Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]([C@H:8]([C@@H:13]([C@@H:18]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:19][C:20](=[O:22])[CH3:21])[O:14][C:15](=[O:17])[CH3:16])[O:9][C:10](=O)C)C=O)(=[O:3])[CH3:2].C1C=CN=CC=1.[FH:34]>ClCCl>[C:25]([O:24][C@H:23]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@@H:8]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[O:9][C@@H:10]1[F:34])(=[O:27])[CH3:26]
Reactant: CC(=O)OC[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](C=O)OC(C)=O
Reactant: F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@H](F)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 40 °C

Procedure:
Mannose pentaacetate (100 g) was stirred with dichloromethane (10 mL) in a FEP Erlenmeyer. Cold HF-pyridine (100 g) was added and the resulting solution stirred at 40° C., sealed, overnight. The solution was poured into a FEP separating funnel containing water and chloroform and shaken. The chloroform layer was washed once with water and once with saturated sodium bicarbonate. The aqueous layers were neutralized with sodium hydroxide. The organic solution was dried over magnesium sulfate and concentrated under reduced pressure. The product was purified by plug chromatography (silica, eluent hexane/EtOAc). Yield 74.06 g, 80%.
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.Cl.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19]N)=[CH:15][CH:14]=1>C(O)C>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]2[NH:19][C:6]3[CH2:5][CH2:4][NH:3][CH2:8][C:7]=3[C:15]=2[CH:14]=1
Reactant: COc1ccc(NN)cc1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1ccc2[nH]c3c(c2c1)CNCC3

Procedure:
A suspension of 4-piperidone monohydrate hydrochloride (1.0 g, 6.5 mmol) and 4-methoxyphenylhydrazine hydrochloride (1.14 g, 6.5 mmol) in ethanol (17 ml) is kept stirring at reflux overnight. The resulting solid is filtered off and washed with diethyl ether to afford crude sub-title compound, which is used without further purification: tR (LC-1) 0.38; ESI-MS (positive ion): m/z 203.19 [M+H]+ (calcd 202.25 for C12H14N2O).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:5]=[C:4]([C:18]#[N:19])[C:3]=1[N+:20]([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:20][C:3]1[C:4]([C:18]#[N:19])=[N:5][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)=[CH:7][C:2]=1[NH2:1]
Reactant: N#Cc1nc(-c2cccc(C(F)(F)F)c2)cc(N)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N#Cc1nc(-c2cccc(C(F)(F)F)c2)cc(N)c1N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.9 %

Procedure:
To a stirring suspension of 4-amino-3-nitro-6-(3-trifluoromethyl-phenyl)-pyridine-2-carbonitrile (300 mg, 0.97 mmol) in ethyl acetate (80 ml) was added 10% palladium on carbon (wet) (300 mg, 2.82 mmol). The vessel was purged with hydrogen (balloon) and stirred at room temperature for 1.5 hrs. Reaction mixture was filtered through celite and concentrated in vacuo to give the title compound as a dark orange solid (240 mg, 89%). 1H NMR (MeOD): δ 8.15 (s, 1H), 8.04 (d, 1H), 7.58-7.65 (m, 2H), 7.18 (s, 1H). MS m/z 279.3 (M+1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[C:10]([NH:14][C:15]2[C:16]3[CH:23]=[C:22]([C:24]4[CH:34]=[CH:33][C:27]([C:28]([N:30]([CH3:32])[CH3:31])=O)=[CH:26][CH:25]=4)[NH:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH:11]=[CH:12][CH:13]=1.[OH-].[Na+].Cl>C1COCC1.CO.O>[ClH:7].[Cl:7][C:8]1[CH:9]=[C:10]([NH:14][C:15]2[C:16]3[CH:23]=[C:22]([C:24]4[CH:34]=[CH:33][C:27]([CH2:28][N:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=4)[NH:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CN(C)C(=O)c1ccc(-c2cc3c(Nc4cccc(Cl)c4)ncnc3[nH]2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CN(C)Cc1ccc(-c2cc3c(Nc4cccc(Cl)c4)ncnc3[nH]2)cc1
Temperature: 60 °C

Procedure:
Lithium aluminum hydride (72 mg, 1.9 mmol) is suspended in dry THF (12 ml) under a nitrogen atmosphere. Solid 4-[4-(3-chloro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-N,N-dimethyl-benzamide (described in WO 97/02266, 140 mg, 0.37 mmol) is added and the mixture heated to 60° C. for 1 h. The reaction mixture is then hydrolized at 0° C. by sequential addition of water (0.072 ml), 15% sodium hydroxide (0.072 ml) and water (0.21 ml). The precipitate is removed by filtration and the filtrate concentrated on a rotary evaporator. The yellow crystalline residue is suspended in methanol, filtered, suspended in toluene, filtered, suspended in methanol again and filtered to give the free base of the title compound [Rf (dichloromethane/methanol 9:1 plus 1 drop of conc. ammonia)=0.36]. This is suspended in methanol (2 ml) and treated with 1 N hydrochloric acid (0.2 ml). The suspension is stirred well and filtered. The crystals are triturated in methanol/water 9:1 and filtered again to give the title compound; m.p. 280-283° C.; MS-ES+: (M+H)+=378.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2Cl)(=[O:3])[CH3:2].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][O:23][C:24]1[C:25]([CH3:31])=[CH:26][C:27]([NH2:30])=[CH:28][CH:29]=1>>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2[NH:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=2)=[C:25]([CH3:31])[CH:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2ncnc(Cl)c2c1
Reactant: Cc1cc(N)ccc1OCc1ccccn1
Product: CC(=O)Oc1ccc2ncnc(Nc3ccc(OCc4ccccn4)c(C)c3)c2c1
Yield: 35 %

Procedure:
Using an analogous procedure to that described in Example 1, 6-acetoxy-4-chloroquinazoline was reacted with 5-amino-2-tolyl 2-pyridylmethyl ether to give 6-acetoxy-4-[3-methyl-4-(2-pyridylmethoxy)anilino]quinazoline in 35% yield, m.p. 149°-151° C.;
Reaction SMILES: [CH2:1]([NH:9][C:10](=[O:24])[C@H:11]([CH2:20][CH:21]([CH3:23])[CH3:22])[NH:12][C@@H:13]([C:15]([O:17]CC)=[O:16])[CH3:14])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CC(O)=O>CO.[OH-].[Na+]>[CH2:1]([NH:9][C:10](=[O:24])[C@H:11]([CH2:20][CH:21]([CH3:23])[CH3:22])[NH:12][C@@H:13]([C:15]([OH:17])=[O:16])[CH3:14])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)[C@@H](C)N[C@@H](CC(C)C)C(=O)NCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)C[C@H](N[C@H](C)C(=O)O)C(=O)NCCc1ccccc1
Reaction time: 12 h
Yield: 61.5 %

Procedure:
N[1-(R)-Ethoxycarbonylethyl]-L-Leucine N-phenethylamide (710 mg, 2.1 mM) was dissolved in MeOH (50 ml) and treated with IN NaOH (3 ml, 3 mM) at room temperature. After 12 h, the reaction mixture was acidified with AcOH and evaporated in vacuo to a solid which was washed with H2O and dried to yield the title compound (400 mg); m.p. 201°-205°; (Found: C,66.44; H,8.55; N,9.11; C17H26N2O3 requires C,66.64; H,8.55; N,9.14%); νmax (Nujol) 3330, 1660 and 1530 cm-1 ; δ(d6DMSO) 0.825 (6H,t,J=6.2 Hz, (CH3)2CH), 1.15 (3H,d, J=6.8 Hz, CH3CH), 1.29 (2H,m,CH2CH), 1.55 (1H, heptet,J=7 Hz, CH(CH3)2), 2.71 (2H,t,J=7 Hz, CH2C6H5), 3.0 (1H,q,J=7 Hz, CHCH3), 3.14 (1H,t,J=7 Hz, α--CH), 3.32 (2H,q,J=6 Hz, NHCH2CH2), 7.12 (5H,m,C6H5), 7.5 (2H,br s, OH and CHNHCH) and 8.15 (2H,t,J=5 Hz, NHCH2).
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][N:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([N-]C(C)C)(C)C.[Li+]>C1COCC1.C(O)(=O)C>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][N:3]=[C:2]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:14])[CH3:13]
Reactant: CCn1c(=O)ccc2cnc(F)cc21
Reactant: Nc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCn1c(=O)ccc2cnc(Nc3ccccc3)cc21
Reaction time: 8 h
Yield: 24 %

Procedure:
A stirred solution of (XV, where R2 is ethyl) (100 mg, 0.52 mmol) and aniline (120 mg, 1.3 mmol) in THF (5.0 mL) under nitrogen at -78° C. was treated with a solution (1.2 mL, 1.8 mmol) of lithium diisopropylamide (1.5 M in cyclohexane), then the temperature was allowed to rise slowly to 20° C. overnight. The resulting solution was treated with 3 drops of glacial acetic acid and concentrated to a brown residue that was purified by silica gel chromatography eluting with EtOAc. The product fractions were pooled and concentrated to a solid that was crystallized to give 1-ethyl-7-phenylamino-1H -[1,6]naphthyridin-2-one (33 mg, 24%): mp (8:1 hexanes/dichloromethane) 174-175° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1.Cl[CH2:13][CH:14]=O.C(=O)(O)[O-].[Na+]>O>[CH3:11][O:10][C:4]1[N:3]2[CH:13]=[CH:14][N:1]=[C:2]2[CH:7]=[C:6]([O:8][CH3:9])[N:5]=1
Reactant: COc1cc(N)nc(OC)n1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COc1cc2nccn2c(OC)n1
Temperature: 80 °C

Procedure:
A mixture of 1.5 g (0.01 mole) of 4-amino-2,6-dimethoxypyrimidine and 3.0 g (0.015 mole) of 50% aqueous chloroacetaldehyde in 20 ml of water was heated at 80° C. for one hour, and was then cooled with an ice bath with concomitant neutralization with sodium bicarbonate. The solid which formed was separated by filtration and recrystallized from cyclohexane with treatment with decolorizing charcoal. White crystals of 5,7-dimethoxyimidazo[1,2-c]pyrimidine, m.p. 120°-121° C., were obtained. Analysis: Calculated for C8H9N3O2 : %C,53.6; %H,5.1; %N,23.5; Found: %C,53.5; %H,5.0; %N,23.6. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][O:9]/[N:10]=[C:11](/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)\[C:12](=[NH:16])[N:13]([OH:15])[CH3:14])[CH:5]=[CH:4][CH:3]=1.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>C(#N)C.CCOC(C)=O>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][O:9]/[N:10]=[C:11](/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)\[C:12]2[N:13]([CH3:14])[O:15][C:23](=[O:24])[N:16]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(O)C(=N)/C(=N\OCc1cccc(Br)n1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cn1oc(=O)nc1/C(=N\OCc1cccc(Br)n1)c1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 102.8 %

Procedure:
To a solution of (2Z)-2-{[(6-bromopyridin-2-yl)methoxy]imino}-N-hydroxy-N-methyl-2-phenylethanimidamide (4.0 g, 11 mmol, 1 eq.) in acetonitrile (100 ml), was added 1,1′-carbonyldiimidazole (2.14 g, 13.2 mmol, 1.2 eq.). After stirring at 80° C. for 1 hours and 2 hours at room temperature, the reaction was diluted with EtOAc (500 mL), subsequently washed with H2O (500 mL) and brine. After separation, the organic phase was dried over MgSO4 then concentrated. The residue was purified by chromatography on silica gel to give 3-[(Z)-{[(6-bromopyridin-2-yl)methoxy]imino}(phenyl)methyl]-2-methyl-1,2,4-oxadiazol-5(2H)-one (4.40 g, 95% yield).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[CH:29]=[CH:28][C:9]([CH2:10][N:11]2[C:20]3[C:15](=[CH:16][C:17]([CH3:21])=[CH:18][CH:19]=3)[C:14]([CH:22]([CH3:26])[C:23](O)=[O:24])=[CH:13][C:12]2=[O:27])=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[CH3:5][C:6]1[CH:29]=[CH:28][C:9]([CH2:10][N:11]2[C:20]3[C:15](=[CH:16][C:17]([CH3:21])=[CH:18][CH:19]=3)[C:14]([CH:22]([CH3:26])[C:23]([Cl:3])=[O:24])=[CH:13][C:12]2=[O:27])=[CH:8][CH:7]=1
Reactant: Cc1ccc(Cn2c(=O)cc(C(C)C(=O)O)c3cc(C)ccc32)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(Cn2c(=O)cc(C(C)C(=O)Cl)c3cc(C)ccc32)cc1

Procedure:
Thionyl chloride (0.109 ml.) was added by syringe to a suspension of α-[1-(4-methylbenzyl)-6-methyl-1,2-dihydro-2-oxoquinol-4-yl]propionic acid (0.335 g.) in toluene (3.5 ml.) (dried over sodium wire). The mixture was heated under reflux until evolution of gas ceased, and was then evaporated in vacuo. The residue was mixed with further dry toluene (5 ml.) and then evaporated in vacuo, and dried at ambient temperature under high vacuum, to give α-[1-(4-methylbenzyl)-6-methyl-1,2-dihydro-2-oxoquinol-4-yl]propionyl chloride, which was dissolved without purification in dry toluene (2.5 ml.). The solution thus obtained was added by syringe to a solution of phenol (0.052 g.) in pyridine (0.044 ml.). The mixture was then stirred at ambient temperature for 45 minutes and then at 80° C. for 30 minutes. After being left at ambient temperature overnight, the reaction solution was mixed with ethyl acetate (20 ml.). The solution was then washed successively with 2 N-hydrochloric acid (20 ml.), water (20 ml.), 2 N-sodium hydroxide solution (2×20 l ml.), water (20 ml.) and then saturated sodium chloride solution (20 ml.). The organic phase was separated, dried (MgSO4) and evaporated in vacuo. The residue was recrystallised from cyclohexane to give phenyl α-[1-(4-methylbenzyl)-6-methyl-1,2-dihydro-2-oxoquinol-4-yl]propionate, m.p. 111°-113° C., in 58% yield.
Reaction SMILES: N1C2C(=CC=CC=2)C=C1.[CH2:10]=[CH:11][C@@H:12]1[C@@H:17]2[CH2:18][C@@H:19]([C@H:20]([OH:31])[C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=[CH:23][CH:22]=3)[N:14]([CH2:15][CH2:16]2)[CH2:13]1>>[CH2:10]=[CH:11][C@@H:12]1[C@@H:17]2[CH2:18][C@H:19]([C@@H:20]([OH:31])[C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=[CH:23][CH:22]=3)[N:14]([CH2:15][CH2:16]2)[CH2:13]1
Reactant: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccccc12
Agent: c1ccc2[nH]ccc2c1
Product: C=C[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](O)c1ccnc2ccccc12

Procedure:
Chemical resolution of the 2-carboxyl derivative of 3-phosphoindoles of Formula I/II was performed on 280.82 g of 1 using (−)-Cinchonidine 2 (Scheme 15, to obtain the required enantiomer, first eluting isomer by chiral HPLC analysis) and (+)-Cinchonine 3 (which can be used to remove the undesired enantiomer from the filtrate, second eluting isomer by chiral HPLC analysis).
Reaction SMILES: [CH:1]1([CH:4]([NH:6][C:7]2[C:19]3[C:18]4[CH:17]=[C:16]([F:20])[CH:15]=[CH:14][C:13]=4[NH:12][C:11]=3[C:10]([C:21]#[N:22])=[CH:9][N:8]=2)[CH3:5])[CH2:3][CH2:2]1.C([O-])([O-])=[O:24].[K+].[K+].OO>CS(C)=O>[CH:1]1([CH:4]([NH:6][C:7]2[C:19]3[C:18]4[CH:17]=[C:16]([F:20])[CH:15]=[CH:14][C:13]=4[NH:12][C:11]=3[C:10]([C:21]([NH2:22])=[O:24])=[CH:9][N:8]=2)[CH3:5])[CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: CC(Nc1ncc(C#N)c2[nH]c3ccc(F)cc3c12)C1CC1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CC(Nc1ncc(C(N)=O)c2[nH]c3ccc(F)cc3c12)C1CC1
Temperature: 70 °C

Procedure:
1-[(1-Cyclopropylethyl)amino]-8-fluoro-5H-pyrido[4,3-b]indole-4-carbonitrile (113.9 mg, 0.39 mmol) and K2CO3 (321 mg, 2.32 mmol) was dissolved in DMSO (1.8 ml). Hydrogen peroxide (30%, 0.30 ml, 3.10 mmol) was added and the solution was heated at 70° C. for 3 h. HPLC/MS then showed complete conversion. The solution was cooled to ambient temperature and directly purified by reverse phase HPLC. Desired fractions were combined, diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound. 1H NMR (600 MHz, CD3COCD3) δ11.14 (br s, 1H); 8.61 (s, 1H); 7.95 (dd, 1H); 7.77 (dd, 1H); 7.17 (dt, 1H); 6.16 (d, 1H); 4.10 (m, 1H); 1.42 (d, 3H); 1.26 (m, 1H); 0.52 (m, 1H); 0.45 (m, 2H); 0.31 (m, 1H). LRMS (APCI) calc'd for (C17H18FN4O) [M+H]+, 313.1. found 313.1.
Reaction SMILES: C(OC([NH:8][NH:9][C:10]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][N:16]=[C:15]2[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[O:11])=O)(C)(C)C.Cl.[OH-].[Na+]>O1CCOCC1>[NH2:8][NH:9][C:10]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][N:16]=[C:15]2[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)NNC(=O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: NNC(=O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reaction time: 4 h
Yield: 91.3 %

Procedure:
To a flask containing N-[(tert-butoxy)carbonylamino][3-(4-fluorophenyl)(1H-indazol-5-yl)]carboxamide (230 mg, 0.62 mmol) was added 4 N HCl in dioxane (6 mL). The reaction was allowed to stir for four hours. The reaction was treated with 10% sodium hydroxide solution to make the reaction slightly basic. The solvent was removed and the reaction was diluted with water and extracted with ethyl acetate. The organic layer was dried with magnesium sulfate, filtered and concentrated to yield the title compound (153 mg, 91.6% yield). 1H NMR (DMSO-d6) δ 13.5 (s, 1H), 9.9 (s, 1H), 8.55 (s, 1H), 8.1 (m, 2H), 7.9 (d, 1H), 7.65 (d, 1H), 7.4 (t, 2H), 4.5 (bs, 1H), 3.6 (s, 1H), ES-MS m/z 271 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=1.[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(OCC)(=O)C.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>[F:13][C:14]1[CH:19]=[C:18]([CH:17]=[CH:16][CH:15]=1)[CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)c1cccc(CBr)n1
Reactant: OB(O)c1cccc(F)c1
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: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cccc(Cc2cccc(F)c2)n1
Temperature: 130 °C
Yield: 18.6 %

Procedure:
A mixture of methyl 6-(bromomethyl)picolinate (0.264 g; 1.15 mmol), 3-fluorophenylboronic acid (0.190 g; 1.31 mmol), tetrakis(triphenylphosphine)palladium(0) (0.066 g; 0.057 mmol) and sodium carbonate (0.244 g; 2.30 mmol) in the mixture of water (1 mL) and 1,2-dimethoxyethane (3 mL) was heated at 130° C. in a microwave oven for 20 minutes. The reaction mixture was diluted with ethyl acetate, and washed with water. The organic layer was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (eluent 0 to 6% of ethyl acetate in dichloromethane) to give 0.0524 g (19%) of methyl 6-(3-fluorobenzyl)picolinate as an oily residue.
Reaction SMILES: C(N=C=NCCCN(C)C)C.[O:12]=[C:13]1[C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][CH2:15][N:14]1[CH2:30][C:31](O)=[O:32].Cl.[F:35][C:36]1[CH:37]=[C:38]2[C:42](=[CH:43][CH:44]=1)[CH2:41][NH:40][CH2:39]2>ClCCl>[F:35][C:36]1[CH:37]=[C:38]2[C:42](=[CH:43][CH:44]=1)[CH2:41][N:40]([C:31](=[O:32])[CH2:30][N:14]1[CH2:15][CH2:16][C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:13]1=[O:12])[CH2:39]2
Reactant: Fc1ccc2c(c1)CNC2
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1Cc2ccc(F)cc2C1
Reaction time: 8 h

Procedure:
A solution of N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.067 mL, 0.381 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.075 g, 0.254 mmol) and 5-fluoroisoindoline hydrochloride (0.044 g, 0.254 mmol) in dichloromethane (0.5 mL) was stirred at room temperature. After stirring overnight, the reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.13-7.40 (m, 11H), 6.88-7.05 (m, 2H), 4.75-4.81 (m, 4H), 4.23 (s, 2H), 3.60 (t, J=6.6 Hz, 2H), 2.85 (t, J=6.6 Hz, 2H); MS (ESI+) m/z 415 (M+H)+.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[CH3:8][C:9]1[CH:13]=[CH:12][NH:11][CH:10]=1>C(OCC)C>[Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([C:12]1[NH:11][CH:10]=[C:9]([CH3:8])[CH:13]=1)=[O:4]
Reactant: Cc1cc[nH]c1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCOCC
Product: Cc1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 52.7 %

Procedure:
To a solution of 2,2,2-trichloroacetyl chloride (5.05 mL, 45.3 mmol) in dry diethyl ether (12 mL) was slowly added a solution of 3-methyl-1H-pyrrole (3.15 g, 39.37 mmol) in 30 mL of dry diethyl ether during 1 h 15 min. Once the addition was finished, the reaction mixture was stirred at 45° C. during 1 hour 30 minutes more. Next, more diethyl ether was added and the organic phase was washed with an aqueous solution of potassium carbonate to neutralize de media, water and brine. The organic phase was dried (Na2SO4) and concentrated to dryness to give a residue that was purified by flash chromatography silica (hexane/dichloromethane) to afford 4.7 g of the title compound (55% yield).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=3)=[N:10][C:9]=2[C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[N:29]=[CH:28][CH:27]=[CH:26]3)[CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N:20]4[CH2:4][CH2:3][CH2:2][CH2:1]4)[CH:15]=3)=[N:10][C:9]=2[C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[N:29]=[CH:28][CH:27]=[CH:26]3)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(-c2[nH]c(Cc3cccc([N+](=O)[O-])c3)nc2-c2ccc3ncccc3c2)n1
Agent: [Pd]
Solvent: CO
Product: Cc1cccc(-c2[nH]c(Cc3cccc(N4CCCC4)c3)nc2-c2ccc3ncccc3c2)n1
Reaction time: 5 h
Yield: 91 %

Procedure:
To a solution of 6-(5-(6-methylpyridin-2-yl)-2-(3-nitrobenzyl)-1H-imidazol-4-yl)quinoline (500 mg, 1.186 mmol, prepared according to the method described in US 2008/0319012 A1) in MeOH (5 mL) was added Pd/C (0.5 mg, 10% w/w) and the mixture was stirred under H2 at atmospheric pressure for 5 hours. The reaction mixture was filtered through celite and the filterate was concentrated under reduced pressure. The residue was purified by MPLC on silica gel (MeOH:CH2Cl2=1:50) to afford the 3-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)aniline (424 mg, 91%). The obtained compound, 3-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)aniline (30 mg, 0.077 mmol) was dissolved in DMF (3 mL), treated with 1,4-dibromobutane (17 mg, 0.080 mmol), and stirred at 120° C. for 12 hours. The reaction mixture was cooled to room temperature, added H2O (30 mL), and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by MPLC (MeOH:CH2Cl2=1:20 (v/v)) and on NH silica gel (MeOH:CH2Cl2=1:100 (v/v)) to afford the title compound (7 mg, 20.5%). (300 MHz, CDCl3) δ 2.50 (3H, s), 4.09 (2H, s), 6.64-6.72 (2H, m), 6.91-6.98 (2H, m), 7.31 (1H, d), 7.39 (1H, t), 8.13 (2H, d), 8.41 (1H, s), 8.84 (2H, dd), MS (ESI) m/z 411 (MH+).
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]4[CH2:30][CH2:29][C:27](=[O:28])[NH:26][C:24]=4[CH:25]=3)[CH2:11][CH2:10]2)[C:4]([Cl:8])=[C:5]([Cl:7])[CH:6]=1.[CH2:31]([N:38]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:39](Cl)=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CC1CCCO1>C(OCC)(=O)C.O>[CH2:42]([N:38]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:39](=[O:40])[O:28][C:27]1[CH2:29][CH2:30][C:23]2[C:24](=[CH:25][C:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][N:9]([C:3]4[CH:2]=[CH:1][CH:6]=[C:5]([Cl:7])[C:4]=4[Cl:8])[CH2:10][CH2:11]3)=[CH:21][CH:22]=2)[N:26]=1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: O=C(Cl)N(Cc1ccccc1)Cc1ccccc1
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Solvent: CC1CCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(OC1=Nc2cc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)ccc2CC1)N(Cc1ccccc1)Cc1ccccc1

Procedure:
A mixture of aripiprazole (1.5 g, 3.3 mmol), dibenzylcarbamoyl chloride (1.74 g, 6.7 mmol) silver carbonate (3.75 g, 13.4 mmol) and 2-methyltetrahydrofuran (30 mL) was heated at reflux for 4 days. The reaction mixture was cooled, diluted with ethyl acetate and water, and then filtered through celite. The organic phase was separated, dried over MgSO4 and evaporated. The residue obtained was further purified on silica eluting with ethyl acetate/tetrahydrofuran to give after evaporation of the major product containing fractions, Compound-80 (1.02 g) was a yellow oil.