Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([CH2:14][C:15]2[C:20]([Cl:21])=[CH:19][N:18]=[CH:17][C:16]=2[Cl:22])=[N:4][N:3]=1.N1CCCCC1.[C:29]1([C:35]#[CH:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH4+].[Cl-]>CN(C=O)C.Cl[Pd]Cl.[Cu]I>[Cl:22][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Cl:21])[C:15]=1[CH2:14][C:5]1[C:6]2[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[C:2]([C:36]#[C:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:3][N:4]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(C#Cc3ccccc3)c2c1
Reaction time: 20 h
Yield: 65 %

Procedure:
A solution of 4-chloro-1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazine (0.52 g, 1.5 mmoles), prepared as described in example 45, in dry DMF (10 ml) under N2 was added with piperidine (1 ml, 10 mmoles), phenylacetylene (0.15 g, 1.5 mmoles), PdCl2 (0.013 g, 0.075 mmole), triphenylphosphine (0.039 g, 0.15 mmole) and CuI (0.014 g, 0.075 mmole). The mixture was stirred for 20 hours, poured into saturated NH4Cl (10 volumes) and extracted twice with CH2Cl2, then washed with 5% HCl, anhydrified and concentrated to give a solid which was flash chromatographed (eluent: CH2Cl2/ethyl ether 9:1). The resultant solid was triturated in ethyl ether to give 0.41 g of the title compound (yield: 52%). m.p.: 213.4-214.4° C. (dec.).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[C:9]([OH:13])(=[O:12])[CH2:10][CH3:11].C([O-])(=O)CC.[K+]>[Mn+3]>[CH3:11][CH:10]1[CH2:1][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[O:13][C:9]1=[O:12]
Reactant: C=CCCCCCC
Reactant: CCC(=O)O
Agent: [Mn+3]
Agent: CCC(=O)[O-]
Agent: [K+]
Product: CCCCCCC1CC(C)C(=O)O1

Procedure:
Octene-1 in an amount of 2.24 g. and 11.65 g. of manganic acetate, Mn(C2H3O2)3. 2H2O, (comprising two equivalents of Mn+3 based on titration value), were refluxed under nitrogen in 200 ml. propionic acid containing 20 g. potassium propionate. In less than an hour a good yield of alphamethyl-gamma-n-hexyl-butyrolactone was obtained.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=1[CH3:17].C(O[C:21](=[NH:23])[CH3:22])C.[C:24]([OH:27])(=[O:26])[CH3:25]>C(#N)C>[C:24]([OH:27])(=[O:26])[CH3:25].[NH:23]=[CH:21][CH2:22][NH:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=1[CH3:17]
Reactant: CCOC(C)=N
Reactant: COc1cc(C)c(-c2c(C)n[nH]c2N)c(C)c1
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1cc(C)c(-c2c(C)n[nH]c2NCC=N)c(C)c1
Reaction time: 8 h

Procedure:
To a solution of 5-amino-4-(4-methoxy-2,6-dimethylphenyl)-3-methylpyrazole (1.89 g) in acetonitrile (30 mL) add ethylacetimidate (free base, 1.8 mL) followed by acetic acid (0.47 mL). Collect the precipitate that formed upon stirring overnight by filtration. Wash the solid with dry ether and dry to afford 2.61 g of (iminoethyl)[4-(4-methoxy-2,6-dimethylphenyl)-3-methylpyrazol-5-yl]amine acetate salt as a white powder.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:30]#[N:31])=[C:18]([O:19][CH:20]4[CH2:25][CH2:24][N:23]([CH2:26][CH:27]([F:29])[F:28])[CH2:22][CH2:21]4)[C:13]=3[C:12]3[CH:32]=[C:33](Br)[CH:34]=[N:35][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].ClCCl>[C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:30]#[N:31])=[C:18]([O:19][CH:20]4[CH2:21][CH2:22][N:23]([CH2:26][CH:27]([F:28])[F:29])[CH2:24][CH2:25]4)[C:13]=3[C:12]3[CH:32]=[CH:33][CH:34]=[N:35][C:11]2=3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1ncc2c(c1OC1CCN(CC(F)F)CC1)c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Agent: [Pd]
Solvent: ClCCl
Product: N#Cc1ncc2c(c1OC1CCN(CC(F)F)CC1)c1cccnc1n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 31.6 %

Procedure:
A suspension of 9-benzenesulfonyl-3-bromo-5-[1-(2,2-difluoroethyl)-piperidin-4-yloxy]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (240 mg, 0.42 mmol) and palladium on carbon (10 wt %, 50 mg) in industrial methylated spirits (5 mL) and dichloromethane (5 mL) was stirred at ambient temperature under an atmosphere of hydrogen for 5 days. The reaction vessel was purged with nitrogen then the reaction mixture was filtered through a PTFE filter cup. The filtrate was evaporated in-vacuo and the resultant residue purified by flash chromatography (silica, 10 g column, ISCO, 0-2% methanol in dichloromethane) to afford the title compound as an off-white solid (66 mg, 32%). LCMS (Method B): RT=3.74 min, M+H+=518.
Reaction SMILES: Cl.[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:10][NH:9]1)=[O:7])#[N:3].[CH:22]1([C:28](O)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:14])=[O:15])[CH2:10][N:9]1[C:28]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:29])=[O:7])#[N:3]
Reactant: O=C(O)C1CCCCC1
Reactant: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)CN1
Agent: Cl
Product: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)CN1C(=O)C1CCCCC1

Procedure:
L2. (2S,4R)-4-Benzenesulfonyl-pyrrolidine-2-carboxylic acid cyanomethyl-amide hydrochloride prepared in analogy to experiment K1 was coupled with cyclohexanecarboxylic acid in analogy to experiment A1 to give (2S,4R)-4-benzenesulfonyl-1-cyclohexanecarbonyl-pyrrolidine-2-carboxylic acid cyanomethyl-amide as a white solid. MS: 404.3 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:25][CH2:26][CH2:27][C:28]#[N:29])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:24])=[CH:10][CH:9]=2)=[O:5])C.CO.[OH-].[Na+]>O1CCCC1>[C:28]([CH2:27][CH2:26][CH2:25][N:7]1[C:8]2[C:13](=[CH:12][C:11]([O:15][CH2:16][C:17]3[C:18]([Cl:24])=[CH:19][CH:20]=[CH:21][C:22]=3[Cl:23])=[CH:10][CH:9]=2)[CH:14]=[C:6]1[C:4]([OH:5])=[O:3])#[N:29]
Reactant: CCOC(=O)c1cc2cc(OCc3c(Cl)cccc3Cl)ccc2n1CCCC#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: N#CCCCn1c(C(=O)O)cc2cc(OCc3c(Cl)cccc3Cl)ccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1-(3-Cyanopropyl)-5-(2,6-dichlorobenzyloxy)-1H-indole-2-carboxylic acid ethyl ester (1.89 g, 4.38 mmol), from Example 1(c), was dissolved in tetrahydrofuran (5 mL). Methanol (5 mL) and 1.0 N NaOH (5 mL) were added and the reaction mixture was stirred at ambient temperature for 12 h. The tetrahydrofuran and methanol were removed under reduced pressure and water (10 mL) was added. The solution was acidified to pH 2 with 10% aqueous HCl solution. The product precipitated as a white solid (1.52 g, 86%) and was collected through vaccuum filtration. (MS(ES) m/e 403.0 [M +H]+.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([C:13]([OH:15])=O)[CH:10]1[CH2:12][CH2:11]1)=[O:7])([CH3:4])[CH3:3].Cl.[NH:17]1[CH2:20][CH:19]([C:21]#[N:22])[CH2:18]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:2]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH:10]1[CH2:11][CH2:12]1)[C:13]([N:17]1[CH2:20][CH:19]([C:21]#[N:22])[CH2:18]1)=[O:15])([CH3:1])([CH3:3])[CH3:4]
Reactant: N#CC1CNC1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CC(C#N)C1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
In a round-bottomed flask Boc-D-cyclopropylglycine (500 mg, 2.32 mmol) and azetidine-3-carbonitrile hydrochloride (441 mg, 3.72 mmol) were dissolved in DMF (10 ml). N,N-Diisopropylethylamine (1.2 ml, 6.87 mmol) was added followed by HATU (972 mg, 2.56 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was triturated with petroleum ether to afford 384 mg (59%) of [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-carbamic acid tert-butyl ester as an off-white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:9]([CH2:10][CH3:11])=[N:8][C:7]2[N:12]([CH2:15][CH3:16])[N:13]=[CH:14][C:6]=2[C:5]=1[NH:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[CH2:24]([CH:28]([C:32](O)=[O:33])[C:29]([OH:31])=[O:30])[CH2:25][CH2:26][CH3:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[CH2:15]([N:12]1[C:7]2=[N:8][C:9]([CH2:10][CH3:11])=[C:4]([CH2:3][NH:2][C:32]([CH:28]([CH2:24][CH2:25][CH2:26][CH3:27])[C:29]([OH:31])=[O:30])=[O:33])[C:5]([NH:17][CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[C:6]2[CH:14]=[N:13]1)[CH3:16]
Reactant: CCCCC(C(=O)O)C(=O)O
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(C(=O)O)C(=O)NCc1c(CC)nc2c(cnn2CC)c1NC1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine hydrochloride (400 mg, 1.18 mmol), 2-butylmalonic acid (200 mg, 1.24 mmol), HBTU (535 mg, 1.41 mmol) and Et3N (0.82 mL, 5.89 mmol) in DCM (8 mL) was stirred at room temperature for 30 min. It was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with water followed by a brine wash. The organic layer was dried over sodium sulfate, filtered, concentrated and purified with purified with a Gilson HPLC (with 0.1% TFA condition) eluting with 10 to 70% CH3CN in water at a flowrate of 20 mL/min. The fractions were dried with EZ GeneVac to give 2-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]hexanoic acid. LC-MS m/z 446 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>C(OCCO)C>[NH:10]([C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1)[NH2:11]
Reactant: NN
Reactant: Cc1ccc(Cl)nc1
Solvent: CCOCCO
Solvent: O
Product: Cc1ccc(NN)nc1

Procedure:
1.0 g (7.8 mmol) 2-chloro-5-methylpyridine are stirred under reflux in 5.7 ml (5.9 g, 117.6 mmol) hydrazine hydrate for 12 h. 10 ml ethylene glycol monoethyl ether are added to the cooled reaction mixture and the solvent is then removed completely on a rotary evaporator. This working step is repeated twice, methylene chloride is then added to the residue, the precipitate is filtered off, the filtrate is concentrated in vacuo and the residue is dried in vacuo.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[N:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)=[CH:16][N:15]=2)[CH2:9][CH2:8]1>[Cl-].[Zn+2].[Cl-].[Na].CO>[CH:1]1([N:7]2[CH2:8][CH2:9][CH:10]([O:13][C:14]3[N:15]=[CH:16][C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=4)=[CH:18][N:19]=3)[CH2:11][CH2:12]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCC1
Reactant: N#Cc1ccc(-c2cnc(OC3CCNCC3)nc2)cc1
Agent: [Cl-]
Agent: [Na]
Agent: [Zn+2]
Solvent: CO
Product: N#Cc1ccc(-c2cnc(OC3CCN(C4CCCC4)CC3)nc2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 89.7 %

Procedure:
Cyclopentanone (0.022 mol) and 0.3 N zinc chloride-sodium borocyanide solution (0.55 ml) were added to a methanol solution (3.0 ml) of 2-(piperidin-4-yloxy)-5-(4-cyanophenyl)pyrimidine (46 mg, 0.16 mmol), and stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with chloroform. The organic layer was washed with saturated saline solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified through partitioning thin-layer chromatography (chloroform:methanol=10:1) to obtain the entitled compound (50 mg, 87%).
Reaction SMILES: [NH3:1].Cl[C:3]1[N:12]2[N:13]=[C:14]([CH:16]3[CH2:20][CH2:19][CH2:18][O:17]3)[N:15]=[C:11]2[C:10]2[CH:9]=[C:8]([Cl:21])[CH:7]=[CH:6][C:5]=2[N:4]=1>[OH-].[NH4+]>[Cl:21][C:8]1[CH:7]=[CH:6][C:5]2[NH:4][C:3](=[NH:1])[N:12]3[N:13]=[C:14]([CH:16]4[CH2:20][CH2:19][CH2:18][O:17]4)[N:15]=[C:11]3[C:10]=2[CH:9]=1
Reactant: Clc1ccc2nc(Cl)n3nc(C4CCCO4)nc3c2c1
Reactant: N
Agent: [NH4+]
Agent: [OH-]
Product: N=c1[nH]c2ccc(Cl)cc2c2nc(C3CCCO3)nn12

Procedure:
Concentrated aqueous ammonium hydroxide (50 ml) in a stainless steel pressure vessel is saturated with gaseous ammonia at 0° and 5,9-dichloro-2-(2-tetrahydrofuryl)[1,2,4]triazolo[1,5-c]-quinazoline (1.22 g) added. The mixture is heated over six hours at an outside temperature of 150°, cooled and filtered. The precipitate is washed with water and dried under high vacuum to afford pure 9-chloro-5-imino-2-(2-tetrahydrofuryl)-5,6-dihydro-[1,2,4]triazolo[1,5-c]-quinazoline (0.45 g), mp 203°-206°. The starting material is prepared as follows:
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:36]([NH2:39])[CH2:37][CH3:38]>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:39][CH2:36][CH2:37][CH3:38])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Reactant: CCCN
Product: CCCNCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1

Procedure:
Method as for preparation 5 using tert-butyl (3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (500 mg, 1.00 mmol) and propylamine (175 mg, 3.00 mmol) as starting materials.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[NH:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21](OCC)=[O:22])[CH:14]=2)[CH:7]=1.[NH:29]([CH2:33][CH2:34][OH:35])[CH2:30][CH2:31][OH:32].O>C(O)C>[OH:32][CH2:31][CH2:30][N:29]([CH2:33][CH2:34][OH:35])[C:21]([CH2:20][O:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[NH:12][C:8]1[CH:7]=[C:6]([NH:5][C:4]2[CH:26]=[CH:27][CH:28]=[C:2]([CH3:1])[CH:3]=2)[N:11]=[CH:10][N:9]=1)=[O:22]
Reactant: CCOC(=O)COc1cccc(Nc2cc(Nc3cccc(C)c3)ncn2)c1
Reactant: OCCNCCO
Solvent: O
Solvent: CCO
Product: Cc1cccc(Nc2cc(Nc3cccc(OCC(=O)N(CCO)CCO)c3)ncn2)c1
Yield: 39 %

Procedure:
A mixture of 6-(3'-methylanilino)-4-[3'-(ethoxycarbonylmethoxy) anilino]pyrimidine (0.10 g) and diethanolamine (0.06 g) in ethanol (7 ml) was heated at reflux for 72 hours. The mixture was cooled and water (20 ml) added. The ethanol was evaporated and the solid filtered off to give 4-(3'-{N,N-di-(2-hydroxyethyl)carbamoylmethoxy}anilino]6-(3'-methylanilino)pyrimidine in 39% yield, m.p. 112°-113° C.;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=O)=[CH:5][C:4]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].O.ON1C2C=CC=CC=2N=N1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.CCN=C=NCCCN(C)C.Cl.C(=O)([O-])O.[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH2:15]([O:14][C:4]1[CH:5]=[C:6](/[CH:7]=[CH:8]/[C:9]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[O:11])[CH:12]=[CH:13][C:3]=1[O:2][CH3:1])[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCOc1cc(C=CC(=O)O)ccc1OC
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCOc1cc(/C=C/C(=O)N2CCOCC2)ccc1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 39.3 %

Procedure:
4-Methoxy-3-pentyloxycinnamic acid (500 mg, 2.62 mmol, 1 eq) and 1-hydroxybenzotriazole hydrate (371 mg, 2.75 mmol, 1.05 eq) were dissolved in DMF (5 ml), and to this solution were successively added morpholine (684 mg, 7.85 mmol, 3.0 eq) and WSC hydrochloride (526 mg, 2.75 mmol, 1.05 eq) under ice-cooling. The mixture was stirred at room temperature for 12 hours. Ice water (5 ml) and a saturated aqueous sodium hydrogencarbonate solution (5 ml) were successively added to this reaction mixture. The mixture was exracted twice with ethyl acetate (20 ml). The organic layers were combined, washed with saturated brine (40 ml) and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=1/2) to give (E)-3-(3-pentyloxy-4-methoxyphenyl)-1-morpholin-4-yl-prop-2-en-1-one (343 mg, 49.8%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([NH2:20])[C:14]3=[C:13](Br)[N:12]=2)[CH2:7][CH2:6]1)=[O:4].[O:22]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O.O.[F-].[K+]>COCCOC.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>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([NH2:20])[C:14]3=[C:13]([C:32]3[CH:33]=[CH:34][C:29]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:30][CH:31]=3)[N:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)[C@H]1CC[C@H](c2nc(Br)c3c(N)nccn32)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)[C@H]1CC[C@H](c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)nccn32)CC1
Temperature: 100 °C

Procedure:
To a stirred mixture of trans-4-(8-amino-1-bromo-imidazo[1,5-a]pyrazin-3-yl)-cyclohexanecarboxylic acid methyl ester (2.00 g, 5.66 mmol) and 4-phenoxyphenylboronic acid (1.454 g, 6.7 mmol) in DME (25.00 mL) and H2O (8.3 mL) was added potassium fluoride dihydrate (1.865 g, 19.82 mmol). The mixture was bubbled with nitrogen for 5 min before Pd(PPh3)4 (330 mg, 0.28 mmol) was added to. The resulting mixture was refluxed overnight at 100° C. Solvent was removed under reduced pressure and the product was purified by flash chromatography (2% MeOH in DCM). 1H NMR (400 MHz, CD3OD) δ 1.59-1.87 (m, 4H), 2.02-2.18 (m, 4H), 2.41-2.53 (m, 1H), 3.09-3.19 (m, 1H), 3.68 (s, 3H), 6.94-7.20 (m, 6H), 7.32-7.44 (m, 2H), 7.52-7.63 (m, 3H). MS (ES+): m/z: 442.97 [MH+]. HPLC: tR=2.48 min (OpenLynx: polar—5 min).
Reaction SMILES: II.Br[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][C:12]1([CH2:16][CH3:17])[CH2:15][O:14][CH2:13]1.[Br:18][C:19]1[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=1.[NH4+].[Cl-]>CC(N(C)C)=O.[Zn].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].C1COCC1>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][C:12]2([CH2:16][CH3:17])[CH2:15][O:14][CH2:13]2)=[CH:21][CH:20]=1
Reactant: Brc1ccc(I)cc1
Reactant: CCC1(COCCCCCCBr)COC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: II
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: CCC1(COCCCCCCc2ccc(Br)cc2)COC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40.9 %

Procedure:
To a mixture of zinc powder (1.80 g, 27.5 mmol) in anhydrous DMA (20 ml) is added iodine (0.5 g, 1.97 mmol). This mixture is stirred until the red color of iodine disappeared (ca. 2 min), followed by the addition of 3-(6-bromohexyloxymethyl)-3-ethyloxetane (5.0 g, 17.9 mmol) and the resultant mixture is stirred at 85° C. for 4.5 h, then cooled to room temperature. In another flask charged with anhydrous THF (30 ml) is added 1-bromo-4-iodobenzene (7.0 g, 24.74 mmol) and Pd(dppf)Cl2 (0.5 g, 0.61 mmol). This mixture is stirred for 10 min, then the organic zinc reagent above is introduced. The reaction mixture is stirred overnight (˜16 h) at room temperature. Sat. aq. NH4Cl solution is added and the mixture is extracted with ethyl acetate (3×70 ml). The extracts are dried (Na2SO4) and evaporated under reduced pressure. The residue is purified by column chromatography on silica, eluting with petrol/ethyl acetate (10:0 to 4:1), to give a brown oil (2.6 g, 41%). 1H NMR (300 MHz, CDCl3): δ(ppm) 7.35 (d, J=8.4 Hz, 2H, Ar—H), 7.01 (d, J=8.4 Hz, 2H, Ar—H), 4.43 (d, J=5.7 Hz, 2H, OCH2), 4.34 (d, J=5.7 Hz, 2H, OCH2), 3.48 (s, 2H, OCH2), 3.41 (t, J=6.4 Hz, 2H, OCH2), 2.53 (t, J=7.9 Hz, 2H, ArCH2), 1.72 (q, J=7.6 Hz, 2H, CH2), 1.56 (m, 4H, CH2), 1.34 (m, 4H, CH2); 0.86 (t, J=7.6 Hz 3H, CH3); 13C NMR (75 MHz, CDCl3): δ (ppm) 141.6 (quat.), 131.2 (CH), 130.2 (CH), 119.3 (quat.), 78.4 (OCH2), 73.4 (OCH2), 71.4 (OCH2), 43.4 (quat.), 35.3 (CH2), 31.3 (CH2), 29.5 (CH2), 29.0 (CH2), 26.8 (CH2), 26.0 (CH2), 8.2 (CH3).
Reaction SMILES: CS(Cl)(=O)=O.O[CH2:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([N:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]1=[O:26])[CH:13]=[CH:12]2.C(N(CC)CC)C.S([O-])(=O)(=O)C.[CH3:39][C@@H:40]1[CH2:44][CH2:43][CH2:42][NH:41]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.O1CCOCC1>C1COCC1.C(#N)C.CCOCC>[CH3:25][C:22]1[CH:23]=[CH:24][N:19]([C:14]2[CH:13]=[CH:12][C:11]3[C:16](=[CH:17][CH:18]=[C:9]([CH2:8][CH2:7][N:41]4[CH2:42][CH2:43][CH2:44][C@H:40]4[CH3:39])[CH:10]=3)[CH:15]=2)[C:20](=[O:26])[CH:21]=1
Reactant: Cc1ccn(-c2ccc3cc(CCO)ccc3c2)c(=O)c1
Reactant: C[C@@H]1CCCN1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: Cl
Solvent: CCOCC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccn(-c2ccc3cc(CCN4CCC[C@H]4C)ccc3c2)c(=O)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 17.2 %

Procedure:
Methanesulfonyl chloride (0.03 mL, 0.301 mmol, 1.2 equiv.) was added dropwise via a syringe to a stirred, 0° C. solution of 1-[6-(2-hydroxy-ethyl)-naphthalen-2-yl]-4-methyl-1H-pyridin-2-one (Example 82A, 70 mg, 0.251 mmol) in anhydrous THF (10 mL) under a dry nitrogen atmosphere. Triethylamine (1.0 mL, 7.175 mmol, 28.6 equiv.) was then added. After two hours of stirring at 0° C., the reaction mixture was concentrated under reduced pressure. The residue was partitioned between EtOAc and saturated aqueous Na2CO3. The organic extract was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure. This crude mesylate (˜89 mg, 0.249 mmol), (2R)-2-methylpyrrolidine (64 mg, 0.747 mmol, 3.0 equiv.), and cesium carbonate (81 mg, 0.249 mmol) in anhydrous acetonitrile (5 mL) were stirred in a sealed tube at 50° C. for 18 hours. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous Na2CO3. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (97:3:trace dichloromethane/methanol/NH4OH). Fractions containing product were combined and concentrated under reduced pressure to provide the free base. This free base was dissolved in Et2O and the solution was treated with HCl-dioxane to precipitate the hydrochloride salt of the title compound (15 mg, 16% yield). 1H NMR (CD3OD, 300 MHz) δ 8.00 (d, J=9 Hz, 1H), 7.98 (d, J=9 Hz, 1H), 7.93-7.89 (m, 2H), 7.62 (d, J=7 Hz, 1H), 7.56 (dd, J=2, 9 Hz, 1H), 7.51 (dd, J=2, 9 Hz, 1H), 6.52 (br s, 1H), 6.45 (dd, J=2, 7 Hz, 1H), 3.83-3.68 (m, 2H), 3.61-3.49 (m, 1H), 3.43-3.17 (m, 4H), 2.43-2.30 (m, 1H), 2.33 (s, 3H), 2.24-1.99 (m, 2H), 1.83-1.69 (m, 1H), 1.49 (d, J=6 Hz, 3H). MS (DCl-NH3) [M+H]+ at 347.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH2:3]1.[C:10](OC(=O)C)(=[O:12])[CH3:11].OS(O)(=O)=O>>[C:10]([N:7]1[CH:2]([CH3:1])[CH2:3][C:4](=[O:9])[NH:5][C:6]1=[O:8])(=[O:12])[CH3:11]
Reactant: CC1CC(=O)NC(=O)N1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)N1C(=O)NC(=O)CC1C

Procedure:
In the manner described above, 65 gm (0.5 mol) of 6-methyl-5,6-dihydrouracil were reacted with 8 mols of acetic acid anhydride in the presence of 2 ml of H2SO4. The product recrystallized from isopropanol had a melting point of 107° C to 109° C and the following analysis values: