Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Mg].C(O[CH2:21][C:22]([F:36])=[CH:23][C:24]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH3:35])=[CH:29][CH:28]=1)([CH3:26])[CH3:25])(=O)C>O1CCCC1>[CH2:34]([O:33][C:30]1[CH:31]=[CH:32][C:27]([C:24]([CH3:25])([CH3:26])[CH:23]=[C:22]([F:36])[CH2:21][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:4]=2)=[CH:28][CH:29]=1)[CH3:35]
Reactant: Fc1ccc(Br)cc1Oc1ccccc1
Reactant: CCOc1ccc(C(C)(C)C=C(F)COC(C)=O)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOc1ccc(C(C)(C)C=C(F)Cc2ccc(F)c(Oc3ccccc3)c2)cc1
Yield: 20.6 %

Procedure:
The method of Example 16 was repeated using a Grignard reagent, prepared from 4-fluoro-3-phenoxyphenyl bromide (0.28 g), tetrahydrofuran (2 ml) and magnesium (20 mg), and 4-(4-ethoxyphenyl)-2-fluoro-4-methylpent-2-enyl acetate (Example 14) (60 mg). The residue after evaporation was purified by preparative thin layer chromatography (solvent: diethyl ether/hexane; 1:9) and then preparative high performance liquid chromatography (column: C18: solvent: 5% water in methanol; flow rate: 3 ml/min) to give the title compound (18 mg, 20%).
Reaction SMILES: O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Br:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1.[NH2:18][CH2:19][C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1C(OC(C)(C)C)=O.C(N(CC)C(=O)C1C(=CC=CC=1)O)C.Cl>CN(C=O)C.[Cu]I>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([NH:18][CH2:19][C@@H:20]2[CH2:24][CH2:23][CH2:22][NH:21]2)=[CH:13][CH:12]=1
Reactant: Brc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Agent: [Cu]I
Agent: CCN(CC)C(=O)c1ccccc1O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(NC[C@@H]2CCCN2)cc1
Temperature: 100 °C
Reaction time: 160 h

Procedure:
2.45 g (10.00 mmol) of potassium phosphate monohydrate was added under argon to a mixture of 1.42 g (5.00 mmol) of 1-bromo-4-iodobenzene, 1.00 g (5.00 mmol) of tert-butyl (S)-2-aminomethylpyrrolidine-1-carboxylate, 48 mg (0.25 mmol) of CuI, and 97 mg (0.50 mmol) of N,N-diethylsalicylamide in 5 mL of DMF and the mixture was stirred for 160 hours at 100° C. The reaction mixture was cooled to RT, combined with 100 mL of 4M aqueous HCl, and stirred for 1 hour at RT. The aqueous phase was washed with MTBE, made basic with concentrated aqueous ammonia, and exhaustively extracted with MTBE. The combined organic extracts were dried over magnesium sulfate, filtered through activated charcoal, and evaporated down in vacuo. The crude product was purified by MPLC (Hyperprep HS C18, 8 μm, gradient 0.15% formic acid in water/acetonitrile 10/90→90/10 v/v). The eluates were evaporated down in vacuo and the residue was neutralized with sat. aqueous sodium bicarbonate solution. The aqueous phase was extracted with DCM, dried over magnesium sulfate and evaporated down in vacuo. Yield: 0.20 g (16% of theoretical); C11H15BrN2 (M=255.2); calc.: molpeak (M+H)+: 255/257 (Br); found: molpeak (M+H)+:255/257 (Br); HPLC-MS: 3.90 minutes (method B).
Reaction SMILES: [CH:1]1([Si:6]([CH:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)([CH3:8])[CH3:7])[CH:5]=[CH:4][CH:3]=[CH:2]1.Br[CH2:15][CH2:16][O:17][Si:18]([CH3:21])([CH3:20])[CH3:19]>C1COCC1>[CH3:19][Si:18]([CH3:21])([CH3:20])[O:17][CH2:16][CH2:15][C:9]1([Si:6]([CH3:7])([CH3:8])[CH:1]2[CH:2]=[CH:3][CH:4]=[CH:5]2)[CH:10]=[CH:11][CH:12]=[CH:13]1
Reactant: C[Si](C)(C)OCCBr
Reactant: C[Si](C)(C1C=CC=C1)C1C=CC=C1
Solvent: C1CCOC1
Product: C[Si](C)(C)OCCC1([Si](C)(C)C2C=CC=C2)C=CC=C1
Reaction time: 12 h
Yield: 52 %

Procedure:
A solution of 11.5 g (61 mmol) of biscyclopentadienyidimethylsilane in THF was added to a suspension of 1.3 g (55 mmol) of HK in THF at −78° C. A purple solution was immediately formed. Then, the volatiles were removed and the residue was washed with hexane to give a pink solid. The solid was solved again in THF and a solution of 10.8 g (55 mmol) of 2-bromo-1-trimethylsiloxyethane in THF was added at room temperature. A pink suspension was immediately formed. The mixture was stirred for 12 h, and then the solvents were removed, the residue was treated with hexane and the supernatant solution was filtered. The removal of the hexane led to a reddish oil. This oil was distilled in order to obtain a yellow oil, which was characterized as a mixture of position isomers of (2-trimethylsiloxyethylcyclopentadienyl) dimethyl cyclopentadienyl silane (Tb: 135–140° C.; 1 mm Hg), (8.7 g, 28.6 mmol, yield: 52%). 1H-RMN(CDCl3): 6.82–6.40 (m, 7H); 3.82 (m, 2H); 3.10 (m, 2H); 2.73 (m, 2H); 0.20 (s, 15 H).
Reaction SMILES: [O:1]=[C:2]1[NH:5][C@H:4]([C:6]([OH:8])=[O:7])[CH2:3]1.ClCCCl.[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:5]2[C:2](=[O:1])[CH2:3][C@H:4]2[C:6]([OH:8])=[O:7])=[CH:16][CH:15]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C1C[C@@H](C(=O)O)N1
Solvent: ClCCCl
Product: O=C(O)[C@@H]1CC(=O)N1c1ccc(Cl)cc1
Reaction time: 0.17 h

Procedure:
To a stirred suspension of (S)-4-oxo-azetidine-2-carboxylic acid (1.0 g; 8.689 mmol) in 1,2-dichloroethane (35 mL) 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) (3.1 mL; 20.854 mmol) is added at room temperature. After 10 min di-μ-hydroxy-bis[N,N,N′,N′-tetramethylenediamine)-copper (II) chloride (Cu-TMEDA) (1.614 g; 3.476 mmol) is added to the clear solution. The mixture is stirred for 10 min and 4-chlorophenylboronic acid (1.495 g; 9.558 mmol) is added. After 20 hours, solvent is evaporated in vacuo, the concentrate taken up in saturated sodium bicarbonate solution (150 mL) and the aqueous layer is washed with ethyl acetate (3×100 mL). The aqueous layer is treated with 1N hydrochloric acid to pH 2 and extracted with ethyl acetate (3×100 mL). Combined organic extracts washed with brine (2×50 mL), dried over anhydrous sodium sulfate and solvent removed in vacuo to give the title compound as an off-white solid, m/z 226 [M+H+]
Reaction SMILES: [NH2:1][OH:2].C[O:4][C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[N:17]2[CH:18]=[N:19][CH:20]=[C:16]2[CH:15]=[CH:14][CH:13]=1)=O>CO>[OH:2][NH:1][C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[N:17]2[CH:18]=[N:19][CH:20]=[C:16]2[CH:15]=[CH:14][CH:13]=1)=[O:4]
Reactant: COC(=O)CCCCCc1cccc2cncn12
Reactant: NO
Solvent: CO
Product: O=C(CCCCCc1cccc2cncn12)NO
Reaction time: 20 h

Procedure:
A solution of hydroxylamine (from 2.06 g of hydroxylamine hydrochloride and 2.02 g of sodium hydroxide) and 5-(5-methoxycarbonylpentyl)imidazo[1,5-a]pyridine (6.08 g) in 25 ml of methanol is allowed to stand at room temperature for 20 hours. The methanol is evaporated and the residue is taken up in 5 ml of water and adjusted to pH=7. The resulting oil crystallizes and the solid is collected, yielding 5-[5-(hydroxycarbamoyl)pentyl]-imidazo[1,5-a]-pyridine, m.p. 138°-140°.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N+:16]([O-])=O)[C:5]2[NH:11][C:10](=[O:12])[C@H:9]([CH3:13])[NH:8][C:7](=[O:14])[C:6]=2[CH:15]=1.O>[Pd].C(O)(=O)C>[NH2:16][C:4]1[C:5]2[NH:11][C:10](=[O:12])[C@H:9]([CH3:13])[NH:8][C:7](=[O:14])[C:6]=2[CH:15]=[CH:2][CH:3]=1
Reactant: C[C@@H]1NC(=O)c2cc(Cl)cc([N+](=O)[O-])c2NC1=O
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Product: C[C@@H]1NC(=O)c2cccc(N)c2NC1=O
Reaction time: 0.25 h
Yield: 88.6 %

Procedure:
6 g (0.022 mol) of (S)-7-chloro-3-methyl-9-nitro-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione, 200 ml of water, 200 ml of acetic acid and 0.5 g of 5% palladium-on-charcoal are placed in a Parr bottle. The catalytic hydrogenation is carried out under 40 psi at 50° C. The catalyst is filtered, is washed with an acetic acid/water (50/50) mixture and the filtrate is concentrated to dryness. It is taken up in water and the pH adjusted to alkaline with a sodium carbonate solution. The mixture is left stirring for 15 minutes, filtration is carried out, drying is carried out and the solvent evaporated to dryness. 4 g of product are obtained.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(O[NH:16][S:17]([NH:20][C:21]1[CH:22]=[C:23]([CH:45]=[CH:46][CH:47]=1)[CH2:24][C:25]1[C:26](=[O:44])[O:27][C:28]2[CH:36]=[C:35]([O:37][C:38](=[O:42])[N:39]([CH3:41])[CH3:40])[C:34]([Cl:43])=[CH:33][C:29]=2[C:30]=1[CH2:31][F:32])(=[O:19])=[O:18])=O)(C)(C)C.C(=O)([O-])O.[Na+]>ClCCl>[NH2:16][S:17]([NH:20][C:21]1[CH:22]=[C:23]([CH:45]=[CH:46][CH:47]=1)[CH2:24][C:25]1[C:26](=[O:44])[O:27][C:28]2[CH:36]=[C:35]([O:37][C:38](=[O:42])[N:39]([CH3:40])[CH3:41])[C:34]([Cl:43])=[CH:33][C:29]=2[C:30]=1[CH2:31][F:32])(=[O:18])=[O:19]
Reactant: CN(C)C(=O)Oc1cc2oc(=O)c(Cc3cccc(NS(=O)(=O)NOC(=O)OC(C)(C)C)c3)c(CF)c2cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)Oc1cc2oc(=O)c(Cc3cccc(NS(N)(=O)=O)c3)c(CF)c2cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.7 %

Procedure:
Trifluoroacetic acid (0.1 mL) was added to a solution of dimethylcarbamic acid 3-{3-((tert-butoxycarbonyloxy)aminosulfonyl)aminobenzyl}-6-chloro-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl ester (compound 1j-1-3-1F-other) (23 mg, 0.039 mmol) in anhydrous dichloromethane (1.0 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was then poured into saturated sodium hydrogen carbonate and extracted with ethyl acetate. The organic extract was washed with saturated saline and dried over magnesium sulfate. A crude solid was then obtained by vacuum concentration, and purified by preparative TLC (ethyl acetate:hexane=1:1) to yield the title compound (19 mg, 100%) as a pale yellow powder.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[C:26]1([NH:32]N)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([N:32]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NNc1ccccc1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Product: O=c1ccn(-c2cccc(OC(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1
Yield: 64 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and phenylhydrazine according to the method described for Example 1 in 64% yield. MS: M=399.1 (M+H)+
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][CH2:16][C:17]2[S:18][CH:19]=[CH:20][C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([CH2:29][OH:30])[C:23]=2[CH3:31])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].CS(Cl)(=O)=O.C(NC1N=CC(/C=C/C(NCC2SC=CC=2C2C=CC(C)=C(CCl)C=2C)=O)=CC=1)(=O)C.O[C:69]1[CH:70]=[CH:71][CH:72]=[C:73]2[C:78]=1[N:77]=[C:76]([CH3:79])[CH:75]=[CH:74]2.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.C(N(CC)CC)C>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][CH2:16][C:17]2[S:18][CH:19]=[CH:20][C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([CH2:29][O:30][C:69]3[CH:70]=[CH:71][CH:72]=[C:73]4[C:78]=3[N:77]=[C:76]([CH3:79])[CH:75]=[CH:74]4)[C:23]=2[CH3:31])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(/C=C/C(=O)NCc2sccc2-c2ccc(C)c(CO)c2C)cn1
Reactant: Cc1ccc2cccc(O)c2n1
Agent: CC(=O)Nc1ccc(/C=C/C(=O)NCc2sccc2-c2ccc(C)c(CCl)c2C)cn1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ccc(/C=C/C(=O)NCc2sccc2-c2ccc(C)c(COc3cccc4ccc(C)nc34)c2C)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 48.5 %

Procedure:
To a mixture of 2-[(E)-3-(6-acetamidopyridin-3-yl)acryloylaminomethyl]-3-(2,4-dimethyl-3-hydroxymethylphenyl)thiophene (45 mg) and triethylamine (13.6 mg) in N,N-dimethylformamide (2 ml) was added methanesulfonyl chloride (14.2 mg) under ice-cooling, and the mixture was stirred for 1 hour at the same temperature and for 5 hours at ambient temperature. The mixture was poured into water and extracted with chloroform. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo to give a residue containing 2-[(E)-3-(6-acetamidopyridin-3-yl)acryloylaminomethyl]-3-(2,4-dimethyl-3-chloromethylphenyl)thiophene. To a mixture of 8-hydroxy-2-methylquinoline (14.8 mg) and potassium carbonate (39 mg) in N,N-dimethylformamide (0.5 ml) was added a solution of the residue obtained above in N,N-dimethylformamide (1.5 ml) at ambient temperature, and the mixture was stirred for 6 hours at 50° C. The mixture was poured into water and extracted with chloroform. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol=20:1, V/V) to give 2-[(E)-3-(6-acetamidopyridin-3-yl)acryloylaminomethyl]-3-[2,4-dimethyl-3-(2-methylquinolin-8-yloxymethyl)phenyl]thiophene (26 mg) as amorphous powder.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][NH:12][CH:13]=1.Cl[CH2:20][C:21]1[CH:40]=[CH:39][C:24]([O:25][CH2:26][C:27]2[N:28]=[C:29]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:30][C:31]=2[CH3:32])=[CH:23][CH:22]=1.CN(C)C=O>O>[CH3:32][C:31]1[O:30][C:29]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[N:28][C:27]=1[CH2:26][O:25][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:12]2[CH:13]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=3)[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11]2)=[CH:40][CH:39]=1
Reactant: CCOC(=O)c1c[nH]cc1-c1ccccn1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1-c1ccccn1
Reaction time: 1 h
Yield: 96.8 %

Procedure:
Sodium hydride (60%, oily, 0.22 g) was added to a mixture of ethyl 4-(2-pyridyl)pyrrole-3-carboxylate (1.10 g), 4-(4-chlorometylphenoxymethyl)-5-methyl-2-phenyloxazole (1.83 g) and N,N-dimethylformamide (25 ml) at 0° C., and the mixture was stirred for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatograpy, and ethyl 1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-(2-pyridyl)pyrrole-3-carboxylate (2.43 g, yield: 97%) was obtained as an oily substance from the fraction eluted with tetrahydrofuran-hexane (1:1, volume ratio).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:27])[C:6]=1[C:7]1[CH:8]=[C:9]([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[CH:10]=[CH:11][C:12]=1[OH:13].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36]([NH2:38])=[O:37]>CC(C)=O>[C:36]([CH2:35][O:13][C:12]1[CH:11]=[CH:10][C:9]([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=2)=[CH:8][C:7]=1[C:6]1[N:5]([CH3:27])[N:4]=[CH:3][C:2]=1[Cl:1])(=[O:37])[NH2:38]
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1O
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1OCC(N)=O
Temperature: 25 °C
Yield: 83.2 %

Procedure:
To a mixture of N-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-3-(trifluoromethyl)benzamide (51 mg, 0.13 mmol) and potassium carbonate (27 mg, 0.20 mmol) in acetone (1 mL) was added 2-bromoacetamide (27 mg, 0.20 mmol). The resultant mixture was heated to 65° C. for 1 hour. Cooled to room temperature and partitioned between EtOAc and water. Layers were separated. The organic layer was washed with water (2×) and brine, dried (MgSO4) and reduced to give the title compound as a white solid (49 mg, 83%). LCMS m/z (%)=453 (M+H 35Cl, 100), 455 (M+H 37Cl, 30). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.73 (s, 3 H), 4.46-4.61 (m, 2 H), 7.09 (d, J=9.09 Hz, 1 H), 7.24 (s, 1 H), 7.38 (s, 1 H), 7.65 (s, 1 H), 7.72 (d, J=2.78 Hz, 1 H), 7.73-7.84 (m, 1 H), 7.87 (dd, J=8.97, 2.65 Hz, 1 H), 7.97 (d, J=6.57 Hz, 1 H), 8.21-8.36 (m, 2 H), 10.53 (s, 1 H).
Reaction SMILES: [CH:1](=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[CH2:7]([Mg]Cl)[CH2:8][CH2:9][CH3:10]>C1COCC1>[CH3:4][CH:3]([CH2:2][CH:1]([OH:6])[CH2:7][CH2:8][CH2:9][CH3:10])[CH3:5]
Reactant: CCCC[Mg]Cl
Reactant: CC(C)CC=O
Solvent: C1CCOC1
Product: CCCCC(O)CC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
A solution of isovaleraldehyde (5.0 g, 58 mmol) in a dry THF (15 ml) was added to a stirred 2M THF solution of n-butylmagnesium chloride (30 ml, 60 mmol) at 0° C. under argon. The mixture was allowed to warm up to room temperature and was stirred overnight. The reaction was quenched by the addition of aqueous ammonium chloride (50 ml) and extracted with diethyl ether (200 ml). The organic extracts were dried over anhydrous potassium carbonate, filtered and concentrated to give 2-methyloctan-4-ol (6.4 g, 77%) as a clear oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO.O>[CH2:12]([NH:19][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCCCOc1cccnc1
Reactant: NCc1ccccc1
Solvent: O
Solvent: CO
Product: c1ccc(CNCCCOc2cccnc2)cc1
Temperature: 120 °C
Yield: 2.2 %

Procedure:
The 3-chloro-1-(3-pyridyloxy)propane (0.65 g, 3.78 mmol) was dissolved in methanol (20 mL) and added to a mixture of benzylamine (13.5 mL) in water (20 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 120° C. (oil bath temperature) for 3 h. After cooling, the mixture was concentrated by rotary evaporation, and saturated NaCl solution (25 mL) was added to the residue. The mixture was acidified to pH 1 with 10% HCl solution and extracted with CHCl3 (2×35 mL) to remove impurities. The aqueous phase was basified to pH 10 with 100% NaOH solution, and the mixture was extracted with chloroform (4×50 mL). The combined chloroform extracts were dried (MgSO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give a brown oil. The oil was concentrated by vacuum distillation to remove excess benzylamine (bp 85° C. at 15 mm Hg). The remaining residue (0.483 g) was purified by column chromatography on silica gel (25g) eluting with CH3OH—NH4OH (50:1, v/v). Fractions containing the product (Rf 0.39) were combined and concentrated on a rotary evaporator. The residue was re-chromatographed on silica gel (10 g). Fractions containing the product were combined and concentrated on a rotary evaporator. The residue was dissolved in CHCL3 and the CHCL3 solution was dried (MgSO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 20 mg (2.2%) of a light-brown oil. The compound exhibits a Ki of 3000 nM. The compound exhibits neurotransmitter release of 29 percent.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]=1[OH:23])[CH:2]=[CH2:3]>C(Cl)Cl.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[F:10][C:8]1[CH:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:5]([OH:23])=[C:4]([CH:1]=[CH:2][CH3:3])[CH:9]=1
Reactant: C=CCc1cc(F)cc(-c2ccccc2-c2ccccc2)c1O
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Solvent: ClCCl
Product: CC=Cc1cc(F)cc(-c2ccccc2-c2ccccc2)c1O
Yield: 93.2 %

Procedure:
Treatment of 3-allyl-5-fluoro-2′-phenylbiphenyl-2-ol (3.0 g, 9.8 mmol) in methylene chloride (100 mL) with dichlorobis(acetonitrile)palladium (II) (0.50 g, 1.93 mmol) according to the procedure described for Example 69, Step 5 provided 2.78 g (93%) of 5-fluoro-2′-phenyl-3-(prop-1-enyl)biphenyl-2-ol as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:28](OCC)[O:29]CC)=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH2:20][CH:21]=[CH2:22])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].Cl>CC(C)=O>[CH3:1][C:2]1[NH:3][C:4]([CH:28]=[O:29])=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH2:20][CH:21]=[CH2:22])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: C=CCOc1ccccc1C1C(C(=O)OCC)=C(C)NC(C(OCC)OCC)=C1C(=O)OCC
Agent: Cl
Solvent: CC(C)=O
Product: C=CCOc1ccccc1C1C(C(=O)OCC)=C(C)NC(C=O)=C1C(=O)OCC
Reaction time: 0.17 h

Procedure:
To a solution of diethyl 2-methyl-4-(2-allyloxyphenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.5 g) in acetone (15 ml) was added 6N-hydrochloric acid (1.5ml) with stirring and the resultant mixture was further stirred for an hour and 45 minutes at room temperature. The solvent was removed, and addition of water to the residue resulted a yellowish suspension with precipitation of an oil, which was immediately solidified. After being allowed to stand for about 10 minutes, the precipitated solids were collected by filteration and washed with water and dried. Thus obtained crude crystals were recrystallized from a mixture of diisopropyl ether and acetone to give orange-yellow granules of diethyl 2-methyl-4-(2-allyloxyphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate, m.p. 129° to 131° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([F:19])[C:10]=1[C:20]1[N:25]=[C:24]2[NH:26][N:27]=[C:28](I)[C:23]2=[CH:22][N:21]=1.[CH3:30][N:31]([CH3:50])[CH2:32][CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=1>>[F:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([F:19])[C:10]=1[C:20]1[N:25]=[C:24]2[NH:26][N:27]=[C:28]([C:38]3[CH:39]=[CH:40][C:35]([O:34][CH2:33][CH2:32][N:31]([CH3:50])[CH3:30])=[CH:36][CH:37]=3)[C:23]2=[CH:22][N:21]=1
Reactant: CN(C)CCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(I)n[nH]c3n2)c1F
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc(OCCN(C)C)cc4)n[nH]c3n2)c1F

Procedure:
This compound was prepared as TFA salt by using procedures analogous to those described for the synthesis of Example 7, Step 3 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and N,N-dimethyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethanamine (Combi-Blocks, Cat. No. PN-3972). LCMS (M+H)+=456.1.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[S:8][C:9]([CH2:12][CH2:13][CH2:14][CH2:15]Cl)=[CH:10][CH:11]=2)[N:6]=1.[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[S:8][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][N:26]3[CH2:27][CH2:28][N:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:24][CH2:25]3)=[CH:10][CH:11]=2)[N:6]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: Nc1nc(-c2ccc(CCCCCl)s2)cs1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(-c2ccc(CCCCN3CCN(c4ccccc4)CC3)s2)cs1
Reaction time: 15 h

Procedure:
A mixture of 5.43 g of 2-amino-4-[5-(4-chlorobutyl)-2-thienyl]thiazole, 4.0 g of 4-phenylpiperazine, 3.2 g of potassium carbonate, 0.1 g of potassium iodide and 50 ml of dimethylformamide is stirred at 70°-80° C. for 15 hours. The resultant mixture is poured into water and extracted with water. The extract is washed with water and dried over magnesium sulfate. After the solvent is distilled off under reduced pressure, the residue is recrystallized from ethanol to give 2-amino-4-[5-(4-(4-phenyl-1-piperazinyl) butyl)-2-thienyl]thiazole, melting at 165°-167° C.