Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([O:5][CH:6]1CN(C(C2OC(C3C=CC=CC=3)=NN=2)=O)C1)(=O)=O.C[C:24]1[CH:31]=[C:30]([O:32][CH:33]2[CH2:36][N:35]([C:37]([C:39]3[O:40][C:41]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[N:42][N:43]=3)=[O:38])[CH2:34]2)[CH:29]=[CH:28][C:25]=1[CH:26]=[O:27].COC1C=CC(C2OC(C(OCC)=O)=NN=2)=CC=1>>[CH3:6][O:5][C:47]1[CH:48]=[CH:49][C:44]([C:41]2[O:40][C:39]([C:37]([N:35]3[CH2:34][CH:33]([O:32][C:30]4[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:31]=4)[CH2:36]3)=[O:38])=[N:43][N:42]=2)=[CH:45][CH:46]=1
Reactant: CS(=O)(=O)OC1CN(C(=O)c2nnc(-c3ccccc3)o2)C1
Reactant: Cc1cc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)ccc1C=O
Agent: CCOC(=O)c1nnc(-c2ccc(OC)cc2)o1
Product: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(C=O)cc4)C3)o2)cc1
Yield: 32 %

Procedure:
Using similar protocols as described in Example 53A, 53B and 53C employing ethyl 5-(4-methoxyphenyl)-1,3,4-oxadiazole-2-carboxylate as starting material afforded 0.47 g (32%) of 55A as a solid. 1H NMR (500 MHz, CDCl3): δ 3.89 (s, 3H), 4.36 (d, 1H), 4.70 (dd, 1H), 4.79 (m, 1H), 5.18 (m, 2H), 6.91 (d, 2H), 7.03 (d, 2H), 7.88 (d, 2H), 8.10 (d, 2H), 9.93 (s, 1H), MS (APCI+) m/z 380 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=[O:22])=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:34](=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.O>O1CCCC1.ClCCl>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH:18]([CH:34]([OH:41])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:17]2=[O:22])=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(N2CCCCC2=O)sc1C(=O)NCc1ccccc1
Reactant: O=Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(N2CCCC(C(O)c3ccccc3)C2=O)sc1C(=O)NCc1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 3 %

Procedure:
To a solution of N-benzyl-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide (0.25 g, 0.76 mmol) in anhydrous tetrahydrofuran (10 mL) at −78° C. was added lithium bis(trimethylsilyl)amide in tetrahydrofuran (0.83 mL, 0.83 mmol) dropwise. The reaction mixture was stirred at −78° C. for 5 minutes, followed by the dropwise addition of benzaldehyde (0.077 mL, 0.76 mmol). The resulting mixture was slowly warmed to −30° C. over 30 minutes, followed by the addition of water (5 mL) and extraction with dichloromethane (3×10 mL). The combined organic solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (ethyl acetate/hexanes (1/1)) to afford the title compound as a white solid (0.010 g, 3%): mp 74-75° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.42-7.22 (m, 10H), 6.01 (t, J=5.5 Hz, 1H), 5.63 (d, J=2.5 Hz, 1H), 4.57 (d, J=5.5 Hz, 2H), 4.38-4.30 (m, 1H), 3.91-3.81 (m, 1H), 2.88-2.82 (m, 1H), 2.63 (s, 3H), 2.09-1.51 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 171.7, 162.6, 152.0, 141.4, 137.9, 128.8, 128.6, 128.4, 127.9, 127.7, 127.5, 125.8, 119.7, 72.7, 49.8, 48.0, 44.1, 21.6, 19.4, 17.3; MS (ES+) m/z 436.2 (M+1).
Reaction SMILES: CO[CH:3]1[C:8](=O)[CH2:7][CH2:6][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4]1.[NH3:17].[H][H]>[Ni].CO>[C:11]1([CH2:10][N:5]2[CH2:6][CH2:7][CH:8]([NH2:17])[CH2:3][CH2:4]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N
Reactant: COC1CN(Cc2ccccc2)CCC1=O
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: NC1CCN(Cc2ccccc2)CC1

Procedure:
A mixture of 83 parts of 3-methoxy-1-(phenylmethyl)-4-piperidinone, oxime and 400 parts of methanol saturated with ammonia was hydrogenated at normal pressure and at 50° C. with 6 parts of Raney-nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 78 parts (100%) of (cis+trans)-3-methoxy-1-(phenylmethyl-4-piperidinamine as a residue (intermediate 71).
Reaction SMILES: [F:1][C:2]([F:16])=[C:3]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:4]([F:7])([F:6])[F:5].CI.[F-:19].[Cs+].[CH3:21]N(C=O)C>O>[F:19][C:2]([F:16])([F:1])[C:3]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)([CH3:21])[C:4]([F:5])([F:6])[F:7]
Reactant: COc1ccc(C(=C(F)F)C(F)(F)F)cc1
Reactant: CN(C)C=O
Reactant: [F-]
Agent: [Cs+]
Solvent: O
Solvent: CI
Product: COc1ccc(C(C)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 72 h
Yield: 10 %

Procedure:
A mixture of Compound 74 (570 mg, 2.4 mmol), MeI (430 mg, 3.0 mmol), and CsF (760 mg, 5.0 mmol) in DMF (4 ml) was stirred at 80° C. for 3 days. The mixture was diluted with H2O. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined solution was dried (Na2SO4) and concentrated in vacuo to give crude product, which was purified by column chromatography on silica gel to give Compound 75 (70 mg, 10%) as a yellow oil.
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[C:4](=[O:10])[NH:3][CH:2]=1.[Br:11]Br.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:11][C:7]1[C:6]2[N:1]=[CH:2][NH:3][C:4](=[O:10])[C:5]=2[S:9][CH:8]=1
Reactant: BrBr
Reactant: O=c1[nH]cnc2ccsc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1[nH]cnc2c(Br)csc12
Temperature: 25 °C
Yield: 64 %

Procedure:
To a solution of 3H-thieno[3,2-d]pyrimid-4-one (82, 0.98 g, 6.4 mmol) in acetic acid (3.4 mL) was added a solution of bromine (1 mL) in acetic acid (3 mL). The reaction mixture was heated at reflux for 8 hours. The resulting suspension was allowed to cool to room temperature and then poured into a saturated aqueous solution of sodium bicarbonate to neutralize. The solid product was collected by vacuum filtration to give 7-bromo-3H-thieno[3,2-d]pyrimid-4-one (0.94 g, 64% yield) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([Sn](CCCC)(CCCC)CCCC)=[CH2:5])[CH3:2].Br[C:20]1[N:25]=[C:24]([O:26][CH3:27])[C:23]([N:28]2[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]2)=[CH:22][CH:21]=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:4]([O:3][C:1]([C:20]1[N:25]=[C:24]([O:26][CH3:27])[C:23]([N:28]2[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]2)=[CH:22][CH:21]=1)=[CH2:2])[CH3:5]
Reactant: COc1nc(Br)ccc1-n1cnc(C)c1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=C(OCC)c1ccc(-n2cnc(C)c2)c(OC)n1
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
1-Ethoxyvinyltri-n-butyltin (3.7 mL) was added to a suspension of 6-bromo-2-methoxy-3-(4-methyl-1H-imidazole-1-yl)pyridine (2.66 g) and bis(triphenylphosphine)palladium (II) chloride (350 mg) in dioxane (25 mL), and the mixture was stirred at 100° C. for five hours and 45 minutes. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography. The target fraction was concentrated. The resulting powder was triturated with diethyl ether-n-hexane and dried under reduced pressure to obtain 1.57 g of the title compound. Then, the mother liquor was concentrated to obtain 858 mg of the title compound. The property values of the compound are as follows: 1H-NMR (CDCl3) δ (ppm): 1.45 (t, J=7.2 Hz, 3H), 2.30 (s, 3H), 3.98 (q, J=7.2 Hz, 2H), 4.04 (s, 3H), 4.38 (d, J=1.6 Hz, 1H), 5.48 (d, J=1.6 Hz, 1H), 6.97 (s, 1H), 7.38 (d, j=8.0 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.78 (s, 1H).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH2:12])[N:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>>[N:13]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH2:12])[N:3]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: C1COCCN1
Reactant: Nc1cc2ccccc2c(Br)n1
Product: Nc1cc2ccccc2c(N2CCOCC2)n1
Yield: 92 %

Procedure:
1-Bromo-3-aminoisoquinoline is reacted with an equimolar quantity of morpholine as described in Example 1 to give 1-morpholinyl-3-aminoisoquinoline.
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22](C(OC(C)(C)C)=O)[C@H:21]([CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH:20]=[C:19]1[C:40]([CH3:42])=[CH2:41])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].C(ON([C@H]1CN[C@H](C(N)=O)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:1]([O:4][N:5]([C@@H:18]1[C:19]([C:40]([CH3:42])=[CH2:41])=[CH:20][C@@H:21]([CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[NH:22][CH2:23]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C(=C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: C=CCON([C@H]1CN[C@H](C(N)=O)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON([C@H]1CN[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C(=C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-((tert-butyldimethylsilyloxy)methyl)-4-(prop-1-en-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 54, 3.04 g, 4.87 mmol) following the procedure described for Intermediate 21. The desired product was obtained as an orange oil (2.53 g, 99%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:16]=[C:15]([C:24]3[CH:32]=[CH:31][CH:30]=[C:29]4[C:25]=3[CH2:26][NH:27][C:28]4=[O:33])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.O.O.O.O.O.O.O.[N+]([O-])([O-])=[O:42].[Mg+2].[N+]([O-])([O-])=O.[Mn]([O-])(=O)(=O)=O.[K+]>CC(C)=O.C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:16]=[C:15]([C:24]3[CH:32]=[CH:31][CH:30]=[C:29]4[C:25]=3[C:26](=[O:42])[NH:27][C:28]4=[O:33])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:10])([F:11])[F:12])[CH:7]=1
Reactant: O=C1NCc2c1cccc2-c1cc(-c2cc(F)cc(OC(F)(F)F)c2)n(-c2cccnc2)n1
Reactant: O=[N+]([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC(C)=O
Solvent: O
Solvent: CC#N
Product: O=C1NC(=O)c2c1cccc2-c1cc(-c2cc(F)cc(OC(F)(F)F)c2)n(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
40 mg (0.09 mmol) of the compound from example 7 are absorbed in 1 ml acetone and mixed with 1 ml water, 74 mg (0.29 mmol) magnesium nitrate hexahydrate and 32 mg (0.20 mmol) potassium permanganate. The reaction mixture is stirred for 24 hours at room temperature, diluted with 5 ml acetonitrile and filtered through a Millipore filter. The filtrate is extracted twice with dichloromethane and the combined organic phases washed with a saturated sodium chloride solution, dried using sodium sulfate, filtered and evaporated under vacuum until dryness. The residue is recrystallized from acetonitrile. This produces 14 mg (25% of theoretical yield, 75% purity) of the title compound.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[CH3:28]C(C)([O-])C.[K+].[CH3:34][Si:35]([CH3:58])([C:54]([CH3:57])([CH3:56])[CH3:55])[O:36][CH2:37][C@@H:38]1[C@@H:45]2[C@@H:41]([O:42][CH:43](O)[CH2:44]2)[CH2:40][C@H:39]1[O:47][CH:48]1[CH2:53][CH2:52][CH2:51][CH2:50][O:49]1.C(=O)([O-])[O-].[K+].[K+].CI>CC(C)=O.O1CCCC1>[CH3:34][Si:35]([CH3:58])([C:54]([CH3:57])([CH3:56])[CH3:55])[O:36][CH2:37][C@H:38]1[C@H:39]([O:47][CH:48]2[CH2:53][CH2:52][CH2:51][CH2:50][O:49]2)[CH2:40][C@H:41]([OH:42])[C@@H:45]1[CH2:44]/[CH:43]=[CH:8]\[CH2:7][CH2:6][CH2:5][C:2]([O:4][CH3:28])=[O:3]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1[C@H]2CC(O)O[C@H]2C[C@H]1OC1CCCCO1
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)CCC/C=C\C[C@@H]1[C@@H](CO[Si](C)(C)C(C)(C)C)[C@H](OC2CCCCO2)C[C@@H]1O
Temperature: 25 °C
Yield: 89.1 %

Procedure:
To an anhydrous tetrahydrofuran (1370 mL) suspension of (4-carboxybutyl)triphenylphosphonium bromide (180.3 g) was added potassium t-butoxide (91.4 g) over 6 minutes while the mixture was stirred on a water bath. The mixture was stirred for 3 hours, and then to the reaction mixture was added dropwise an anhydrous tetrahydrofuran (130 mL) solution of the compound 2 (70.7 g) over 5 minutes. The mixture was further stirred at room temperature for 1 hour, the reaction mixture was then poured into ice water (4.2 L), and a 10% aqueous oxalic dihydrate solution (about 195 mL) was added to adjust pH to 5 to 6. The reaction mixture was extracted (1 L×3 times) with a mixed liquid of hexane (500 mL) and ethyl acetate (500 mL), and the organic layers were combined, and washed with a saturated saline (500 mL). The mixture was dried with anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a crude product (161.1 g), which was dissolved in acetone (260 mL). To this solution were added potassium carbonate (34.0 g) and methyl iodide (20 mL), and the mixture was stirred at room temperature for 14 hours, and further refluxed for 1 hour. After allowing to cool to room temperature, an insoluble solid was filtered away, and the filtrate was concentrated under reduced pressure to about ½ of the original volume. To this solution was added water (750 mL), and the mixture was extracted with a mixed liquid of hexane (250 mL) and ethyl acetate (250 mL). The extract was washed with a saturated saline (500 mL), and washing water and the aqueous layer were combined, and extracted again with ethyl acetate (200 mL). The organic layers were combined, dried with anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→1:1) to obtain a titled compound (79.6 g) having the following physical property values.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH:12]=[C:10]([CH3:11])[C:8](=[O:9])[NH:7][C:5]1=[O:6].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH2:24].O>CS(C)=O>[CH2:24]([N:7]1[C:8](=[O:9])[C:10]([CH3:11])=[CH:12][N:4]([CH3:3])[C:5]1=[O:6])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=[CH2:14]
Reactant: Cc1cn(C)c(=O)[nH]c1=O
Reactant: C=CCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCCCCCCCCCn1c(=O)c(C)cn(C)c1=O
Reaction time: 0.33 h
Yield: 83.4 %

Procedure:
This example illustrates a synthesis of 3-(11,10-Oxidoundecyl)-1-methylthymine (inventive compound no. 1932). Sodium hydride (95%) (168 mg, 7 mmol) was added to a solution of 1-methylthymine (700.5 mg, 5 mmol) in dimethylsulfoxide (15 mL). After 20 minutes of stirring, 1-bromundec-10-ene (1.165 g, 5 mmol) was added and stirred for 12 hours at room temperature. The reaction mixture was then poured into a separatory funnel containing 100 mL of water and extracted with dichloromethane (5×75 mL). The organic extracts were combined, washed with water (50 mL) and saturated aqueous salt solution (50 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was further purified by flash chromatography over silica gel using a 20% ethyl acetate/hexane eluant to yield 1.22 g (83.7% yield) 3-(10-undecenyl)-1-methylthymine (inventive compound no. 1931).
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[NH:8]/[C:7]/1=[N:16]\[NH2:17])[CH2:2][CH2:3][CH2:4][CH3:5].O=[CH:19][CH2:20][CH2:21][NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C>[O:15]=[C:9]1[NH:8]/[C:7](=[N:16]\[N:17]=[CH:19]/[CH2:20][CH2:21][NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)/[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]2[N:13]=[CH:12][NH:11][C:10]1=2
Reactant: O=CCCNC(=O)OCc1ccccc1
Reactant: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]cnc21
Solvent: CCO
Product: CCCCCn1/c(=N/N=C\CCNC(=O)OCc2ccccc2)[nH]c(=O)c2[nH]cnc21
Yield: 97.9 %

Procedure:
A mixture of (2E)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone (2.3 g, 9.6 mmol) and benzyl (3-oxopropyl)carbamate (2.0 g, 9.6 mmol) in ethanol (30 mL) was refluxed overnight. The reaction mixture was concentrated to give the product (4.0 g, 58% yield), which was used for next step without further purification. LCMS calculated for C21H28N7O3 (M+H): 426.2. found: 426.1.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[N:20]=[C:19]([CH3:21])[NH:18][N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[Cl:28][C:29]1[CH:34]=[C:33]([CH2:35]Cl)[CH:32]=[CH:31][N:30]=1>CN(C=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:15]=[C:14]([C:16]3[N:20]=[C:19]([CH3:21])[N:18]([CH2:35][C:33]4[CH:32]=[CH:31][N:30]=[C:29]([Cl:28])[CH:34]=4)[N:17]=3)[O:13][N:12]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCc1ccnc(Cl)c1
Reactant: Cc1nc(-c2nc(-c3ccc(C(C)(C)C)cc3)no2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2nc(-c3ccc(C(C)(C)C)cc3)no2)nn1Cc1ccnc(Cl)c1
Reaction time: 0.08 h
Yield: 44.5 %

Procedure:
3-(4-(tert-Butyl)phenyl)-5-(5-methyl-1H-1,2,4-triazol-3-yl)-1,2,4-oxadiazole (140 mg, 0.495 mmol) was placed in DMF (10 mL) and Cs2CO3 (193 mg, 0.594 mmol) was added. The reaction was stirred for 5 min and 2-chloro-4-(chloromethyl)pyridine (96 mg, 0.594 mmol) was added. The reaction was stirred at 45° C. overnight and was then partitioned between H2O (25 mL) and EtOAc (25 mL). The organic layer was separated, washed with H2O (2×25 mL) and brine (15 mL), dried over Na2SO4, filtered, and concentrated to afford the crude product which was purified by silica gel chromatography (EtOAc/Hexane 0%-100% EtOAc) to afford 3-(4-(tert-butyl)phenyl)-5-(1-((2-chloropyridin-4-yl)methyl)-5-methyl-1H-1,2,4-triazol-3-yl)-1,2,4-oxadiazole as a yellow solid (90 mg, 45%). MS (ES+) C21H21ClN6O requires: 408. found 409 [M+H]+; 1H NMR (600 MHz, CDCl3) δ 8.42 (d, J=5.2 Hz, 1H), 8.16 (d, J=8.5 Hz, 2H), 7.52 (d, J=8.5 Hz, 2H), 7.16 (s, 1H), 7.05 (d, J=5.2 Hz, 1H), 5.46 (s, 2H), 2.57 (s, 3H), 1.37 (s, 9H).
Reaction SMILES: [CH2:1]1[C:5]2[C:6]3[C:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:4]=2[CH:3]=[C:2]1[Si:18]([CH3:21])([CH3:20])Cl)=[CH:10][CH:9]=[CH:8][CH:7]=3.[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23]>CCCCCC>[CH2:1]1[C:5]2[C:6]3[C:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:4]=2[CH:3]=[C:2]1[Si:18]([CH3:21])([CH3:20])[NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: C[Si](C)(Cl)C1=Cc2c(c3ccccc3c3ccccc23)C1
Reactant: CC(C)(C)N
Solvent: CCCCCC
Product: CC(C)(C)N[Si](C)(C)C1=Cc2c(c3ccccc3c3ccccc23)C1

Procedure:
To a 500 ml round bottom flask containing 1.98 g (0.0064 mole) of (1H-cyclopenta[1]phenanthrene-2-yl)dimethylchlorosilane and 250 ml of hexane was added 2.00 ml (0.0160 mole) of t-butylamine. The reaction mixture was allowed to stir for several days, then filtered using diatomaceous earth filter aid (Celite™), washed twice with hexane. The product was isolated by removing residual solvent under reduced pressure. The isolated yield was 1.98 g (88.9 percent).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)([CH3:25])[CH3:24]>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:35]2[CH2:36][CH2:37][N:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[CH:23]([CH3:25])[CH3:24])[CH2:33][CH2:34]2)=[O:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Reactant: CC(C)c1ccccc1N1CCNCC1
Product: COc1nc2ccccc2nc1NC(=O)N1CCN(c2ccccc2C(C)C)CC1
Yield: 77.5 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)carbamate and 1-(2-isopropylphenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2([C:28]([OH:30])=O)[CH2:27][CH2:26]2)=[O:24])=[CH:18][CH:17]=1.[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23]([C:25]2([C:28]([NH:37][CH2:36][C:35]3[CH:38]=[CH:39][C:32]([F:31])=[CH:33][CH:34]=3)=[O:30])[CH2:27][CH2:26]2)=[O:24])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)C4(C(=O)O)CC4)cc3)c2cc1OC
Reactant: NCc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2nccc(Oc3ccc(NC(=O)C4(C(=O)NCc5ccc(F)cc5)CC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
To a solution of 1-[4-(6,7-dimethoxy-quinolin-4-yloxy)-phenylcarbamoyl]-cyclopropanecarboxylic acid (74.3 mg, 0.182 mmol), 4-Fluoro benzylamine (25 μL, 0.219 mmol), DIEA (90.0 μL, 0.544 mmol) in DMA (1.0 mL) was added HATU (203 mg, 0.534 mmol). The resulting solution was stirred at room temperature for 1 hour before adding dropwise to water (10 mL) with stirring. The slurry was sonicated, filtered and the solids were washed with 1 N NaOH followed by water. After air drying, the solids were further purified by prep HPLC, affording ‘N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-[(4-fluorophenyl)methyl]cyclopropane-1,1-dicarboxamide (33 mg, 35% yield, 98% pure) as a white solid. 1H NMR (DMSO, d6): 10.82 (s, 1H), 8.80 (d, 1H), 8.50 (t, 1H), 7.83 (d, 2H), 7.74 (s, 1H), 7.56 (s, 1H), 7.30-7.38 (m, 4H), 7.15 (t, 2H), 6.80 (d, 1H), 4.32 (d, 2H), 4.04 (s, 3H), 4.03 (s, 3H), 1.42 (s, 4H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[S:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24]([NH2:27])(=[O:26])=[O:25])(=[O:16])=[O:15])=[CH:8][CH:7]=1.CO>C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][S:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24]([NH2:27])(=[O:26])=[O:25])(=[O:15])=[O:16])=[CH:8][CH:7]=1
Reactant: NS(=O)(=O)c1ccccc1NS(=O)(=O)/C=C/c1ccc(-c2ccco2)cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)CCc1ccc(-c2ccco2)cc1
Yield: 12.7 %

Procedure:
2-[[(E)-2-[4-(2-Furyl)phenyl]ethenyl]sulfonylamino]benzenesulfonamide (Example 18) (140 mg, 0.35 mmol) was dissolved in ethyl acetate (1.5 mL) and methanol (1.5 mL) and the mixture was subjected to reduction using the H-cube instrument. The reaction mixture was eluted through the Pd/C (10%) cartridge using full hydrogen (1 atm) at 0.5 ml/min. The solvent was then removed and the crude material was purified on semi-preparative HPLC using an X-Terra column to give the title compound (18 mg, 13%) as a white solid. The compound of Example 17 was also obtained.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH3:2].[Cl:13][CH2:14][Si:15](Cl)([CH3:17])[CH3:16]>>[CH2:1]([NH:3][C:4](=[O:12])[C:5]1[C:10]([Si:15]([CH2:14][Cl:13])([CH3:17])[CH3:16])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH3:2]
Reactant: C[Si](C)(Cl)CCl
Reactant: CCNC(=O)c1ccccc1Cl
Product: CCNC(=O)c1c(Cl)cccc1[Si](C)(C)CCl

Procedure:
The title compound was prepared from the compound of Example f and 2.0 eq (chloromethyl)dimethylsilyl chloride according to General Method C. Recrystallization from ethyl acetate gave 3.0 g of the desired compound as a white solid, a 52% yield. m.p. 88-89° C.