Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH:18]([OH:22])[CH2:17]3)=[CH:11][CH:10]=2)[C:7](=[O:23])[C:6]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:41][C:40](=[O:42])[O:39][N:38]=3)=[CH:27][CH:26]=2)=[C:5]([CH2:43][CH2:44][CH3:45])[N:4]=1)[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>ClCCl.C(OCC)(=O)C>[CH2:1]([C:3]1[N:8]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][C:18](=[O:22])[CH2:17]3)=[CH:13][CH:14]=2)[C:7](=[O:23])[C:6]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:41][C:40](=[O:42])[O:39][N:38]=3)=[CH:27][CH:26]=2)=[C:5]([CH2:43][CH2:44][CH3:45])[N:4]=1)[CH3:2]
Reactant: CCCc1nc(CC)n(-c2ccc(OC3CCCC(O)C3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)n(-c2ccc(OC3CCCC(=O)C3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 1 h
Yield: 76.3 %

Procedure:
2-Ethyl-3-{4-[(3-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one (0.5 g) and 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.52 g) were dissolved in dichloromethane (5 mL) and the mixture was stirred for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.38 g, 76%) as a colorless amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)[CH:3]=1.[CH:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].C1(=O)CCCCC1>C(O)(=O)C>[NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)[C:3]=1[C:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1.[CH:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: Cn1nc([C@H]2CCCN2)cc1N
Agent: O=COCc1ccccc1
Solvent: CC(=O)O
Solvent: O=C1CCCCC1
Product: Cn1nc([C@H]2CCCN2)c(C2=CCCCC2)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 149.4 %

Procedure:
To a 500 mL of reaction flask were added the compound of Example 4C (47.86 g, 159.32 mmol), cyclohexanone (31.27 g, 318.64 mmol) and acetic acid (300 mL). The mixture was heated to 50° C. to 60° C. under nitrogen atmosphere. The reaction was kept overnight. The reaction was stopped and cooled to room temperature. Acetic acid was rotary-evaporated to obtain a crude product. The crude product was separated by column chromatography to give 45.53 g of the title compound as white solid. Yield: 75.1%. MS (ESI): m/z 381 (M+H)+
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][C:11]([C:13]2[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=2)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].FC(F)(F)C([O-])=O.Cl[C:28]1[C:29]2[CH2:36][CH2:35][CH2:34][C:30]=2[N:31]=[CH:32][N:33]=1.Cl.C[O-].[Na+].CO>C(Cl)(Cl)Cl>[N:31]1[C:30]2[CH2:34][CH2:35][CH2:36][C:29]=2[C:28]([NH:17][C:16]2[CH:15]=[CH:14][C:13]([C:11](=[O:12])[CH2:10][CH:7]3[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]3)=[CH:19][CH:18]=2)=[N:33][CH:32]=1
Reactant: CC(=O)N1CCC(CC(=O)c2ccc(N)cc2)CC1
Reactant: Clc1ncnc2c1CCC2
Agent: C[O-]
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(=O)N1CCC(CC(=O)c2ccc(Nc3ncnc4c3CCC4)cc2)CC1
Yield: 90.5 %

Procedure:
To 50 ml of chloroform were added 6.63 g of 4-[(1-acetylpiperidin-4-yl)acetyl]aniline·trifluoroacetate and 3.01 g of 4-chloro-5,6-dihydro-7H-cyclopenta[d]pyrimidine, and after adding 10 ml of a chloroform solution of hydrochloric acid (containing 0.6 g of hydrochloric acid), the mixture was reacted under reflux for 3 hours. After the reaction, a 28% sodium methylate-methanol solution was added to the reaction mixture under cooling to make it alkaline. After removing solid material, the filtrate was condensed under reduced pressure and the obtained residue was applied to silica gel column chromatography to obtain 6.08 g of the title compound as yellowish white powder.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:21][CH:22]1[C:31]2[CH:30]=[C:29]([C:32]([O:34][CH3:35])=[O:33])[CH:28]=[CH:27][C:26]=2[CH2:25][CH2:24][CH2:23]1>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH2:17][NH:21][CH:22]3[C:31]4[CH:30]=[C:29]([C:32]([O:34][CH3:35])=[O:33])[CH:28]=[CH:27][C:26]=4[CH2:25][CH2:24][CH2:23]3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)c1ccc2c(c1)C(N)CCC2
Reactant: CCCCc1ccc(C#Cc2ccc(C=O)cc2)cc1
Product: CCCCc1ccc(C#Cc2ccc(CNC3CCCc4ccc(C(=O)OC)cc43)cc2)cc1

Procedure:
The titled compound was prepared following the procedure L using 4-[(4-butylphenyl)ethynyl]benzaldehyde and methyl 8-amino-5,6,7,8-tetrahydronaphthalene-2-carboxylate as a yellow oil (95%). 1H NMR (CDCl3, 300 MHz) δ 7.96 (d, J=1.7 Hz, 1H), 7.72 (dd, J=7.9, 1.7 Hz, 1H), 7.29-7.42 (m, 5H), 7.17 (d, J=2.8 Hz, 1H), 7.07 (m, 3H), 3.82 (m, 5H), 3.75 (m, 1H), 2.67-2.82 (m, 2H), 2.50 (m, 2H), 1.92 (m, 1H), 1.82 (m, 2H), 1.62 (m, 1H), 1.51 (m, 2H), 1.28 (m, 2H), 0.83 (m, 3H). M+ (ESI): 452.2. HPLC, Rt: 4.37 min (Purity: 60.1%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][N:3]=1.[OH:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.[H-].[Na+]>CN(C)C=O>[F:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([O:9][CH2:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH:7]=1
Reactant: Fc1ccnc(Cl)c1
Reactant: N#Cc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(COc2cc(F)ccn2)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 81.6 %

Procedure:
To an N,N-dimethylformamide (15 mL) solution of 2-chloro-4-fluoropyridine (2.88 g, 21.9 mmol) and 4-(hydroxymethyl)benzonitrile (4.37 g, 32.9 mmol) was added sodium hydride (1.29 g, 32.9 mmol, 60% in oil) at room temperature. This mixture was stirred for 4 hours at 70° C. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1-2:1) to obtain the title compound (4.08 g, 82%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]([CH2:18][C:19]([OH:21])=O)[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:36]([NH2:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1CCCC1>[C:37]1([CH2:36][NH:43][C:19](=[O:21])[CH2:18][N:17]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[C:9]2[C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:23])([F:22])[F:1])=[CH:4][CH:5]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(O)Cn1c(-c2ccc(C(F)(F)F)cc2)nc2cccnc21
Reactant: NCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2ccc(C(F)(F)F)cc2)nc2cccnc21)NCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 2-(4-trifluoromethylphenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.21 g, 0.010 mole), 1,1'-carbonyldiimidazole (1.62 g, 0.010 mole), and anhydrous tetrahydrofuran (75 ml) was stirred at room temperature with a stream of nitrogen bubbling through for 3 hours. The nitrogen flow was stopped and a solution of benzylamine (1.39 g, 0.013 mole) in dry tetrahydrofuran (25 ml) was added. The solution was stirred at room temperature under nitrogen for 1 hour. The reaction mixture was concentrated in vacuo and the residue triturated in potassium bicarbonate solution (50 ml) and filtered. The filter cake was washed with water and recrystallized from isopropyl alcohol-isopropyl ether, giving 2.8 g (68%). Recrystallization from isopropyl alcohol-isopropyl ether gave 2.3 g of white flakes, mp 224°-225° C.
Reaction SMILES: [O:1]=[C:2]1[CH:18](C(OC)=O)[C:17](=[O:23])[C:5]2([CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][CH2:6]2)[CH2:4][NH:3]1>C(#N)C.O>[O:1]=[C:2]1[CH2:18][C:17](=[O:23])[C:5]2([CH2:9][N:8]([C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH2:7][CH2:6]2)[CH2:4][NH:3]1
Reactant: COC(=O)C1C(=O)NCC2(CCN(C(=O)OC(C)(C)C)C2)C1=O
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CNC(=O)CC2=O)C1
Yield: 66.7 %

Procedure:
A solution of D5 (1.90 mmol, 0.62 g) in 40 mL acetonitrile/water (1/1) was refluxed for 5 hours. The reaction mixture was evaporated in vacuo. The crude product was purified by flash silicagel chromatography (DCM/MeOH=95/5) yielding 0.34 g of a yellow oil (66%). 1H-NMR (400 MHz, CDCl3, 300K): δ=1.46 (9H, s), 1.88 (1H, m), 2.26 (1H, m), 3.50 (8H, m), 6.70 (1H, br d, 34.8 Hz); MS (ES) C13H20N2O4 requires: 268. found: 269.4 [M+H]+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:5]([CH3:22])=[C:6]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15](=[O:21])[CH2:14][CH2:13]3)[CH:7]=[N:8][CH:9]=1.[CH3:23][C:24]1[C:28]([C:29](O)=[O:30])=[C:27]([CH3:32])[O:26][N:25]=1>>[CH3:22][C:5]1[C:6]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15](=[O:21])[CH2:14][CH2:13]3)=[CH:7][N:8]=[CH:9][C:4]=1[CH2:3][NH:2][C:29]([C:28]1[C:24]([CH3:23])=[N:25][O:26][C:27]=1[CH3:32])=[O:30]
Reactant: Cc1noc(C)c1C(=O)O
Reactant: Cc1c(CN)cncc1-c1ccc2c(c1)CCC(=O)N2C
Agent: Cl
Product: Cc1noc(C)c1C(=O)NCc1cncc(-c2ccc3c(c2)CCC(=O)N3C)c1C

Procedure:
In analogy to the procedure described for the preparation of example 219, 6-(5-aminomethyl-4-methyl-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-quinolin-2-one hydrochloride (example 222) has been coupled with 3,5-dimethyl-isoxazole-4-carboxylic acid to give the title compound as an off-white solid. MS: 405.5 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:15]Br>>[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:15][N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]([CH2:15][C:14]2[CH:17]=[CH:18][C:19]([F:20])=[C:12]([F:11])[CH:13]=2)[C:2]1=[NH:1]
Reactant: Nc1nc2ccccc2[nH]1
Reactant: Fc1ccc(CBr)cc1F
Product: N=c1n(Cc2ccc(F)c(F)c2)c2ccccc2n1Cc1ccc(F)c(F)c1

Procedure:
The title compound was prepared from 2-aminobenzimidazole and 3,4-difluorobenzyl bromide by Procedure A. The product was isolated by preparative LCMS to give the title compound as the free base (white solid, mp 114-117° C.). MS(ES+) m/z 387 ([M+1]+, 100). 1NMR (DMSO-d6) δ 5.08 (br s, 4H), 5.86 (br s, 1H), 6.72-6.96 (m, 4H), 7.05-7.22 (m, 2H), 7.35-7.45 (m, 4H).
Reaction SMILES: I[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])[C:5]2=[N:4][CH:3]=1)=[CH:11][C:10]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([F:29])([F:28])[F:27])=[CH:9][CH:8]=3.[NH:30]1[C:34](B(O)O)=[CH:33][CH:32]=[N:31]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd](Cl)Cl>[NH:30]1[C:34]([C:2]2[N:6]3[C:7]4[C:12]([N:13]=[C:14]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])[C:5]3=[N:4][CH:3]=2)=[CH:11][C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:27])[F:28])=[CH:9][CH:8]=4)=[CH:33][CH:32]=[N:31]1
Reactant: OB(O)c1ccn[nH]1
Reactant: OCCCNc1nc2cc(-c3ccccc3C(F)(F)F)ccc2n2c(I)cnc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: OCCCNc1nc2cc(-c3ccccc3C(F)(F)F)ccc2n2c(-c3ccn[nH]3)cnc12
Yield: 40.2 %

Procedure:
A solution of 3-({1-iodo-7-[2-(trifluoromethyl)phenyl]imidazo[1,2-a]quinoxalin-4-yl}amino)propan-1-ol (42 mg; 0.082 mmol; 1 eq), 1,1′bis(diphenylphosphino) ferrocene)palladium dichloride. dichloromethane complex (20.1 mg; 0.025 mmol; 0.3 eq), 1H-pyrazole-5-boronic acid (18.3 mg; 0.164 mmol; 2 eq) and sodium carbonate (26 mg; 0.246 mmol; 3 eq) in anhydrous dimethylformamide (0.37 ml) is stirred under argon at 100° C. for 4 h. Partition (aqueous sodium hydrogenocarbonate/ethyl acetate), filtration over Celite, extraction of the aqueous phase (ethyl acetate), reunion of the organic phases, drying (magnesium sulphate) and purification by prep CCM on silicagel (dichloromethane/methanol 95:5) affords the title product (15 mg; 0.033 mmol; 39%) as an off-white solid.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1>C(Cl)Cl.C(N(CC)CC)C>[CH3:5][O:4][C:2](=[O:3])[N:16]([C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH3:6])[CH:8]=[CH:9]2)[C:17]1[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=1
Reactant: COC(=O)Cl
Reactant: Cn1ccc2cc(Nc3ccncc3)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N(c1ccncc1)c1ccc2c(ccn2C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
A solution of methyl chloroformate (1.3 g) in 5 ml DCM was added to a solution of 1-methyl-5-(4-pyridinylamino)-1H-indole (2.5 g) in 120 ml DCM and 6 ml triethylamine (4.4 g). After stirring one hour at ambient temperature the reaction mixture was washed with water and saturated sodium chloride, dried (anhydrous magnesium sulfate), filtered and evaporated to 4 g of a solid. Elution through silica with 50% ethyl acetate in dichloromethane via flash column chromatography yielded 3.1 g of a solid. Recrystallization from methanol yielded 2.4 g of crystals, mp 157°-159° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.Cl.[NH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][C:16](O)=[O:17]>>[ClH:1].[NH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][C:16]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:17]
Reactant: NCC(=O)CCC(=O)O
Reactant: OCc1ccc(Cl)cc1
Agent: Cl
Product: NCC(=O)CCC(=O)OCc1ccc(Cl)cc1
Reaction time: 24 h

Procedure:
From 4-chlorobenzyl alcohol (5.0 g; 35 mmol) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol). The reaction was complete after 24 h at 100° C. The yield was 0.56 g (32%). Mp 127-129° C.
Reaction SMILES: [CH2:1]([N:3]([CH3:25])[C:4]1[N:24]=[C:7]2[CH:8]=[C:9]([NH:12][C:13]([C:15]3[N:19]([CH3:20])[N:18]=[CH:17][C:16]=3[C:21]([OH:23])=O)=[O:14])[CH:10]=[CH:11][N:6]2[N:5]=1)[CH3:2].[NH:26]1[CH2:29][CH2:28][CH2:27]1.CCCP(=O)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:1]([N:3]([CH3:25])[C:4]1[N:24]=[C:7]2[CH:8]=[C:9]([NH:12][C:13]([C:15]3[N:19]([CH3:20])[N:18]=[CH:17][C:16]=3[C:21]([N:26]3[CH2:29][CH2:28][CH2:27]3)=[O:23])=[O:14])[CH:10]=[CH:11][N:6]2[N:5]=1)[CH3:2]
Reactant: C1CNC1
Reactant: CCN(C)c1nc2cc(NC(=O)c3c(C(=O)O)cnn3C)ccn2n1
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCN(C)c1nc2cc(NC(=O)c3c(C(=O)N4CCC4)cnn3C)ccn2n1
Yield: 94.2 %

Procedure:
A mixture of 5-(2-(ethyl(methyl)amino)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (144 mg, 419 μmol), azetidine (84.8 μl, 1.26 mmol), propylphosphonic anhydride (50% in ethyl acetate, 618 μl, 1.05 mmol) and N,N-diisopropylethylamine (214 μl, 1.26 mmol) in tetrahydrofuran (7 ml) was refluxed for 2.5 days (weekend). The solvent was evaporated, the residue was triturated with sodium hydrogencarbonate solution. The precipitated solid was filtered off, washed with water and dried affording 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid [2-(ethyl-methylamino)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (151 mg white solid, 94.1%) as a white solid. mp: 229-232° C., MS: m/z=383.1 (M+H+)
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:28][CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>>[C:34]([Si:31]([CH3:33])([CH3:32])[O:30][CH2:29][CH2:28][N:22]1[CH2:21][CH2:20][N:16]2[C:17]3[CH:18]=[CH:19][C:11]([O:10][CH:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[CH:12][C:13]=3[CH:14]=[C:15]2[C:23]1=[O:24])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(CCO[Si](C)(C)C(C)(C)C)C2=O)CC1
Yield: 52 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and (2-bromoethoxy)-tert-butyldimethylsilane, to give the desired product as a white solid (52%).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([C:28]1[CH:33]=[CH:32][C:31]([CH:34]2[CH2:39][CH2:38][CH:37]([CH:40]3[CH2:45][CH2:44][CH:43]([CH:46]=O)[CH2:42][CH2:41]3)[CH2:36][CH2:35]2)=[CH:30][CH:29]=1)[CH2:26][CH3:27]>ClCCl>[Br:2][C:1]([Br:5])=[CH:46][CH:43]1[CH2:42][CH2:41][CH:40]([CH:37]2[CH2:38][CH2:39][CH:34]([C:31]3[CH:30]=[CH:29][C:28]([CH2:25][CH2:26][CH3:27])=[CH:33][CH:32]=3)[CH2:35][CH2:36]2)[CH2:45][CH2:44]1
Reactant: BrC(Br)(Br)Br
Reactant: CCCc1ccc(C2CCC(C3CCC(C=O)CC3)CC2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCc1ccc(C2CCC(C3CCC(C=C(Br)Br)CC3)CC2)cc1
Reaction time: 0.5 h

Procedure:
34.0 g (0.10 mol) of carbon tetrabromide are initially introduced in 120 ml of dichloromethane, and 53.7 g (0.21 mol) of triphenylphosphine are added in portions. When the addition is complete, the mixture is stirred for 30 min, and a suspension of 16.0 g (51.2 mmol) of 4′-(4-propylphenyl)bicyclohexyl-4-carbaldehyde in 45 ml of dichloromethane is slowly added. The mixture is stirred for 22 h, and the precipitate is filtered off. The filtrate is concentrated to completion, and the residue is purified by column chromatography (SiO2, n-heptane). 4-(2,2-Dibromovinyl)-4′-(4-propylphenyl)bicyclohexyl is obtained as a colourless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH2:12]([C:14]1[N:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17])C>>[CH3:12][C:14]1[N:22]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:20]=[CH:19][C:15]=1[C:16]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)=[O:17]
Reactant: CCc1nc(C(F)(F)F)ccc1C(=O)O
Reactant: Nc1ccc2cccnc2c1
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc2cccnc2c1

Procedure:
Using the procedure outlined in Example 45, the title compound was prepared from 7-aminoquinoline (D55) (30 mg, 21 mmol) and 2-ethyl -6-trifluoromethylnicotinic acid (51 mg, 0.25 mmol) as a yellow solid. MS(ES): MH+ 332, M-H+ 330
Reaction SMILES: [C:1]1([CH:7]([CH2:11][O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)CCl.[NH2:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[CH:34]=[N:33][CH:32]=[CH:31]2>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH:34]1[C:35]2[C:30](=[CH:29][C:28]([NH:27][C:8](=[O:9])[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:11][O:12][Si:13]([CH:17]([CH3:19])[CH3:18])([CH:20]([CH3:22])[CH3:21])[CH:14]([CH3:15])[CH3:16])=[CH:37][CH:36]=2)[CH:31]=[CH:32][N:33]=1
Reactant: CC(C)[Si](OCC(C(=O)O)c1ccccc1)(C(C)C)C(C)C
Reactant: Nc1ccc2cnccc2c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(C)[Si](OCC(C(=O)Nc1ccc2cnccc2c1)c1ccccc1)(C(C)C)C(C)C
Reaction time: 8 h

Procedure:
To 2-phenyl-3-(triisopropylsilyloxy)propanoic acid (E400) in pyridine was added EDC, DMAP, and 6-aminoisoquinoline, and the solution was flushed with N2, capped, and stirred overnight. The mixture was poured into NaHCO3(sat) and extracted with EtOAC. The combined organics were dried (Na2SO4), filtered, and evaporated. Column chromatography (3-4% MeOH/CH2Cl2) gave pure N-(isoquinolin-6-yl)-2-phenyl-3-(triisopropylsilyloxy)propanamide (E401).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][C:6](=[O:8])[CH:5]=[CH:4][CH2:3]1.[N+:10]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1)([O-:12])=[O:11].C(C1C(O[SiH](C)C)=C(Br)C(OC)=CC=1CC1C(=O)C=CCC1(C)C)(C)(C)C>>[N+:10]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17][CH:7]2[C:6](=[O:8])[CH:5]=[CH:4][CH2:3][C:2]2([CH3:9])[CH3:1])=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: CC1(C)CC=CC(=O)C1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: COc1cc(CC2C(=O)C=CCC2(C)C)c(C(C)(C)C)c(O[SiH](C)C)c1Br
Product: CC1(C)CC=CC(=O)C1Cc1ccc([N+](=O)[O-])cc1

Procedure:
This compound was prepared from 5,5-dimethylcyclohex-2-en-1-one (11) (0.600 g, 4.83 mmol) and p-nitrobenzyl bromide (1.581 g, 7.32 mmol) in the manner previously described for the synthesis of enone 13, affording 627 mg (50%), of the nitro-enone as a pale yellow oil. 1H NMR (400MHz, CDCl3) δ1.02 and 1.18 (2s, 2×3H, geminal-CH3 's), 2.83 and 3.10 (d of ABq, 2H, benzylic-CH2), 6.00 (ddd, 1H, 2-H), 6.81 (ddd, 1H, 3-H), 7.38 and 8.10 ppm (ABq, 2×2H, Ar--H).
Reaction SMILES: C([O:3][C:4]([O:6]/[N:7]=[C:8](/[NH2:42])\[C:9]1[CH:14]=[C:13]([C:15]2[N:20]3[CH:21]=[C:22](/[CH:24]=[CH:25]/[C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)[N:23]=[C:19]3[C:18]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[N:17][CH:16]=2)[CH:12]=[N:11][CH:10]=1)=O)C.C1CCN2C(=NCCC2)CC1>C(#N)C>[O:39]1[CH2:38][CH2:37][N:36]([C:18]2[C:19]3[N:20]([CH:21]=[C:22](/[CH:24]=[CH:25]/[C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)[N:23]=3)[C:15]([C:13]3[CH:14]=[C:9]([C:8]4[N:42]=[C:4]([OH:3])[O:6][N:7]=4)[CH:10]=[N:11][CH:12]=3)=[CH:16][N:17]=2)[CH2:41][CH2:40]1
Reactant: CCOC(=O)O/N=C(/N)c1cncc(-c2cnc(N3CCOCC3)c3nc(/C=C/c4ccc5ccccc5n4)cn23)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Oc1nc(-c2cncc(-c3cnc(N4CCOCC4)c4nc(/C=C/c5ccc6ccccc6n5)cn34)c2)no1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
Compound 77a (26.5 mg, 0.469 mmol) was placed in an 8 mL vial equipped with a stir bar. ACN (1 mL) and DBU (0.358 μL, 0.00235 mmol) were added. The reaction was stirred at 100° C. for 18 h and then cooled to rt. The precipitate was collected by filtration and then the solid was washed with ACN (2×5 mL). The residual solvent was removed under reduced pressure to afford the title compound 28. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 9.06 (d, J=2.0 Hz, 1H), 8.85 (d, J=2.0 Hz, 1H), 8.32-8.37 (m, 2H), 8.27 (s, 1H), 7.97 (d, J=8.6 Hz, 1H), 7.94 (d, J=7.6 Hz, 1H), 7.87 (d, J=3.5 Hz, 1H), 7.90 (d, J=4.0 Hz, 1H), 7.75 (t, J=7.1 Hz, 1H), 7.66 (d, J=16.2 Hz, 1H), 7.56 (t, J=7.3 Hz, 1H), 7.52 (s, 1H), 4.29-4.39 (m, 4H), 3.81-3.87 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C28H22N8O3: 519.2 (M+H). found: 519.3.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH2:14][C:15]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([CH:24]([CH3:31])[CH2:25][C:26]([O:28]CC)=[O:27])=[N:22][CH:23]=2)=[O:16])[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])(=O)C.[OH-].[Na+]>CO.O>[OH:4][C:5]1[CH:6]=[C:7]([CH2:14][C:15]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([CH:24]([CH3:31])[CH2:25][C:26]([OH:28])=[O:27])=[N:22][CH:23]=2)=[O:16])[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: CCOC(=O)CC(C)c1ccc(NC(=O)Cc2ccc([N+](=O)[O-])c(OC(C)=O)c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(CC(=O)O)c1ccc(NC(=O)Cc2ccc([N+](=O)[O-])c(O)c2)cn1
Temperature: 50 °C
Yield: 40.6 %

Procedure:
A solution of (RS) ethyl 3-{5-[2-(3-acetoxy-4-nitrophenyl)-acetylamino]-pyridin-2-yl}-butanoate (6.18 g, Reference Example 27) in methanol (100 mL) was treated with a solution of sodium hydroxide (3.5 g) in water (20 mL). The mixture was heated at 50° C. for 5 hours and then evaporated. The residue was dissolved in water and the resulting solution was washed with ethyl acetate, then acidified to pH 5 by addition of glacial acetic acid and then extracted with ethyl acetate. The extracts were washed with water, then dried over magnesium sulphate and then evaporated. The residual dark oil was subjected to flash chromatography on silica eluting with ethyl acetate to give the title compound (2.1 g) as a brown solid.