Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:15]([O-])=O)=[C:7]([CH:14]=1)[O:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12].[H][H]>C(OCC)(=O)C.[Pd]>[CH3:13][N:11]([CH3:12])[CH2:10][CH2:9][O:8][C:7]1[CH:14]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[NH2:15]
Reactant: COc1ccc([N+](=O)[O-])c(OCCN(C)C)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(N)c(OCCN(C)C)c1
Yield: 89.4 %

Procedure:
A mixture of [2-(5-methoxy-2-nitrophenoxy)ethyl]dimethylamine (1.2 g, 5.0 mmol) and 5% Pd—C (0.3 g) in ethyl acetate (75 mL) was shaken under 50 psi of hydrogen for 24 hours. The mixture was filtered through Celite and evaporated, providing 0.94 g of the product, in 90% yield: 1H NMR (CDCl3) δ 2.34 (s, 6H), 2.75 (t, J=5.8 Hz, 2H), 3.74 (s, 3H), 4.08 (t, J=5.8 Hz, 2H), 6.36 (dd, J=8.4 Hz, J=2.5 Hz, 1H), 6.47 (d, J=2.5 Hz, 1H), 6.65 (d, J=8.4 Hz, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]=2)[CH:2]=1.Cl.[CH3:25][O:26][C:27](=[O:31])[C@H:28]([CH3:30])[NH2:29].Cl.CN(C)CCCN=C=NCC.ON1C(=O)C2C=CC=CC=2N=N1.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(N(CC)CC)C>[CH3:25][O:26][C:27](=[O:31])[C@H:28]([CH3:30])[NH:29][C:13](=[O:14])[C:12]1[CH:16]=[CH:17][C:9]([CH2:8][O:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:10][C:11]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)c1ccc(COc2cccnc2)cc1-c1ccccc1
Reactant: COC(=O)[C@H](C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C)NC(=O)c1ccc(COc2cccnc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 100 mg (0.33 mmol) of 4-(3-pyridyloxymethyl)-2-phenylbenzoic acid, L-alanine methyl ester hydrochloride (1.5 mmol), 69 mg (0.36 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 59 mg (0.36 mmol) of 3-hydroxy1,2,3-benzotriazin-4(3H)-one in 1 mL of N,N-dimethylformamide was added 5 drops of triethylamine. The mixture was stirred at ambient temperature for 24 hours, then poured into 10 mL of 0.6M aqueous sodium bicarbonate and extracted with ethyl acetate (3×5 mL). The combined ethyl acetate layers were back extracted with water (2×5 mL), then brine (1×5 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The product was purified via chromatography over silica gel, eluting with an appropriate mixture of hexanes and ethyl acetate.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH:34]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH:34]1([C:39]([N:29]2[CH2:28][CH2:27][CH:26]([N:23]3[C:19]4=[N:20][CH:21]=[N:22][C:17]([O:16][C:15]5[CH:14]=[CH:13][C:12]([S:9]([CH3:8])(=[O:11])=[O:10])=[CH:33][CH:32]=5)=[C:18]4[CH:25]=[N:24]3)[CH2:31][CH2:30]2)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Reactant: O=C(Cl)C1CCCC1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)C3CCCC3)CC2)cc1

Procedure:
Cyclopentyl-{4-[4-(4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-yl}-methanone was prepared according to General Procedure I by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27) with cyclopentanecarbonyl chloride (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 1.54-1.79 (m, 8H), 1.93-2.10 (m, 4H), 2.82-2.87 (m, 1H), 3.02-3.08 (m, 1H), 3.30 (methyl sulfonyl and water peak), 4.14-4.17 (m, 1H), 4.53-4.56 (m, 1H), 5.07-5.12 (m, 1H), 7.63-7.65 (m, 2H), 8.05-8.07 (m, 2H), 8.38 (s, 1H), 8.57 (s, 1H). Mass spectrum MH+=470.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C@@H:5]([C:6]2[N:10]=[CH:9][NH:8][N:7]=2)[CH2:4][C@H:3]1[NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1.CC1C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:1][C:2]1([CH3:22])[C@@H:5]([C:6]2[N:10]=[CH:9][N:8]([CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][O:23]3)[N:7]=2)[CH2:4][C@H:3]1[NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C1=COCCC1
Reactant: CC1(C)[C@@H](c2nc[nH]n2)C[C@H]1NC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC1(C)[C@@H](c2ncn(C3CCCCO3)n2)C[C@H]1NC(=O)OCc1ccccc1
Yield: 90.5 %

Procedure:
To a mixture of benzyl ((1R,3S)-2,2-dimethyl-3-(1H-1,2,4-triazol-3-yl)cyclobutyl)carbamate (380 mg, 1.26 mmol), and 3,4-dihydro-2H-pyran (127 mg, 1.51 mmol) in dry DCM (10 mL) was added pyridinium 4-methylbenzenesulfonate (476 mg, 1.89 mmol). The mixture was refluxed overnight. After removal of the solvent, the residue was purified by silica gel column chromatography (12% ethyl acetate in petroleum ether) to afford the title compound (438 mg, 1.14 mmol, 90% yield). MS (ESI) m/z 385.4 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2=[N:13][N:14]([CH2:26][CH2:27][CH3:28])[C:15]([CH2:16][CH2:17][NH:18]C(=O)OC(C)(C)C)=[C:11]2[C:10]2[CH:9]=[CH:8][CH:7]=[N:6][C:5]=2[N:4]=1>C(O)C>[NH2:18][CH2:17][CH2:16][C:15]1[N:14]([CH2:26][CH2:27][CH3:28])[N:13]=[C:12]2[C:11]=1[C:10]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[N:4]=[C:3]2[NH2:2]
Reactant: CCCn1nc2c(N)nc3ncccc3c2c1CCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: CCCn1nc2c(N)nc3ncccc3c2c1CCN
Temperature: 80 °C
Yield: 126.5 %

Procedure:
Hydrochloric acid (3 mL of 2.7 M in ethanol) was added to a suspension of tert-butyl 2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]-1,8-naphthyridin-1-yl)ethylcarbamate (0.52 g) in ethanol (10 mL). The mixture was heated at 80° C. for about 1 hour and then concentrated under reduced pressure. The residue was partitioned between water (50 mL) and dichloromethane (30 mL). The layers were separated. The aqueous layer was made basic with ammonium hydroxide and then extracted with dichloromethane (2×50 mL). The combined organics were washed with brine (1×50 mL), dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to provide 0.29 g of crude product as a white solid. The reaction was repeated using 2.05 g of starting material to provide 1.18 g of crude product as a white solid. The two lots were combined and purified by chromatography on a HORIZON HPFC system (silica gel eluting with a gradient of 20-60% of 80:20 CMA:chloroform in chloroform) to provide 0.48 g of 1-(2-aminoethyl)-2-propyl-2H-pyrazolo[3,4-c]-1,8-naphthyridin-4-amine as a white solid.
Reaction SMILES: [C:1]1([N:7]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:20]N1C(=O)CCC1=O>C(O)(=O)C>[I:20][C:16]1[CH:17]=[CH:18][C:19]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: c1ccc(-n2c3ccccc3c3ccccc32)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: Ic1ccc2c(c1)c1ccccc1n2-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
24.3 g (100 mmol) of 9-phenylcarbazole was dissolved in 600 mL of glacial acetic acid, 22.5 g (100 mmol) of N-iodosuccinimide was slowly added thereto, and the mixture was then stirred overnight at a room temperature. The obtained precipitate was filtered, and the residue was washed with a saturated sodium hydrogen carbonate water solution, water, and methanol and then dried. 24.7 g (yield: 67%) of 3-iodo-9-phenylcarbazole which was white powder, was obtained.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[OH:9][C:10]1[CH:11]=[C:12]([CH2:16][C:17](O)=[O:18])[CH:13]=[CH:14][CH:15]=1.B(F)(F)F.CCOCC.C([O-])(=O)C.[Na+]>C1(C)C=CC=CC=1.O>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[C:17](=[O:18])[CH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([OH:9])[CH:11]=1
Reactant: Oc1cccc(O)c1
Reactant: O=C(O)Cc1cccc(O)c1
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=C(Cc1cccc(O)c1)c1ccc(O)cc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.7 %

Procedure:
A solution of resorcinol (3.56 g, 32.3 mmol), 2-(3-hydroxyphenyl)acetic acid (5.39 g, 35.4 mmol), and boron trifluoride etherate (12 mL) in toluene (10 mL) was heated at 90° C. for 2 h. The reaction mixture was allowed to cool to room temperature, and a solution of 12% sodium acetate in H2O (17 mL) was added. After stirring for 3 h, the resulting precipitate was collected by filtration to give 1-(2,4-dihydroxyphenyl)-2-(3-hydroxyphenyl)ethanone (4.47 g, 57%) as a yellow solid. 1H NMR (DMSO-d6): δ 12.57 (s, 1H), 10.67 (s, 1H), 9.34 (s, 1H), 7.92 (d, 1H), 7.09 (m, 2H), 6.65 (m, 2H), 6.40 (m, 1H), 6.25 (s, 1H), 4.14 (s, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25].O>ClCCl>[CH2:27]([O:26][C:24]([N:1]1[CH2:2][CH:3]=[C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:5][CH2:6]1)=[O:25])[CH3:28]
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)N1CC=C(c2c[nH]c3ccccc23)CC1
Reaction time: 2 h
Yield: 76.6 %

Procedure:
5 g of 3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole prepared in Example 1 (part A) were dissolved in 25 mL of dichloromethane and 3.22 g of triethylamine were added to the solution. Keeping the temperature between 20 and 25° C., 3.14 g of ethyl chloroformate were added dropwise. The mixture was stirred for 2 hours and 20 mL of water were added. The organic layer was separated and the solvent was was removed under reduced pressure affording 5.22 g of a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:27])[N:19]([CH2:23][C:24]([OH:26])=O)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.[CH3:34][N:35]([CH3:40])[S:36]([NH2:39])(=[O:38])=[O:37]>>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:27])[N:19]([CH2:23][C:24]([NH:39][S:36](=[O:38])(=[O:37])[N:35]([CH3:40])[CH3:34])=[O:26])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:30]([F:33])([F:31])[F:32])[CH:3]=1
Reactant: CN(C)S(N)(=O)=O
Reactant: O=C(O)CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Product: CN(C)S(=O)(=O)NC(=O)CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
2-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]-N-(dimethylsulfamoyl)acetamide was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]acetic acid (Example 4) and N,N-dimethylsulfamide following General Procedure L.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:29])([CH3:28])[C@@H:11]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:12]([O:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=[O:13])(=[O:7])=[O:6].[N-:30]=[N+:31]=[N-:32].[Na+]>CS(C)=O>[N:30]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:29])([CH3:28])[C@@H:11]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:12]([O:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=[O:13])(=[O:7])=[O:6])=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: CN(C)CCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)CCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCN=[N+]=[N-]

Procedure:
Following the general procedure for the preparation of azides of Description 16, 2-(dimethylamino)ethyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoate (28a) (0.70 g, 1.5 mmol) dissolved in 5 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 0.22 g (3.0 mmol) of sodium azide (NaN3). After work-up, the crude material (28b) was used in the next step without further purification. MS (ESI) m/z 456.90 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH2:22]O)=[CH:9]\[C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH:24]1([NH2:27])[CH2:26][CH2:25]1.CO.[BH4-].[Na+]>C(OCC)(=O)C>[CH:24]1([NH:27][CH2:22]/[C:8](/[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)[CH2:26][CH2:25]1
Reactant: NC1CC1
Reactant: COC(=O)C=Cc1ccc(/C=C(/CO)c2ccc(F)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C=Cc1ccc(/C=C(/CNC2CC2)c2ccc(F)cc2)cc1
Reaction time: 0.5 h

Procedure:
A mixture of methyl 3-(1E)(4-(2-(4-fluorophenyl)-3-hydroxyprop-1-en-1-yl)phenyl)acrylate (0.44 g, 1.4 mmol) and cyclopropylamine (0.14 g, 2.4 mmol) was stirred with MeOH (40 mL) for 3 hours. To the reaction mixture, sodium borohydride (0.09 g, 2.3 mmol) was added and stirred for 30 minutes. Subsequently the reaction mixture was diluted with ethyl acetate (300 mL) and washed successively with water (2×100 ml) and brine (1×100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to afford the pure title compound as a pale yellow sticky compound (0.4 g, 80% yield).
Reaction SMILES: N[C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:6][C:5]=2[S:4][C:3]=1[CH2:17][CH3:18].[B-](F)(F)(F)F.FC(F)(F)C([O-])=[O:27].[K+].FC(F)(F)C(O)=O>>[CH2:17]([C:3]1[S:4][C:5]2[N:6]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:8][C:9](=[O:11])[C:10]=2[C:2]=1[OH:27])[CH3:18]
Reactant: CCOC(=O)c1nc2sc(CC)c(N)c2c(=O)[nH]1
Reactant: O=C([O-])C(F)(F)F
Agent: F[B-](F)(F)F
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nc2sc(CC)c(O)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The diazonium fluoroborate salt is prepared as in Procedure 63 from the amino compound produced in Procedure 51 yielding 0.03 mole of the required idazonium fluoborate. The latter is added in one portion to a solution of 0.03 mole of potassium trifluoroacetate in 13 ml. of trifluoroacetic acid at 0° C. The mixture is stirred at 25° C. for 1 hour and then refluxed overnight. The trifluoroacetic acid is evaporated in vacuo to give a residue which is triturated with water and filtered to give the desired product.
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3](=[O:18])[N:4]1[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:5]1=[N:6]2.[CH:19](Br)([CH3:21])[CH3:20]>>[CH:19]([N:11]1[C:5]2=[N:6][C:7]3[C:2]([C:3](=[O:18])[N:4]2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]1=2)=[CH:1][CH:10]=[CH:9][CH:8]=3)([CH3:21])[CH3:20]
Reactant: O=c1c2ccccc2nc2[nH]c3ccccc3n12
Reactant: CC(C)Br
Product: CC(C)n1c2ccccc2n2c(=O)c3ccccc3nc12

Procedure:
6-Isopropylbenzimidazo[2,1-b]quinazolin-12(6H)one is prepared with benzimidazo[2,1-b]quinazolin-12(6H)one and isopropyl bromide.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:18]([O-])=O.[Na+].[ClH:22]>O>[ClH:22].[ClH:22].[NH:1]([C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[NH2:18]
Reactant: Nc1cc(-c2ccccc2)c2ccccc2n1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1cc(-c2ccccc2)c2ccccc2n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A stirred slurry of 2-amino-4-phenylquinoline (22 g.) in concentrated hydrochloric acid (50 ml.) was treated dropwise at 0° C. or below with sodium nitrite (7.0 g.) in cold water (35 ml.). The mixture was stirred for 0.5 hours at about 0° C. Stannous chloride dihydrate (56.7 g.) in cold concentrated hydrochloric acid (70 ml.) was added at 0° C. dropwise. The slurry was refrigerated overnight, filtered, and the precipitate was washed with saturated sodium chloride. The filtered solid was treated with excess concentrated sodium hydroxide solution and the hydrazine was extracted into ethyl acetate. The organic extract was washed, dried, decolorized and saturated with dry hydrogen chloride. On removal of the solvent, 2-hydrazino-4-phenylquinoline dihydrochloride was obtained. This compound was reacted with acrylonitrile using the same procedure described in Example 1.
Reaction SMILES: [CH2:1]([N:4]([CH3:28])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)=[O:19])=[C:14]([OH:27])[CH:13]=1)[CH:2]=[CH2:3].[CH:29]([Mg]Cl)=[CH2:30].C(O)(=O)C.O.C(=O)(O)[O-].[Na+]>C1COCC1.CCOCC.C(Cl)Cl>[CH2:1]([N:4]([CH3:28])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)([OH:19])[CH:29]=[CH2:30])=[C:14]([OH:27])[CH:13]=1)[CH:2]=[CH2:3]
Reactant: C=C[Mg]Cl
Reactant: C=CCN(C)CCCCCCOc1ccc(C(=O)c2ccc(Br)cc2)c(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: O
Product: C=CCN(C)CCCCCCOc1ccc(C(O)(C=C)c2ccc(Br)cc2)c(O)c1
Temperature: 25 °C

Procedure:
1.0 g of [4-[6-(allyl-methyl-amino)-hexyloxy]-2-hydroxy-phenyl]-(4-bromo-phenyl)-methanone (Ex. 35) in 9 ml of THF/ether (1:1) is added dropwise during 45 min. to 4.8 ml of (1.7M in THF) vinylmagnesium chloride solution at 0° C. The solution is left to warm to room temperature overnight, treated with 3 ml of acetic acid/water (1:1) and worked up with saturated sodium bicarbonate solution/methylene chloride. After drying the organic phase is concentrated and the residue is purified over silica gel with methylene chloride/methanol (95:5). There is obtained 0.64 g of (RS)-5-[6-(allyl-methyl-amino)-hexyloxy]-2-[1-(4-bromo-phenyl)-1-hydroxy-allyl]-phenol, MS: m/e 474 (M+H+, 1Br).
Reaction SMILES: C(=O)([O-])[O-].[Mg+2:5].[NH2:6][CH2:7][C:8]([OH:10])=[O:9].OCl>O>[NH2:6][CH2:7][C:8]([O-:10])=[O:9].[Mg+2:5].[NH2:6][CH2:7][C:8]([O-:10])=[O:9]
Reactant: NCC(=O)O
Agent: O=C([O-])[O-]
Agent: OCl
Agent: [Mg+2]
Solvent: O
Product: NCC(=O)[O-]
Reaction time: 0.25 h

Procedure:
Magnesium glycinate was prepared by reacting 3 g. of basic magnesium carbonate (26.1% Mg) with 5 g. of glycine in 40 g. of H2O, while agitating at 75° C. for one half hour. To the cooled slurry was added 100 g. of 33-1/3% zirconyl hydroxychloride solution (4.4% Zr) with agitation. After 15 minutes of stirring, the solution cleared and had a pH of 3.4. The product was oven-dried at 50° C. under a vacuum of 35 cm. of Hg, and found to contain 2.06% Mg, 36.9% Zr, and 13.1% glycine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.C(COC)OC.C([O-])(O)=O.[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH3:9])[N:5]=[CH:4][N:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: Clc1cc(Cl)ncn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccccc1-c1cc(Cl)ncn1

Procedure:
To a solution of 4,6-dichloropyrimidine (6.0 g, 40 mmol) and 2-methoxyphenylboronic acid (4.41 g, 29 mmol) in mixture of dimethoxyethane (120 mL) and water (18 mL) were added NaHCO3 (6.72 g, 80 mmol) and (PPh3)2PdCl2 (0.84 g) and the reaction mixture was refluxed for 8 h, and concentrated under reduced pressure. The resulting residue was taken up in CH2Cl2 (100 mL) and the solution washed with water, dried over anhydrous K2CO3, filtered and the solvent removed under reduced pressure. The obtained crude product was purified by flash chropatography on silica (eluent CH2Cl2) and recrystallized from hexanes. Yield of 4-chloro-6-(2-ethoxyphenyl)-pyrimidine 4.78 g (75%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][N:3]=1.[C:13]1([CH2:19][CH2:20][C:21](Cl)=[O:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1.C(OCC)(=O)C>[C:7]1([C:5]2[NH:4][N:3]=[C:2]([NH:1][C:21](=[O:22])[CH2:20][CH2:19][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:6]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: Nc1cc(-c2ccccc2)[nH]n1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(CCc1ccccc1)Nc1cc(-c2ccccc2)[nH]n1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
3-Amino-5-phenylpyrazole (160 mg) was dissolved in pyridine (1 ml) to which was subsequently added 3-phenylpropionyl chloride (0.15 ml), and the mixture was stirred at room temperature for 14 hours and then at 50° C. for 30 minutes. The reaction solution was diluted with ethyl acetate (15 ml), washed with water (15 ml), 10% citric acid (15 ml), 1 N aqueous sodium hydroxide solution (15 ml) and saturated brine (15 ml) and then dried over anhydrous sodium sulfate. The solvent was distilled away under a reduced pressure, and the resulting residue was crystallized from ethanol to obtain the title compound (139 mg) as white crystals (melting point: 168 −170° C.).
Reaction SMILES: C([O:8][CH2:9][CH2:10][C@H:11]([O:33][CH2:34][CH2:35][O:36]CC1C=CC=CC=1)[CH2:12][O:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[OH:36][CH2:35][CH2:34][O:33][C@H:11]([CH2:12][O:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:10][CH2:9][OH:8]
Reactant: c1ccc(COCCO[C@@H](CCOCc2ccccc2)COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: OCCO[C@@H](CCO)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 15 h
Yield: 77.5 %

Procedure:
(S)-4-Benzyloxy-2-(2-benzyloxyethoxy)-1-trityloxy-butane (51 mg, 0.092 mmol) was dissolved in ethyl acetate (3 ml). To the solution was added 5% Pd—C (5.0 mg) and the mixture was stirred under an atmosphere of hydrogen for 15 hours at 50° C. After filtering off catalyst, the filtrate was condensed in vacuo, and the residue was subjected to silica gel chromatography to give (S)-3-(2-hydoxyethoxy)-4-trityloxybutanol (28 mg, yield 78%).
Reaction SMILES: CI.[Mg].[Cl:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([Cl:13])[CH:12]=1)C#N.Cl.CC[O:17][CH2:18][CH3:19]>C1C=CC=CC=1.O>[Cl:4][C:5]1[CH:6]=[C:7]([C:18](=[O:17])[CH3:19])[CH:10]=[C:11]([Cl:13])[CH:12]=1
Reactant: N#Cc1cc(Cl)cc(Cl)c1
Reactant: CCOCC
Agent: Cl
Agent: [Mg]
Solvent: O
Solvent: c1ccccc1
Solvent: CI
Product: CC(=O)c1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of methyl iodide (4 mL) in anhydrous Et2O (40 mL) was dropped into a suspension of magnesium (1.6 g) in anhydrous Et2O (16 mL) under a Nitrogen atmosphere. At the end of the dropping, benzene (120 mL) was added and the Et2O eliminated with a Nitrogen flux. Then, a solution of 3,5-dichlorobenzonitrile (4 g) in benzene (48 mL) was added and the mixture was heated to reflux for 3 hours. The solution was cooled to 0° C. and a 6N hydrochloric acid solution was added and the mixture was stirred overnight at r.t. Water and Et2O were added and the layers were separated. The organic phase was washed with a saturated sodium hydrogen carbonate solution and brine, dried and concentrated in vacuo. The residue was purified by flash chromatography (CH/AcOEt 95:5) to give the title compound (2.55 g) as an orange oil.