Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5](Br)[S:4][C:3]=1[CH3:8].[F:9][C:10]([F:21])([F:20])[C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Br:1][C:2]1[CH:6]=[C:5]([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:10]([F:21])([F:20])[F:9])[CH:16]=2)[S:4][C:3]=1[CH3:8]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1sc(Br)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1sc(-c2cccc(C(F)(F)F)c2)cc1Br
Yield: 85.7 %

Procedure:
Under a nitrogen atmosphere, a mixture of 3,5-dibromo-2-methylthiophene (2.00 g), 3-(trifluoromethyl)phenylboronic acid (2.23 g), tetrakis(triphenylphosphine)palladium (0.45 g), cesium carbonate (5.09 g) and tetrahydrofuran (40 mL) was heated under reflux for 16 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (2.15 g) as a solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([NH:10][CH:11]([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[NH2:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[C:17]#[N:18]>>[NH2:14][C:15]1[C:16]([C:17]#[N:18])=[C:19]([CH:20]=[CH:21][CH:22]=1)[O:1][CH:2]1[CH2:3][CH2:4][CH:5]([C:8]([NH:10][CH:11]([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CC(C)NC(=O)C1CCC(O)CC1
Reactant: N#Cc1c(N)cccc1F
Product: CC(C)NC(=O)C1CCC(Oc2cccc(N)c2C#N)CC1

Procedure:
Prepared as in Example 22b from 4-hydroxy-N-isopropylcyclohexanecarboxamide (Example 45c) and 2-amino-6-fluorobenzonitrile as an off-white solid (17%). 1H NR (400 MHz, DMSO-d6) δ 1.01 (d, J=6.4 Hz, 6H), 1.47-1.57 (m, 4H), 1.67-1.77 (m, 2H), 1.89-1.93 (m, 2H), 2.08-2.15 (m, 1H), 3.75-3.84 (m, 1H), 4.57 (brs, 1H), 5.93 (s, 2H), 6.19 (d, J=8.0 Hz, 1H), 6.28 (d, J=8.0 Hz, 1H), 7.13 (t, J=8.0 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H). MS 302 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:25](Cl)(=[O:27])[CH3:26]>>[C:25]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:27])[CH3:26]
Reactant: Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1
Reactant: CC(=O)Cl
Product: CC(=O)Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.004 mL (0.061 mMol) acetyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: C(N[C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:8][C:7]=1[N+:19]([O-:21])=[O:20])(CC)C.C(C1C=CC([OH:32])=CC=1)(C)(C)C.[N+]([O-])(O)=O>C(O)(=O)C>[N+:19]([C:7]1[CH:8]=[C:9]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:6]=1[OH:32])([O-:21])=[O:20]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: CCC(C)Nc1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Product: CC(C)(C)c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1

Procedure:
The synthesis of N-sec-butyl-4-tert-butyl-2,6-dinitroaniline is generally described in a number of U.S. patents including, for example, U.S. Pat. Nos. 3,672,866; 3,927,127 and 3,991,116 all to Damiano. The process described in U.S. Pat. Nos. 3,672,866 and 3,991,116 begins with a starting material, 4-tert-butylphenol. The 4-tert-butylphenol is subjected to nitration utilizing nitric acid in acetic acid solution to produce 2,6-dinitro-4-tert-butylphenol. The 2,6-dinitro-4-tert-butylphenol is then chlorinated to produce 2,6-dinitro-4-tert-butylchlorobenzene. This 2,6-dinitro-4-tert-butylchlorobenzene is then converted into N-sec-butyl-4-tert-butyl-2,6-dinitroaniline by amination with sec-butylamine.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[O:12][C@@H:11]([N:23]2[C:36]3[N:35]=[C:30]([NH:31][C:32](=[O:34])[NH2:33])[NH:29][C:27](=[O:28])[C:26]=3[N:25]=[CH:24]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[C:46]1([N:52]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:53](Cl)=[O:54])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>N1C=CC=CC=1>[Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:17])[CH3:18])[O:12][C@@H:11]([N:23]2[C:36]3[N:35]=[C:30]([NH:31][C:32](=[O:34])[NH2:33])[N:29]=[C:27]([O:28][C:53](=[O:54])[N:52]([C:56]4[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=4)[C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:26]=3[N:25]=[CH:24]2)[CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(NC(N)=O)nc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(OC(=O)N(c4ccccc4)c4ccccc4)nc(NC(N)=O)nc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
The above-obtained 3′,5′-bis-O-(tert-butyldimethylsilyl)-2-N-carbamoyldeoxyguanosine (1.23 g, 2.29 mmol) was azeotroped with anhydrous pyridine three times and then dissolved in anhydrous pyridine (23 mL). To the resulting solution, diisopropylethylamine (797 μL, 4.58 mmol) and then diphenylcarbamoyl chloride (689 mg, 2.98 mmol) were added, and the mixture was stirred at room temperature for 0.5 hours. Then, the reaction was terminated by adding sodium bicarbonate water (5 ml) thereto. The reaction solution was extracted with ethyl acetate (180 mL)/sodium bicarbonate water (150 mL) once and then with ethyl acetate (180 mL)/brine (100 mL) twice. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (C200) with ethyl acetate/50% to 60% hexane to give 3′,5′-bis-O-(tert-butyldimethylsilyl)-2-N-carbamoyl-6-O-diphenylcarbamoyldeoxyguanosine (1.53 g, 91%).
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)=O.[OH:22][CH:23]([CH2:28][NH2:29])[CH2:24][C:25]([OH:27])=[O:26].N12CCN(CC1)CC2>O>[N:1]1([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:29][CH2:28][CH:23]([OH:22])[CH2:24][C:25]([OH:27])=[O:26])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1ccc(N2CCCCCC2)cc1
Reactant: NCC(O)CC(=O)O
Agent: C1CN2CCN1CC2
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)CC(O)CNS(=O)(=O)c1ccc(N2CCCCCC2)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 150.4 %

Procedure:
4.1 g of (4-hexahydro-azepin-1-yl-benzenesulphonyl) chloride then 12 cm3 of acetone are added to a solution of 1.4 g of 3-hydroxy-4-amino butanoic acid and 3.36 g of 1,4-diazabicyclo [2.2.2]octane (DABCO) in 18 cm3 of water. Agitation is carried out for 6 hours at ambient temperature, the acetone is evaporated off, the residue is cooled down to 0° C. and 7.5 cm3 of 2N hydrochloric acid is added. Extraction is carried out with chloroform, the extracts are dried and evaporated to dryness. 6.3 g of desired product is obtained, used as it is for the following stage.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([NH:13][NH2:14])=[N:5][N:4]=1.C(N(CC)CC)C.[C:22](Cl)(=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCOCC1>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2=[N:13][N:14]=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:5]2[N:4]=1
Reactant: NNc1nnc(Cl)c2ccccc12
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Clc1nn2c(-c3ccccc3)nnc2c2ccccc12

Procedure:
To a solution of 1-chloro-4-hydrazinophthalazine hydrochloride (10 g) in dioxan (220 ml) was added triethylamine (7.24 ml) and benzoyl chloride (6.04 ml). This mixture was heated at reflux for 8 hours under nitrogen. After cooling the reaction mixture was concentrated under vacuum and the solid obtained was collected by filtration, washed with water and diethyl ether and dried under vacuum, to yield the title compound (12.0 g). 1H NMR (250 MHz, DMSO) δ 7.60 (3H, m), 8.00 (1H, t, J=8.4Hz), 8.19 (1H, t, J=8.4Hz), 8.31 (3H, m), 8.61 (1H, d, J=6.3Hz).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[F:15])[CH3:2].C[Al](C)C.[NH:20](/[C:24](/[CH3:30])=[CH:25]\[C:26](OC)=[O:27])[C:21]([CH3:23])=O>C(Cl)Cl>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:26](=[O:27])[CH:25]=[C:24]([CH3:30])[N:20]=[C:21]2[CH3:23])=[CH:10][C:9]=1[F:15])[CH3:2]
Reactant: CCOCCCNc1ccc(N)cc1F
Reactant: COC(=O)/C=C(/C)NC(C)=O
Agent: C[Al](C)C
Solvent: ClCCl
Product: CCOCCCNc1ccc(-n2c(C)nc(C)cc2=O)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.7 %

Procedure:
To a solution of N1-(3-ethoxypropyl)-2-fluorobenzene-1,4-diamine (5.52 g, 26 mmol) in CH2Cl2 (40 mL) was added trimethylaluminium (52 mL, 104 mmol, 2 M in toluene) slowly. The mixture was stirred at rt for 0.5 h, followed by the addition of a solution of methyl 3-acetaminocrotonate (4.87 g, 31 mmol) in CH2Cl2 (10 mL). The reaction mixture was stirred at rt for 72 h, then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (150 mL×3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as pale yellow oil (2.22 g, 27%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=O.Cl.[NH2:15][OH:16].C(=O)(O)[O-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[N:15][OH:16]
Reactant: NO
Reactant: COc1cccc2c1CCCC2=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cccc2c1CCCC2=NO
Yield: 79.5 %

Procedure:
17.7 g (0.1 mole) of commercial 5-methoxy-1-tetralone (from Aldrich), 18.4 g (0.26 mole) of hydroxylamine hydrochloride and 22.6 g of sodium bicarbonate (0.26 mole), in 450 ml of methanol and 80 ml of water, are refluxed for 36 hours. The solvent is then removed on a rotary evaporator, the residue is thoroughly stirred with water and the precipitate is filtered off, dried and recrystallized from toluene. 15.2 g of 5-methoxy-tetralone-1-oxime (79.6% yield), of melting point 158°-159° C., are obtained.
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[C@H:20]([CH3:25])[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+].[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:28]1([S:34]([N:22]2[CH2:21][C@@H:20]([CH3:25])[N:16]3[C:17]4[CH:18]=[CH:19][C:11]([O:10][CH:7]5[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]5)=[CH:12][C:13]=4[CH:14]=[C:15]3[C:23]2=[O:24])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CN(S(=O)(=O)c3ccccc3)C2=O)CC1
Yield: 43 %

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8), sodium hydride and benzenesulfonyl chloride, to give the desired product as a yellow oil (43%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH2:9][CH2:10][N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])[N:3]=1.[F:22][C:23]([F:29])([F:28])[CH2:24][N:25]=[C:26]=[S:27].CN(C)C=O>C(#N)C>[F:22][C:23]([F:29])([F:28])[CH2:24][NH:25][C:26](=[S:27])[NH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH2:9][CH2:10][N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])[N:3]=1
Reactant: FC(F)(F)CN=C=S
Reactant: Nc1ccnc(SCCN2C(=O)c3ccccc3C2=O)n1
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCSc1nccc(NC(=S)NCC(F)(F)F)n1
Reaction time: 72 h
Yield: 59.5 %

Procedure:
A mixture of 4-amino-2-(2-phthalimidoethylthio)pyrimidine (0.8 g.), 2,2,2-trifluoroethylisothiocyanate (0.56 g.) and dimethyl formamide (2 ml.) was stirred at 70° for 72 hours. The mixture was cooled, diluted with acetonitrile and filtered to give 4-[3-(2,2,2-trifluoroethyl)thioureido]-2-(2-phthalimidoethylthio)pyrimidine (0.7 g.), m.p. 238°-241°.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][N:7]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:26]3[C:27]4[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=4[N:29]=[C:25]3[N:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)C(=O)OC(C)(C)C)=[N+:2]=[N-:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]([CH2:4][CH2:5][CH2:6][NH:7][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:26]3[C:27]4[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=4[N:29]=[C:25]3[N:24]=[CH:23][CH:22]=2)=[CH:19][CH:20]=1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N(CCCN=[N+]=[N-])c1ccc(-c2ccnc3nc4ccccc4n23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: [N-]=[N+]=NCCCNc1ccc(-c2ccnc3nc4ccccc4n23)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl (3-azidopropyl)(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-4-yl)phenyl)carbamate (above mentioned material) in 3 mL of DCM was added TFA (1 mL). The mixture was stirred at rt for 1.5 h and concentrated under reduced pressure. The residue was purified by reversed phase HPLC (TFA buffered water/MeCN) to afford the title compound as a orange-colored oil (61 mg, TFA salt). MS (ESI) m/z [M-1-H]+344.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]2[N:8]=[C:9]([NH2:11])[CH:10]=[C:4]2[CH2:3]1.Br[C:13]1[C:14](=[O:20])[NH:15][N:16]=[C:17]([Cl:19])[CH:18]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Cl>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1COCC1.O1CCOCC1>[Cl:19][C:17]1[CH:18]=[C:13]([NH:11][C:9]2[CH:10]=[C:4]3[CH2:3][N:2]([CH3:1])[CH2:7][CH2:6][N:5]3[N:8]=2)[C:14](=[O:20])[NH:15][N:16]=1
Reactant: O=c1[nH]nc(Cl)cc1Br
Reactant: CN1CCn2nc(N)cc2C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: O
Product: CN1CCn2nc(Nc3cc(Cl)n[nH]c3=O)cc2C1
Temperature: 25 °C
Yield: 74.8 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was charged with 1,4-dioxane (5.0 mL), 5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-amine (152 mg, 1.00 mmol), 4-bromo-6-chloropyridazin-3(2H)-one (209 mg, 1.00 mmol) and a 1 M THF solution of LiHMDS (5.0 mL, 5.00 mmol). After bubbling nitrogen through the resulting solution for 30 min, Xantphos (49 mg, 0.05 mmol) and tris(dibenzylideneacetone)dipalladium(0) (59 mg, 0.085 mmol) were added, and the reaction mixture was heated at reflux for 3 h. After this time, the reaction was cooled to room temperature, and water (10 mL) was added, The pH was adjusted to 6.5 with 2 N hydrochloric acid. The resulting precipitate was collected by vacuum filtration, washed with water (2×25 mL), absorbed on silica gel and purified by flash chromatography to afford a 74% yield (210 mg) of 6-chloro-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridazin-3(2H)-one as a light brown solid: 1H NMR (300 MHz, DMSO-d6) δ 12.94 (s, 1H), 9.55 (s, 1H), 7.68 (s, 1H), 5.96 (s, 1H), 4.04 (t, 1H, J=5.7 Hz), 3.53 (s, 2H), 2.82 (t, 2H, J=5.7 Hz), 2.36 (s, 3H); MS (ESI+) m/z 281.1 (M+H).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7]C[CH2:5][CH2:4][CH2:3]1.[CH2:8]=[C:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.CC(CCC)=C.CC(=CC(C)(C)C)C.C1(C(CC2C=CC=CC=2)=C)C=CC=CC=1>>[CH3:7][C:2]([CH2:3][CH2:4][CH3:5])=[CH2:1].[CH3:8][C:9](=[CH:10][CH2:11][CH3:12])[CH3:13]
Reactant: C=C1CCCCC1
Reactant: C=C1CCCC1
Agent: C=C(C)CCC
Agent: C=C(Cc1ccccc1)c1ccccc1
Agent: CC(C)=CC(C)(C)C
Product: CCC=C(C)C

Procedure:
Under similar reaction conditions as in Example 5, methylenecyclohexane, methylenecyclopentane, 2-methyl-1-pentene, 2,4,4-trimethyl-2-pentene and 2,3-diphenyl-1-propene underwent the isomerization to the thermodynamically more stable isomers shown in Table 1. The isomerization of 2-methyl-1-pentene afforded only 2-methyl-2-pentene and 4-methyl-2-pentenes were not observed.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:22]=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[C:16]([O:29][CH3:30])=[CH:15][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12](I)=[CH:13][C:8]=2[N:7]=[CH:6]1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+].N1CCC[C@H]1C(O)=O>CS(C)=O.[OH-].[NH4+].[Cu]I>[F:1][C:2]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:22]=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[C:16]([O:29][CH3:30])=[CH:15][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)=[CH:13][C:8]=2[N:7]=[CH:6]1
Reactant: COc1ccc(COc2cc(F)c(Cn3cnc4cc(I)ccc43)cc2OC)cn1
Reactant: CN1CCNCC1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: COc1ccc(COc2cc(F)c(Cn3cnc4cc(N5CCN(C)CC5)ccc43)cc2OC)cn1
Temperature: 120 °C
Reaction time: 16 h
Yield: 32.3 %

Procedure:
To a stirred suspension of 1-(2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-iodo-1H-benzo[d]imidazole (0.20 g, 0.39 mmol) in dimethyl sulfoxide (4 mL) was added 1-methylpiperazine (0.039 g, 0.39 mmol), copper(I) iodide (0.009 g, 0.046 mmol), potassium carbonate (0.19 g, 1.35 mmol), and L-proline (0.010 g, 0.092 mmol). The light yellow reaction mixture was heated to 120° C. After 16 h, the reaction mixture was allowed to cool to room temperature and was diluted with 3 N ammonium hydroxide solution (20 mL). The mixture was extracted with dichloromethane. The organic phase was washed with water (2×15 mL), brine, dried over magnesium sulfate, filtered, and concentrated. Chromatographic purification (CombiFlash, 40 g SiO2 column, 1-5% methanol/dichloromethane elute) provided 0.062 g of impure material. Subsequent re-purification via Prep-HPLC afforded 0.030 g (16%) of the product as a solid: 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J=2.0 Hz, 1H), 7.88 (s, 1H), 7.65 (dd, J=8.5, 2.5 Hz, 1H) 7.33 (d, J=2.1 Hz, 1H), 7.29-7.22 (m, 2H), 7.07-6.99 (m, 1H), 6.78-6.69 (m, 2H), 6.56 (d, J=7.1 Hz, 1H), 5.30 (s, 2H), 5.00 (s, 2H), 3.94 (s, 3H), 3.69 (s, 3H), 3.25-3.18 (m, 4H), 2.71-2.59 (m, 4H), 2.39 (s, 3H) ppm; (M+1)=492.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([NH2:17])[CH2:14][CH2:15][CH3:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29](O)=[O:30])[CH:24]=[CH:25][C:26]=1[CH3:27])[CH3:19]>>[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29]([NH:17][CH:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:14][CH2:15][CH3:16])=[O:30])[CH:24]=[CH:25][C:26]=1[CH3:27])[CH3:19]
Reactant: CCCC(N)c1ccccc1N1CCCCC1
Reactant: CCOc1cc(CC(=O)O)ccc1C
Product: CCCC(NC(=O)Cc1ccc(C)c(OCC)c1)c1ccccc1N1CCCCC1

Procedure:
Prepared from 1-(2-piperidino-phenyl)-1-butylamine and 3-ethoxy-4-methyl-phenylacetic acid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:16][CH2:17][Cl:18])[C:5]1[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8].[CH2:19](O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][CH2:2][CH2:3][N:4]([CH2:16][CH2:17][Cl:18])[C:5]1[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][C:6]=1[C:7]([O:9][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:8]
Reactant: Cc1cc(C)c(N(CCCl)CCCl)c(C(=O)O)c1
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C)c(N(CCCl)CCCl)c(C(=O)OCc2ccccc2)c1
Reaction time: 17 h
Yield: 91.5 %

Procedure:
2-Bis(2'-chloroethyl)amino-3,5-dimethylbenzoic acid (1.0 g, 3.45 mmol), benzyl alcohol (0.75 g, 6.90 mmol), 1,3-dicyclohexylcarbodiimide (0.82 g, 3.975 mmol), and 4-dimethylaminopyridine (0.50 g, 4.03 mmol) were dissolved in 25 mL dichloromethane at room temperature to form a reaction mixture. The mixture was stirred for 17 hours, diluted with hexanes (10 mL), cooled in the freezer for 20 minutes, and then filtered, It was then concentrated and then subjected to flash chromatographic purification (silica gel, 5% to 10% ethyl acetate in hexanes) to afford the product as a white oil (1.20 g, 92%). 1H NMR (300 MHz, CDCl3): 7.4 (m, 5H), 7.33 (d, J=2.1 Hz, 1H), 7.17 (d, J=2.1 Hz, 1H), 5.32 (s, 2H), 3.46 (m, 4H), 3.30 (br m, 4H), 2.33 (s, 3H), 2.29 (s, 3H). ESMS calcd (C20H23Cl2NO3): 379.1; found: 380.2 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][O:29][C:23]=3[CH:22]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][O:29][C:23]=4[CH:22]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Cc1sc2nc(Cl)nc(NCCc3ccc4c(c3)OCO4)c2c1C
Reactant: c1nc[nH]n1
Product: Cc1sc2nc(-n3cncn3)nc(NCCc3ccc4c(c3)OCO4)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5,6-dimethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5,6-dimethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][NH2:25].Cl>C(OCC)(=O)C>[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][NH:25][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:9][C:8](=[O:12])[C:7]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2c(O)c1-c1ccccc1
Reactant: CN(C)CCCN
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(C)CCCNc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12

Procedure:
7-Chloro-4-hydroxy-3-phenyl-2(1H)-quinolone (1 g) and 3-dimethylaminopropylamine (30 ml) were heated together in a similar manner to that described for Example 10 to give the crude product, which was suspended in a mixture of 1:1 ethyl acetate and 1N HCl and filtered. The aqueous phase was basified to pH14 with sodium hydroxide and then extracted into ethyl acetate. The organic layer was dried (MgSO4) and the solvent was removed to give the title compound (0.090 g); mp 177°-179° C. (diethyl ether). Found: C, 67.27; H, 6.22; N, 11.61. C20H22ClN3O requires C, 67.50; H, 6.23; N, 11.81%; δ (360 MHz, DMSO-d6) 1.38 (2H, m, NCH2CH2CH2N(CH3)2), 1.98 (2H, m, NCH2CH2CH2N(CH3)2), 2.04 (6H, s, N(CH3)2), 2.58 (2H, m, NCH2CH2CH2N(CH3)2), 6.58 (1H, m, NHCH2CH2CH2N), 7.19-7.94 (8H, m, aromatics), 11.15 (1H, br s, NHCO); m/z (CI-) 355 (M+).