 1 h 30. After returning to ambient temperature, the medium is filtered in order to remove an impurity, diluted with water and ethyl acetate and brought to pH 9 with NaHCO3. The organic phase is then washed with a saturated NaCl solution, dried over Na2SO4 and concentrated under vacuum. The residue is chromatographed on silica (gradient: heptane 100 to heptane/ethyl acetate 40:60) to give 201 mg of the expected product in the form of a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>CN(C=O)C.O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:23][CH:22]=1
Reactant: Brc1cnc2ccccc2c1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(-c2cnc3ccccc3c2)cc1
Temperature: 80 °C
Yield: 65.3 %

Procedure:
3-Bromo quinoline (2 g, 0.0096 mol) was dissolved in DMF:water (3:1, 20 mL), and potassium phosphate (6 g, 0.0288 mol) and 4-fluorophenyl boronic acid (1.6 g, 0.011 mol) were added at RT. The reaction mixture was degassed for 5 min, and Pd(PPh3)4 (0.55 g, 0.00048 mol) was added. The reaction mixture was heated by microwave at 80° C. for 1 h. After completion of reaction (monitored by TLC), the mixture was diluted with water (150 mL) and extracted with EtOAc (3×150 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum, the residue was purified by column chromatography (30% EtOAc:Hexane in silica 100-200 mesh, diameter of column—5.0 cm, height of silica—approx. 5 inch) to provide the desired compound as a white solid (1.4 g, 66% yield).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.B(O)(O)[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[N:20][CH:19]=1>>[F:24][C:21]1[N:20]=[CH:19][C:18]([C:2]2[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:4][CH:3]=2)=[CH:23][CH:22]=1
Reactant: Brc1ccc(OCCN2CCOCC2)cc1
Reactant: OB(O)c1ccc(F)nc1
Product: Fc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1

Procedure:
In another aspect, the invention relates to a process for preparing 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide dihydrochloride comprising the steps of: (1) reacting 4-(2-chloroethyl)morpholine with 4-bromophenol to yield 4-(2-(4-bromophenoxy)ethyl)morpholine; (2) coupling 4-(2-(4-bromophenoxy)ethyl)morpholine with 6-fluoropyridin-3-yl-3-boronic acid to yield 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine; (3) reacting 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine with acetonitrile to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetonitrile; (4) converting 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetonitrile to methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate; (5) reacting methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate with benzylamine to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide; and (6) contacting 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide with hydrochloric acid to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide dihydrochloride.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][C@@H:7]1[NH:19][C@@H:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:21])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:8][C@@H:7]1[NH:19][CH:20]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH3:21])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@@H]1N[C@H](C)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)[C@H]1CCN(C(=O)OC(C)(C)C)C[C@@H]1NC(C)c1ccccc1
Yield: 14.7 %

Procedure:
In a dry flask (3R,4R)-3-[(R)-1-phenyl-ethylamino]-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (31.32 g, 83.0 mmol) was dissolved in ethanol (400 mL). Potassium carbonate (68.72 g) was added and the mixture was refluxed for 6 hours. The reaction mixture was cooled, filtered through a bed of celite, and concentrated in vacuo to give a crude oil. Purification by flash column chromatography (20-50% ethyl acetate/hexanes) provided a colorless oil (4.59 g, 15%). Unepimerized ester was also isolated (23.49 g, 75%). 1H NMR (300 MHz, CDCl3), δ: 7.25 (t, J=5, 2H), 7.245 (t, J=2, 2H), 7.20 (d, J=5, 1H), 4.19 (q, J=7, 2H), 3.94 (bd, J=13, 2H), 3.86 (m, 2H), 2.85 (m, 1H), 2.71 (m, 2H), 2.32 (d, J=7, 2H), 2.20 (d, J=15, 1H), 1.68 (bs, 3H), 1.51 (s, 9H). MS (ESI), m+/z: (M+H)+=377.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:3]=1.S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)Cc1cccnc1
Reactant: CO
Agent: Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of pyridin-3-yl-acetic acid hydrochloride (10 g, 57.6 mmol) in MeOH (30 mL) was treated with thionyl chloride (4.2 mL, 57.6 mmol) and the mixture was stirred at room temperature for 2 h. Solvent was removed in vacuo and the residue was partitioned between saturated aqueous NaHCO3 and EtOAc. The organic phase was collected, dried over MgSO4 and evaporated to give the title compound (7.9 g) as a colourless oil. 1H NMR (CDCl3): 8.53 (2H, m), 7.64 (1H, d), 7.33-7.20 (1H, m), 3.72 (3H, s), 3.64 (2H, s).
Reaction SMILES: [C-:1]#[N:2].[K+].Cl[C:5]1[S:6][C:7]2[CH:13]=[C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:11]=[CH:10][C:8]=2[N:9]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O>[C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:11]=[CH:10][C:8]=2[N:9]=1)#[N:2]
Reactant: [C-]#N
Reactant: CCCCNc1ccc2nc(Cl)sc2c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCNc1ccc2nc(C#N)sc2c1
Temperature: 120 °C

Procedure:
Potassium cyanide (18 mg) and 2-chloro-6-butylaminobenzothiazole (18 mg) were dissolved in 1 ml DMSO and heated to 120° C. for 4 h. After cooling to room temperature, the reaction was poured into 0.2M potassium phosphate, pH 4.5. The aqueous layer was extracted with ethyl acetate three times, washed with water, and dried over sodium sulfate. The solvent was removed by rotary evaporation and the residue purified by silica gel chromatography (20% ethyl acetate in hexanes). 1H-NMR (d6-DMSO): δ 7.84 (d, 1H, J=8.8 Hz), 7.14 (d, 1H, J=2.4 Hz), 6.99 (dd, 1H, J=2.4, 9.2 Hz), 6.67 (br t, 1H), 3.06 (m, 2H), 1.55 (m, 2H), 1.39 (m, 2H), 0.90 (t, 3H, J=7.4 Hz).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([NH2:13])[CH2:7]2.[CH3:14][O:15]C1C=C2C(=CC=1OC)C(=O)CC2>>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[O:15][CH3:14])[CH2:9][CH:8]([NH2:13])[CH2:7]2
Reactant: COc1ccc2c(c1)CC(N)C2
Reactant: COc1cc2c(cc1OC)C(=O)CC2
Agent: Cl
Product: COc1cc2c(cc1OC)CC(N)C2

Procedure:
This compound was prepared in the same manner as [5-(methyloxy)-2,3-dihydro-1H-inden-2-yl]amine hydrochloride from 5,6-bis(methyloxy)-2,3-dihydro-1H-inden-1-one.