Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:10]([C@H:11]2[CH2:14][C@H:13]([NH:15]C(=O)OCC3C=CC=CC=3)[CH2:12]2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[O:3]1.Br>C(O)(=O)C>[NH2:15][C@H:13]1[CH2:14][C@H:11]([N:10]2[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[O:3][C:2]2=[O:1])[CH2:12]1
Reactant: O=C(N[C@H]1C[C@H](n2c(=O)oc3cccnc32)C1)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: N[C@H]1C[C@H](n2c(=O)oc3cccnc32)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of benzyl (trans-3-(2-oxooxazolo[4,5-b]pyridin-3(2H)-yl)cyclobutyl)carbamate (0.225 g, 0.666 mmol) in acetic acid (1 mL) was added hydrogen bromide (33 wt. % in acetic acid, 2 ml, 36.8 mmol). The resulting mixture was stirred at room temperature for 1 hour. The mixture was quenched with addition of 1N sodium hydroxide solution and rotovapped and dried by vacuum pump overnight.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([C:17]#[N:18])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:19][NH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][CH2:21][N:20]([CH2:2][CH2:3][C:4]([C:17]#[N:18])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:19])=[CH:28][CH:27]=1
Reactant: CNCCc1ccc(Cl)cc1
Reactant: N#CC(CCBr)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCc1ccc(Cl)cc1)CCC(C#N)(c1ccccc1)c1ccccc1

Procedure:
A mixture containing 3-bromo-1-cyano-1,1-diphenylpropane (0.9 g--see Preparation 4), N-methyl-4-chlorophenethylamine (0.51 g, see CA 61:15224h), anhydrous potassium carbonate (0.83 g) and acetonitrile (40 ml) was heated under reflux for 24 hours then partitioned between dichloromethane (50 ml) and water (50 ml). The dichloromethane layer was dried (Na2SO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with hexane containing dichloromethane (25% up to 40%) and then with dichloromethane containing methanol (0% up to 5%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a gum yield, 0.25 g.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1.N1C=CN=C1.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].O>CN(C)C=O>[Si:30]([O:1][CH2:2][CH2:3][O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@]12CC[C@H](OCCO)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCO[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Yield: 93 %

Procedure:
To a solution of 2.0 g of 3β-(2-hydroxyethoxy)-androst-5-en-17-one (Julia S. et al., Bull. Soc. Chim. France, 1960, 297) in 20 ml of dimethylformamide, 3.5 g of imidazole and 4.0 g of t-butyldimethylsilyl chloride were added at 0° C. After 12 hrs the mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure to give 2.5 g of crude 3β-(2-tert-butyldimethylsilyloxyethoxy)-androst-5-en-17-one.
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[C:27]1([S:33]([N:36]2[CH:47]=[CH:46][C:45]3[C:37]2=[N:38][CH:39]=[C:40]2[C:44]=3[N:43]([CH:48]3[CH2:53][CH2:52][C:51](=O)[CH2:50][CH2:49]3)[N:42]=[N:41]2)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[C:27]1([S:33]([N:36]2[CH:47]=[CH:46][C:45]3[C:37]2=[N:38][CH:39]=[C:40]2[C:44]=3[N:43]([CH:48]3[CH2:53][CH2:52][C:51](=[CH2:2])[CH2:50][CH2:49]3)[N:42]=[N:41]2)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1CCC(n2nnc3cnc4c(ccn4S(=O)(=O)c4ccccc4)c32)CC1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C1CCC(n2nnc3cnc4c(ccn4S(=O)(=O)c4ccccc4)c32)CC1
Reaction time: 1 h
Yield: 50.3 %

Procedure:
To a solution of Methyltriphenylphosphonium iodide (1.0 g, 2.5 mmol) in tetrahydrofuran (10 mL) was added slowly n-butyllithium (2.5 M in diethyl ether, 1 mL, 2.5 mmol) at −78° C., then the reaction mixture was stirred for 1 hour under nitrogen. To the reaction mixture was added 4-(6-Benzenesulfonyl-6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclohexanone (400 mg, 1.01 mmol) slowly, then the reaction mixture was stirred for 3 hours under nitrogen and quenched with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate. The organic phase was concentrated under reduce pressure to give 200 mg (76%) of 6-Benzenesulfonyl-1-(4-methylene-cyclohexyl)-1,6-dihydro-1,2,3,5,6-pentaaza-as-indacene. 1H NMR (400 MHz, DMSO-d6): δ: 9.18 (s, 1H), 8.15-8.12 (m, 3H), 7.72-7.68 (m, 1H), 7.63-7.59 (m, 2H), 7.44-7.43 (m, 1H), 5.22 (s, 1H), 4.76 (s, 2H), 2.49-2.41 (m, 4H), 2.26-2.23 (m, 2H), 2.05-2.02 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH2:11][CH2:12][CH:13]=O)=[CH:8][CH:9]=2)[CH2:4][O:3]1.[OH:15][CH:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1>>[OH:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:13][CH2:12][CH2:11][C:7]2[N:6]=[C:5]3[CH2:4][O:3][C:2](=[O:1])[C:10]3=[CH:9][CH:8]=2)[CH2:17]1
Reactant: OC1CCCNC1
Reactant: O=CCCc1ccc2c(n1)COC2=O
Product: O=C1OCc2nc(CCCN3CCCC(O)C3)ccc21
Yield: 74.2 %

Procedure:
In a process similar to that described in Preparation 8, 3-(5-Oxo-5,7-dihydro-furo[3,4-b]pyridin-2-yl)-propionaldehyde (76 mg, 0.4 mmol) and 3-hydroxypiperidine (41 mg, 0.4 mmol) are reacted to provide the title compound as a white solid (82 mg, 74%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[F:13][C:14]([F:25])([F:24])[O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.C(O)(C(F)(F)F)=O>>[F:13][C:14]([F:24])([F:25])[O:15][C:16]1[CH:17]=[CH:18][C:19]([CH:20]2[C:5]3[NH:6][C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:4]=3[CH2:3][CH2:2][NH:1]2)=[CH:22][CH:23]=1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: NCCc1c[nH]c2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)Oc1ccc(C2NCCc3c2[nH]c2ccccc32)cc1
Yield: 38.5 %

Procedure:
This product was prepared using the same procedure as for Intermediate 1 with tryptamine (2.0 g, 12.5 mmol), 4-trifluoromethoxybenzaidehyde (2.4 g, 1 equiv.) and TFA (1.9 mL, 2 equiv.) to give the title compound (1.6 g, 38%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:5]2[N:6]=[C:7]([NH:16][NH2:17])[CH:8]=[C:9]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:4]2[N:3]=1.C(O)(=O)C.[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O>C(O)C>[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=[N:17][NH:16][C:7]1[CH:8]=[C:9]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[N:4]2[N:3]=[C:2]([CH3:1])[CH:18]=[C:5]2[N:6]=1
Reactant: Cc1cc2nc(NN)cc(N3CCOCC3)n2n1
Reactant: Cc1cccc(C=O)c1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cccc(C=NNc2cc(N3CCOCC3)n3nc(C)cc3n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
There was dissolved, in ethanol (2 mL), (2-methyl-7-morpholin-4-yl-pyrazolo-[1,5-a]pyrimidin-5-yl)-hydrazine (24.7 mg, 0.0995 mM), then acetic acid (5.0 μL, 0.087 mM) and 3-methyl-benzaldehyde (12.9 μL, 0.109 mM) were added to the solution and the resulting mixture was stirred at room temperature for 2 hours. This reaction liquid was filtered and the resulting solid was washed with methanol to thus give the title compound (29.6 mg, yield: 85%).
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2].[NH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:24])[CH3:23]>CCO>[C:22]([NH:21][CH2:20][CH2:19][NH:18][C:8]1[CH:9]=[CH:10][C:5]([C:4]([N:3]([CH2:16][CH3:17])[CH2:1][CH3:2])=[O:15])=[CH:6][C:7]=1[N+:12]([O-:14])=[O:13])(=[O:24])[CH3:23]
Reactant: CCN(CC)C(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(=O)NCCN
Solvent: CCO
Product: CCN(CC)C(=O)c1ccc(NCCNC(C)=O)c([N+](=O)[O-])c1
Temperature: 90 °C
Yield: 62.3 %

Procedure:
Following general procedure 2B: A mixture of N,N-diethyl-4-fluoro-3-nitrobenzamide (0.200 g, 0.833 mmol), N-(2-aminoethyl)acetamide (0.077 g, 0.757 mmol) in 80% aq. EtOH (5 mL) was heated at 90° C. overnight. After work-up, the crude product was purified by silica gel column chromatography (100% EtOAc to 5% MeOH/EtOAc) to provide the title compound (0.152 g, 63%) as a bright yellow solid. 1H-NMR (CDCl3): δ 8.27 (d overlapping with br s, J=2.0 Hz, 2H), 7.55 (dd, J=8.4 Hz, J=2.0 Hz, 1H), 6.99 (d, J=9.2 Hz, 1H), 6.06 (br s, 1H), 3.58–3.50 (m, 4H), 3.44 (br s, 4H), 2.02 (s, 3H), 1.22 (t, J=7.2 Hz, 6H). MS (ESI) (M+H)+=323.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]3[S:26][C:25]4[CH:27]=[CH:28][S:29][C:24]=4[CH:23]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:30]([O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][C:45](Cl)=[O:46])=[CH:40][CH:39]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:30]([O:37][C:38]1[CH:39]=[CH:40][C:41]([CH2:44][C:45]([NH:21][C:18]2[C:17]([C:22]3[S:26][C:25]4[CH:27]=[CH:28][S:29][C:24]=4[CH:23]=3)=[N:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])=[CH:14][CH:13]=3)=[CH:20][N:19]=2)=[O:46])=[CH:42][CH:43]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(-c3cc4sccc4s3)n2)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2-c2cc3sccc3s2)cc1
Temperature: 50 °C
Reaction time: 13 h
Yield: 58.2 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-(thieno[3,2-b]thiophen-2-yl)pyrazin-2-amine (7k) (250 mg, 569 μmol) and 4-(dimethylamino)pyridine (12.3 mg, 101 μmol) dissolved in anhydrous pyridine (15 mL) was added 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was heated with stirring at 50° C. for 13 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (100 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 30 g, n-hexane/ethyl acetate=3/1) to give Compound 11k (228 mg, 331 μmol, 58.2%) as a yellow solid. R=0.26 (n-hexane/ethyl acetate=3/1); 1H NMR (400 MHz, DMSO-d6) δ 0.17 (s, 6H), 0.22 (s, 6H), 0.93 (s, 9H), 0.95 (s, 9H), 3.67 (s, 2H), 6.78-6.86 (AA′BB′, 2H), 6.96-7.04 (AA′BB′, 2H), 7.20-7.30 (AA′BB′, 2H), 7.41 (d, 1H, J=5.2 Hz), 7.57 (s, 1H), 7.73 (d, 1H, J=5.2 Hz), 8.04-8.13 (AA′BB′, 2H), 8.92 (s, 1H), 10.69 (s, 1H); IR (KBr, cm−1) 527, 635, 702, 779, 837, 918, 1007, 1074, 1169, 1256, 1362, 1445, 1508, 1603, 1655, 2857, 2886, 2928, 2955, 3211.
Reaction SMILES: [H-].[Na+].CN([C:6]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[C:7]([C:10]1[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=1)[CH:8]=O)C.[C:25]([CH2:27][C:28]([NH2:30])=[O:29])#[N:26].P([O-])(O)(O)=O.[Na+]>CN(C)C=O.CO>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:6]2[NH:30][C:28](=[O:29])[C:27]([C:25]#[N:26])=[CH:8][C:7]=2[C:10]2[CH:11]=[CH:12][C:13]([S:16][CH3:17])=[CH:14][CH:15]=2)=[CH:19][CH:20]=1
Reactant: N#CCC(N)=O
Reactant: CSc1ccc(C(C=O)=C(c2ccc(F)cc2)N(C)C)cc1
Agent: O=P([O-])(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CSc1ccc(-c2cc(C#N)c(=O)[nH]c2-c2ccc(F)cc2)cc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
To 1.45 g of 60% dispersion of sodium hydride in mineral oil (containing 869 mg, 36.2 mMol), washed once with hexane, in 20 ml of dry dimethylformamide, was added dropwise a solution of 9.42 g (29.9 mMol) of 1-(N,N-dimethylamino)-1-(4-fluorophenyl)-2-(4-methylthiophenyl)prop-1-en-3-one from Step 4, cyanoacetamide (2.59 g, 30.3 mMol), and 2.9 ml of methanol in 50 ml of dimethylformamide. After the addition was complete, the resulting dark solution was stirred overnight at 70-80° C. After cooling, the mixture was added in portions to 500 ml of 1M aqueous sodium dihydrogen phosphate, producing a yellow solid. The solid was filtered, washed with water, and dried to give 9.24 g of 1,2-dihydro-6-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-2-oxo-pyridine-3-carbonitrile.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[CH:10]=[C:11]3[C:18](=[O:19])[NH:17][CH2:16][CH:15]([CH3:20])[N:12]3[C:13]=2[CH:14]=1)=[O:5])C.[OH-].[Na+]>C1COCC1.CCO>[CH3:20][CH:15]1[N:12]2[C:13]3[CH:14]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[CH:8][C:9]=3[CH:10]=[C:11]2[C:18](=[O:19])[NH:17][CH2:16]1
Reactant: CCOC(=O)c1ccc2cc3n(c2c1)C(C)CNC3=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1CNC(=O)c2cc3ccc(C(=O)O)cc3n21
Temperature: 75 °C
Yield: 77 %

Procedure:
To a suspension of ethyl ester from step d above (3.2 g, 11.75 mmol) in 100 mL of THF/EtOH (1:1 v/v) was added 1 N aq NaOH (43 mL, 43 mmol). The reaction mixture became a clear solution upon addition of 1 N NaOH. The clear solution was heated at 75° C. for 2 h. The reaction was concentrated and the crude residue was dissolved in water, and extracted with ether. The aqueous layer was acidified to pH ˜4 with 3 N HCl (˜16 mL). A large amount of white precipitate formed which was filtered off and rinsed with cold ether. The wet product was dried in the vacum oven (50° C.) to provide 2.2 g of 4-Methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-7-carboxylic acid, yield 77% for two steps.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][CH:17]2[CH2:26][C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:19][CH2:18]2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:28]([O:32][C:33]([N:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[C:36]1[CH2:44]Cl)=[O:34])([CH3:31])([CH3:30])[CH3:29].CCN(C(C)C)C(C)C>CC#N>[C:28]([O:32][C:33]([N:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[C:36]1[CH2:44][N:16]([CH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:27])=[CH:10][CH:11]=1)[CH:17]1[CH2:26][C:25]2[N:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:19][CH2:18]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)NCc1ccc(CNC2CCc3cccnc3C2)cc1
Reactant: CC(C)(C)OC(=O)n1c(CCl)nc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCc1ccc(CN(Cc2nc3ccccc3n2C(=O)OC(C)(C)C)C2CCc3cccnc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
{4-[(5,6,7,8-Tetrahydro-quinolin-7-ylamino)-methyl]-benzyl}-carbamic acid tert-butyl ester (88 mg, 0.24 mmol), 2-Chloromethyl-benzimidazole-1-carboxylic acid tert-butyl ester (80 mg, 0.30 mmol), DIPEA (0.10 mL, 0.54 mmol), and KI (19 mg, 0.11 mmol) were heated to 80° C. in CH3CN (1.5 mL) for 2 h under N2, then it was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate, washed with NH4Cl (aq), NaCl (aq), and dried (MgSO4). Evaporation of the solvent and purification of the residue by flash chromatography on silica gel (1:1:98 CH3OH—NH3 H2O—CH2Cl2) afforded the title compound (80 mg, 56%) as a white foam.
Reaction SMILES: I[C:2]1[C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:21][CH3:22])[N:12]=[CH:11][CH:10]=[C:9]2[O:8][C:7]1[C:2]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[O:25][CH3:24])=[N:3][C:4]([CH3:23])=[CH:5][CH:6]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: COc1ccccc1B(O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3ccccc3OC)c2cc1OC
Temperature: 80 °C
Reaction time: 3 h
Yield: 28.7 %

Procedure:
4-(2-Iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxyquinoline (compound 116) (84 mg), 2-methoxyphenylboronic acid (152 mg), and tetrakistriphenylphosphine palladium (12 mg) were disssolved in toluene (1 ml) to prepare a solution. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was added to the solution, and the mixture was stirred at 80° C. for 3 hr. The reaction solution was filtered, the solvent was then removed by distillation under the reduced pressure, and the residue was purified by column chromatography using methanol-chloroform to give the title compound (23 mg, yield 29%).
Reaction SMILES: [CH:1]([O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON1C([C:38](=[O:58])[CH:39]=[CH:40][C:41]2[CH:46]=[C:45]([O:47][CH3:48])[C:44]([O:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH3:55])=[C:43]([O:56][CH3:57])[CH:42]=2)(OCOCCOC)C(OC)SC1=S>O1CCCC1>[CH3:48][O:47][C:45]1[CH:46]=[C:41]([CH:40]=[CH:39][C:38]([N:21]2[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH2:15][O:14][CH:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:19][CH2:20]2)=[O:58])[CH:42]=[C:43]([O:56][CH3:57])[C:44]=1[O:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH3:55]
Reactant: COCCOCOc1c(OC)cc(C=CC(=O)C2(OCOCCOC)C(OC)SC(=S)N2OC)cc1OC
Reactant: c1ccc(C(OCCCN2CCNCC2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCOCOc1c(OC)cc(C=CC(=O)N2CCN(CCCOC(c3ccccc3)c3ccccc3)CC2)cc1OC

Procedure:
To a solution of 160 mg (0.52 mmol) of N-(3-benzhydroxypropyl) piperazine in dry tetrahydrofuran (5 ml) was added a solution of 206 mg (0.5 mmol) of N-[3-(3,5-dimethoxy-4-(β-methoxyethoxymethoxy) (3,5-dimethoxy-4(β-methoxyethoxymethoxy) phenyl-2-propenoyl]thiazolidine-2-thione in dry tetrahydrofuran, and the mixture was allowed to react at room temperature overnitht. The reaction mixture was concentrated by evaporation under reduced pressure, diluted with chloroform and washed, in turn, with 2N aqueous solution of sodium hydroxide and water. The organic layer was dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with chloroform - methanol (50 : 1), to give 270 mg (0.45 mmol) of N-[3-[3,5-dimethoxy-4-(β-methoxyethoxymethoxy) phenyl]-2-propenoyl]-N'-(3-benzhydroxypropyl)piperazine.
Reaction SMILES: [Na].[N:2](=[C:4]([C:10]#[N:11])[C:5](OCC)=[O:6])[OH:3].Cl.[CH2:13]([O:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([NH2:28])=[NH:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>CO>[NH2:11][C:10]1[N:27]=[C:26]([C:25]2[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=2[O:23][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[NH:28][C:5](=[O:6])[C:4]=1[N:2]=[O:3]
Reactant: CCCCCCCCCCOc1ccccc1C(=N)N
Reactant: CCOC(=O)C(C#N)=NO
Agent: Cl
Agent: [Na]
Solvent: CO
Product: CCCCCCCCCCOc1ccccc1-c1nc(N)c(N=O)c(=O)[nH]1
Reaction time: 4 h

Procedure:
Sodium (7.35 g.) was dissolved in anhydrous methanol (130 ml.), treated with ethyl α-oximinocyanoacetate (11.4 g.) and 2-decyloxybenzamidine hydrochloride (25 g.) and heated to reflux, with stirring, for 4 hours. The mixture was allowed to stand at room temperature overnight and the solid which separated was filtered off, washed with water and dried at 75° C. to give the crude sodium salt of 4-amino-2-(2-decyloxyphenyl)-5-nitrosopyrimid-6-one, pure enough for use in the next stage of the preparation. An aliquot was treated with dilute acetic acid and the solid obtained recrystallised from dilute acetic acid and then from methanol to give pure 4-amino-2-(2-decyloxyphenyl)-5-nitrosopyrimid-6-one, m.p. 144°-146° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:4]([F:13])[C:3]=1[OH:14].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:25])=[C:20]([N:22]=[C:23]=S)[CH:21]=1>CO>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:25])=[C:20]([NH:22][C:23]2[O:14][C:3]3[C:4]([F:13])=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=3[N:1]=2)[CH:21]=1
Reactant: Cc1ccc(Cl)cc1N=C=S
Reactant: COC(=O)Cc1ccc(N)c(O)c1F
Solvent: CO
Product: COC(=O)Cc1ccc2nc(Nc3cc(Cl)ccc3C)oc2c1F
Temperature: 25 °C
Reaction time: 120 h
Yield: 104.6 %

Procedure:
In methanol (30 ml) was dissolved methyl (4-amino-2-fluoro-3-hydroxyphenyl)acetate (1.0 g, 5.02 mmol). To the resulting solution was added 5-chloro-2-methylphenyl isothiocyanate (0.674 ml, 4.58 mmol). After the mixture was stirred at room temperature for 5 days, mercuric oxide (yellow) (1.14 g, 4.36 mmol) was added thereto. The resulting mixture was stirred at 70° C. for 6 hours. After cooling to room temperature, the reaction mixture was filtered through Celite and washed with methanol. The filtrate was distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from chloroform/ethyl acetate (30/1, v/v) eluate fractions, methyl (2-(5-chloro-2-methylphenylamino)-7-fluoro-6-benzoxazolyl)acetate (1.67 g, 100%) was obtained as a brown solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[C:6](O)=[O:7].S(Cl)([Cl:25])=O>ClC(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[C:6]([Cl:25])=[O:7]
Reactant: O=C(O)C(CCCBr)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C(Cl)C(CCCBr)(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
To a stirred solution of 29.5 parts of α-(3-bromopropyl)-4-fluoro-α-(4-fluorophenyl)benzeneacetic acid in 300 parts of trichloromethane were added 28.8 parts of thionyl chloride and the whole was stirred and refluxed for 3 hours. The reaction mixture was evaporated, yielding 30 parts of α-(3-bromopropyl)-4-fluoro-α-(4-fluorophenyl)-benzeneacetyl chloride as a residue.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.Cl.[N:16]1([CH2:22][CH2:23][C:24]2[N:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]3=[C:26]([C:33](Cl)=[O:34])[N:25]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(Cl)Cl>[N:2]1([NH:1][C:33]([C:26]2[N:25]=[C:24]([CH2:23][CH2:22][N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[N:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=23)=[O:34])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: NN1CCCCC1
Reactant: O=C(Cl)c1nc(CCN2CCOCC2)n2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NN1CCCCC1)c1nc(CCN2CCOCC2)n2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.2 %

Procedure:
To a solution of 1-aminopiperidine (0.060 mL, 0.54 mmol) and triethylamine (0.16 mL, 1.14 mmol) in CH2Cl2 (10 mL) was added 3-(2-morpholin-4-yl-ethyl)-imidazo[1,5-a]pyridine-1-carbonyl chloride hydrochloride (150 mg, 0.45 mmol). The mixture was stirred at ambient temperature for 1 h. then washed with sat. aq. NaHCO3 (20 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica to yield the title compound (55 mg, 34%). 1H NMR (DMSO-d6) δ 8.59 (1H), 8.35 (1H), 8.02 (1H), 7.08 (1H), 6.82 (1H), 3.57 (4H), 3.18 (2H), 2.80 (4H), 2.75 (2H), 2.44 (4H), 1.60 (4H), 1.38 (2H); m/z (M+H)=385.31.