Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1([CH3:16])[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[NH:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH2:19][CH2:18]1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[CH3:16][C:3]1([CH2:2][N:26]2[CH2:27][CH2:28][CH:23]([C:20]3[CH:19]=[CH:18][N:17]=[CH:22][CH:21]=3)[CH2:24][CH2:25]2)[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1
Reactant: c1cc(C2CCNCC2)ccn1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CBr)O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(c3ccncc3)CC1)O2
Temperature: 180 °C
Reaction time: 15 h
Yield: 70.4 %

Procedure:
In an autoclave, a mixture of 2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine (0.85 g), 4-(4-piperidinyl)pyridine (0.97 g), and triethylamine (1.3 mL) was stirred under nitrogen gas at 180° C. for 15 hours. To this reaction mixture were added saturated aqueous NaHCO3 and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The pooled organic layer was washed with water and saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=20.1) and crystallized from ethyl acetate/hexane to provide 0.77 g of the title compound. Yield 70%.
Reaction SMILES: CC1C=CC(S([CH2:11][N:12]=[CH2:13])(=O)=O)=CC=1.[C:14]([O:24][CH3:25])(=[O:23])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O1CCCC1.[H-].[Na+]>O>[C:17]1([C:16]2[C:15]([C:14]([O:24][CH3:25])=[O:23])=[CH:11][NH:12][CH:13]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)C=Cc1ccccc1
Reactant: C=NCS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1c[nH]cc1-c1ccccc1
Temperature: 25 °C

Procedure:
p-Tosylmethyl isocyanide (1 g., 5 mmoles) and methyl cinnamate (0.8 g., 5 mmoles) were combined in 50 ml. of tetrahydrofuran and dissolved by stirring at room temperature. The solution was cooled to -50° C. and sodium hydride (57% dispersion in oil, 210 mg., 5 mmoles) added. After stirring for 15 minutes at -50° C., the reaction was warmed to room temperature and stirred for approximately 16 hour. Water (20 ml.) was added and the product extracted into 35 ml. ether. The ether was back-washed with 20 ml. of water, evaporated to dryness, the residue triturated with ether and methyl 4-phenylpyrrole-3-carboxylate (230 mg., m.p. 182°-185° C., m/e 201) recovered by filtration. The product was recrystallized from acetone/hexane (210 mg., m.p. 184°-187° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[CH2:14]([NH:21][CH2:22][CH2:23][NH2:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([NH:21][CH2:22][CH2:23][NH:24][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCCNCc1ccccc1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Product: O=C(NCCNCc1ccccc1)c1cc2cc(Cl)ncc2[nH]1

Procedure:
The title compound was prepared as outlined in EXAMPLE 1 from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18) and 2-benzylaminoethylamine. The product was purified by mass directed purification to give the title compound as an off-white solid. m/z (ES+)=329 [M+H]+; RT=2.75 min.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:17][OH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:17][O:18][S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=1)(=[O:28])=[O:27])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H]1CCCC[C@H]1CO)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCC[C@H]2NC(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
A solution of (1R,2R)-(2-hydroxymethylcyclohexyl)-carbamic acid benzyl ester (6.0 g, 22.8 mmol) in pyridine (35 mL) was stirred on an ice-acetone bath and treated with toluene-4-sulfonyl chloride (4.78 g, 25.1 mmol). The reaction was stirred on an ice-water bath for 3 hours, then ice-cold water (35 mL) was added slowly. The mixture was diluted further with ice water and the resulting slurry was stirred at room temperature for 1 hour. The solid was collected by filtration, washed with water, and dried under vacuum to provide a white powdery solid (9.1 g, 96%).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][OH:14].[H-].[Na+]>>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:14][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[O:10][CH3:9])[N:3]=1
Reactant: COc1ccccc1CO
Reactant: Clc1cncc(Cl)n1
Agent: [H-]
Agent: [Na+]
Product: COc1ccccc1COc1cncc(Cl)n1

Procedure:
The title compound was prepared according to the procedure of example 4, step 1 starting from 2,6-dichloropyrazine (298 mg, 2.00 mmol), 2-methoxybenzyl alcohol (303 mg, 2.20 mmol) and NaH (55% in mineral oil, 96 mg, 2.2 mmol). The yield of the crude product was 0.49 g (98%) and was used directly as such in the next step. MS m/z 250 (M)+. HRMS m/z calcd for C12H11ClN2O2 (M)+ 250.0509, found 250.0522.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][CH:7]1[CH2:9][O:8]1.[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][NH:14]1.CC(=O)OCC>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][CH:7]([OH:8])[CH2:9][N:14]1[CH2:15][CH2:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13]1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Brc1cccc(OCC2CO2)c1
Solvent: CO
Solvent: CCOC(C)=O
Product: OC(COc1cccc(Br)c1)CN1CCc2ccccc2C1
Yield: 75.9 %

Procedure:
To a solution of 2-((3-bromophenoxy)methyl)oxirane (1.5 g, 6.55 mmol) in MeOH (15 mL) were added 1,2,3,4-tetrahydroisoquinoline (1.0 g, 7.86 mmol) at 8° C. The mixture was refluxed for 16 h. TLC (PE: EA=2:1) showed that the reaction was completed and the mixture was concentrated to yield crude material which was purified using column chromatography on silica gel to give the desired compound (1.8 g, 78.3%) as colorless oil. LCMS (m/z): 362.1/363.1 [M+H]+/[M+2H]+
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4].ClC1C=C(C=CC=1)C(OO)=[O:36].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-:36])=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCc1nc2cnc3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCc1nc2c[n+]([O-])c3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Reaction time: 5 h
Yield: 85.9 %

Procedure:
A solution of tert-butyl 2-[2-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (4.12 g, 10.0 mmol) in 50 mL of CH2Cl2 was treated with 3-chloroperoxybenzoic acid (MCPBA, 77%, 2.5 g, 11.2 mmol). After stirring for 5 h, the reaction mixture was treated with saturated NaHCO3 solution and the layers were separated. The organic portion was washed with H2O and brine then dried over Na2SO4 and concentrated to give 3.68 g of tert-butyl 2-[2-(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a light brown foam.
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22]>CN(C=O)C>[OH:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[NH:15][C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Reactant: Nc1ccccc1O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(Nc2ccccc2O)[nH]c1=O
Temperature: 110 °C
Reaction time: 18 h
Yield: 56.4 %

Procedure:
Ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (40 g) and 2-aminophenol (22.4 g) are added to DMF (80 ml), and the mixture is heated with stirring at 110° C. for 18 hour. After cooling, the precipitate is collected by filtration and recrystallized from DMF to give ethyl 1,6-dihydro-2-(2-hydroxyanilino)-6-oxo-5-pyrimidinecarboxylate (29 g). M.p. 289°-291° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[C:4]([NH:9][NH2:10])=[N:5][CH:6]=[CH:7][CH:8]=1.[I:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16](F)[C:15]=1[CH:21]=O>CN1C(=O)CCC1>[I:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[N:9]([C:4]3[C:3]([C:2]([F:1])([F:11])[F:12])=[CH:8][CH:7]=[CH:6][N:5]=3)[N:10]=[CH:21][C:15]=12
Reactant: NNc1ncccc1C(F)(F)F
Reactant: O=Cc1c(I)ccnc1F
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1cccnc1-n1ncc2c(I)ccnc21
Temperature: 185 °C
Yield: 89.3 %

Procedure:
To a dry 15 mL ChemGlass pressure bottle under nitrogen was added 3-(trifluoromethyl)pyrid-2-ylhydrazine (499 mg, 2.82 mmol), 4-iodo-2-fluoro-3-formylpyridine (706.8 mg, 2.82 mmol) and anhydrous NMP (4.5 mL). The reaction mixture was flushed with argon, securely capped and heated to 185° C. for 1.5 h. The reaction mixture was worked up according to the procedure described in Intermediate 69A to give 982 mg (89%) of the title compound as an oil. LC/MS (Condition B): ret. T=3.4 min, (M+H)+ 390.94.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.[CH:12]([OH:15])(C)[CH3:13]>O>[CH3:6][CH:1]([CH2:2][CH3:3])[CH:11]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:13][CH:12]=[O:15]
Reactant: CC(C)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCC(C)C(CC=O)c1ccccc1
Reaction time: 8.5 h
Yield: 59 %

Procedure:
Under a nitrogen atmosphere, a n-butyllithium/tetrahydrofuran solution (1.53 M, 1.2 mL) was added to a tetrahydrofuran solution of (methoxymethyl) triphenylphosphonium chloride (627 mg) at −78° C., and then the temperature of the mixture was raised to 0° C. After 20 minutes, the outer temperature was lowered to −78° C., and then 4-methyl-3-phenyl-pentanal (200 mg) was added thereto together with tetrahydrofuran (4 mL). After 45 minutes, the temperature of the mixture was returned to room temperature, and the mixture was further stirred for 20 minutes. The organic layer was separated by adding diethyl ether and an aqueous saturated ammonium chloride thereto. The resulting organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. After filtering off the drying agent, the mixture was evaporated, to give the title compound as a colorless oil (200 mg). The resulting compound was dissolved in isopropanol (2 mL)/water (2 mL), p-toluenesulfonic acid (6 mg) was added thereto, and then the reaction was carried outfor 8.5 hours under refluxing. The organic layer was separated by adding diethyl ether and an aqueous saturated ammonium chloride thereto. The resulting organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. After filteringoff thedryingagent, themixturewasevaporated. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate system), to give the title compound as a colorless oil (103 mg, 59%, 3 steps).
Reaction SMILES: [CH2:1]([NH:4][C@H:5]1[CH2:14][CH2:13][C:12]2[C:11]([OH:15])=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6]1)[CH2:2][CH3:3].CC1C=CC(S(O[CH2:27][CH2:28][C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)(=O)=O)=CC=1.S([O-])([O-])=O.[Na+].[Na+]>C1(C)C(C)=CC=CC=1>[CH2:1]([N:4]([CH2:27][CH2:28][C:29]1[S:30][CH:31]=[CH:32][CH:33]=1)[C@H:5]1[CH2:14][CH2:13][C:12]2[C:11]([OH:15])=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6]1)[CH2:2][CH3:3]
Reactant: Cc1ccc(S(=O)(=O)OCCc2cccs2)cc1
Reactant: CCCN[C@H]1CCc2c(O)cccc2C1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CCCN(CCc1cccs1)[C@H]1CCc2c(O)cccc2C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 53.4 %

Procedure:
2.00 kg (9.74 mol) of (S)-5,6,7,8-tetrahydro-6-propylamino-1-naphthol, 4.12 kg (14.62 mol) of 2-(2-thienyl)ethyl 4-methylbenzenesulfonate (with a sulfonate/starting material mole ratio of 1.5/1), 3.69 kg (29.25 mol) of sodium sulfite (with a sodium sulfite/starting material mole ratio of 3.0/1) and 25 L of xylene were mixed to form a mixture, and the mixture was refluxed. After 48 hours, the reaction was stopped. The mixture was cooled to room temperature, and washed with an appropriate amount of water. Active carbon was added to decolorize the mixture. The mixture was filtered and left standing. An organic phase was reserved and concentrated under vacuum to obtain a residue. The residue was separated by silica gel column chromatography, and eluted with ethyl acetate and hexane (1:19), to obtain 1.64 kg of (S)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino]-1-naphthol, which was converted into a hydrochlorate thereof. The yield was 47.8%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:91]=[CH:90][C:6]([CH2:7][O:8][C@@H:9]([C@@H:84]([CH3:89])/[CH:85]=[CH:86]\[CH:87]=[CH2:88])[C@@H:10]([CH3:83])[C@H:11]([O:75][Si:76]([C:79]([CH3:82])([CH3:81])[CH3:80])([CH3:78])[CH3:77])[CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([CH3:74])[C@@H:17]([O:66][Si:67]([C:70]([CH3:73])([CH3:72])[CH3:71])([CH3:69])[CH3:68])[C@@H:18]([CH3:65])/[CH:19]=[CH:20]\[C@@H:21]([O:57][Si:58]([C:61]([CH3:64])([CH3:63])[CH3:62])([CH3:60])[CH3:59])[CH2:22][C@H:23]([O:49][Si:50]([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51])[C@H:24]([CH3:48])/[CH:25]=[CH:26]/[CH2:27][O:28]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1>CCOC(C)=O.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C@@H:9]([C@@H:84]([CH3:89])/[CH:85]=[CH:86]\[CH:87]=[CH2:88])[C@@H:10]([CH3:83])[C@H:11]([O:75][Si:76]([C:79]([CH3:82])([CH3:81])[CH3:80])([CH3:77])[CH3:78])[CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([CH3:74])[C@@H:17]([O:66][Si:67]([C:70]([CH3:71])([CH3:72])[CH3:73])([CH3:69])[CH3:68])[C@@H:18]([CH3:65])/[CH:19]=[CH:20]\[C@@H:21]([O:57][Si:58]([C:61]([CH3:62])([CH3:63])[CH3:64])([CH3:60])[CH3:59])[CH2:22][C@H:23]([O:49][Si:50]([C:53]([CH3:54])([CH3:55])[CH3:56])([CH3:52])[CH3:51])[C@H:24]([CH3:48])/[CH:25]=[CH:26]/[CH2:27][OH:28])=[CH:90][CH:91]=1
Reactant: C=C/C=C\[C@H](C)[C@H](OCc1ccc(OC)cc1)[C@@H](C)[C@@H](CCCC[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C\[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](C)/C=C/COC(c1ccccc1)(c1ccccc1)c1ccccc1)O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=C/C=C\[C@H](C)[C@H](OCc1ccc(OC)cc1)[C@@H](C)[C@@H](CCCC[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C\[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](C)/C=C/CO)O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Yield: 177769.8 %

Procedure:
The procedure for 45 was used with 74 (0.58 g, 0.22 μmol), ZnBr (0.25 g, 1.11 mmol) to yield 75 (0.42 g, 89%) after flash column chromatography (EtOAc/hexane 3:17) as a colorless oil: IR (CHCl3) 3402, 2956, 2929, 2856, 1614, 1514, 1471, 1251, 1085, 836, 773 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.47-7.44 (m, 2H), 7.04-7.01 (m, 2H), 6.76 (ddd, J=16.8, 10.6, 10.5 Hz, 1H), 6.19 (t, J=11.0 Hz, 1H), 5.87-5.72 (m, 3H), 5.59 (t, J=10.0 Hz, 1H), 5.45 (dd, J=10.9, 8.3 Hz, 1H), 5.35 (d, J=16.8 Hz, 1H), 5.27 (d, J=10.2 Hz, 1H), 4.75-4.65 (m, 3H), 4.22 (d, J=4.5 Hz, 2H), 4.09 (m, 1H), 3.94 (s, 3H), 3.83 (m, 1H), 3.56 (m, 1H), 3.51 (m, 1H), 3.17 (m, 1H), 2.77 (m, 1H), 2.57 (m, 1H), 1.95 (m, 1H), 1.85 (m, 1H), 1.78-1.55 (m, 8H), 1.53-1.40 (m, 3H), 1.29 (d, J=6.7 Hz, 3H), 1.56-1.06 (m, 45H), 1.01 (d, J=6.7 Hz, 3H), 0.29-0.22 (m, 24H); 13C NMR (75 MHz, CDCl3) δ 158.9, 134.8, 134.5, 132.8, 132.4, 132.3, 131.2, 129.2, 129.1, 128.9, 117.1, 113.6, 84.3, 80.2, 75.0, 72.4, 72.2, 66.5, 63.6, 55.1, 42.3, 41.5, 40.5, 37.9, 35.7, 35.2, 33.8, 28.1, 26.2, 25.9, 25.6, 19.3, 18.8, 18.4, 18.2, 18.0, 14.6, 13.0, 9.2, −3.0, −3.5, −3.7, −3.9, −4.3, −4.4, −4.5; LRMS (ESI) 1095.7 [M+Na]+, 809.6, 677.5, 537.4, 413.2; HRMS (ESI) calcd for C61H116O7Si4Na 1095.7696 [M+Na]+, found 1095.7712; [α]20D+4.8 (c 1.7, CHCl3).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:17])=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=2)[O:4][N:3]=1.[CH:22](OCC)(OCC)[O:23][CH2:24][CH3:25]>>[CH3:16][C:13]([C:11]1[CH:12]=[C:7]([C:5]2[O:4][N:3]=[C:2]([N:1]=[CH:22][O:23][CH2:24][CH3:25])[N:6]=2)[CH:8]=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[OH:17])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1cc(-c2nc(N)no2)cc(C(C)(C)C)c1O
Reactant: CCOC(OCC)OCC
Product: CCOC=Nc1noc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)n1
Yield: 67.5 %

Procedure:
A mixture of 0.87 g (0.003 mole) of 4-(3-amino-1,2,4-oxadiazol-5-yl)-2,6-bis(1,1-dimethylethyl)phenol and 25 ml (22.3 g; 0.15 mole) of anhydrous triethyl orthoformate is stirred at reflux (under a nitrogen atmosphere) for 24 hours. The cooled mixture is evaporated, and the residue is distributed between 75 ml of dichloromethane and 100 ml of saturated aqueous sodium bicarbonate solution. The aqueous layer is extracted several times with fresh dichloromethane, and the combined organic layers are washed with brine. The organic layer is dried (anhydrous sodium sulfate) and evaporated. Recrystallization of the residue from aqueous acetonitrite yields 0.70 g (67% yield) of ethyl N-[5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,2,4-oxadiazol-3-yl]methanimidoate, mp 159°-161° C.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[NH:10][N:9]=1)=[O:7])C>CO>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][C:11]2[NH:10][N:9]=[C:8]([C:6]([OH:7])=[O:5])[CH:12]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1cc(CCc2ccc(OC)cc2)[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CCc2cc(C(=O)O)n[nH]2)cc1

Procedure:
Freshly prepared aq. NaOH (10 M in H2O, 25.4 mmol) was added to a stirring, room temperature solution of 23 (1.391 g, 5.07 mmol) in MeOH (12.7 mL, 0.4 M) under N2. The reaction was then heated to reflux until the reaction was judged complete by HPLC (30 min): The reaction was concentrated and then dissolved in 10 mL H2O. The reaction was extracted with a small amount of EtOAc, then the aqueous layer was made acidic (pH=2) with the dropwise addition of 10% aq. HCl. The white solid that precipitated from the reaction was filtered off and washed with cold H2O. The solid was dried under vacuum overnight to obtain 0.3771 g of relatively pure 24. 24 was further purified by recrystallization from warm MeOH to obtain 0.1317 g of pure 24. No attempts were made to recover remaining 24 from the mother liquor. 1H (CD3OD, 400 MHz): δ 7.07 (2H, d, J=8.2 Hz), 6.84 (2H, d, J=8.6 Hz), 6.53 (1H, s), 3.73 (3H, s), 2.97-2.84 (4H, m) ppm. 13C (CD3OD, 100 MHz): δ 164.86, 159.60, 148.26, 143.15, 134.01, 130.36, 114.81, 107.50, 55.60, 35.67, 29.10 ppm.
Reaction SMILES: Cl[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:3]=1N.[CH:12](O)=[O:13]>>[CH:12]([NH:9][C:6]1[CH:7]=[CH:8][CH:2]=[CH:3][CH:5]=1)=[O:13]
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Reactant: O=CO
Product: O=CNc1ccccc1

Procedure:
2-Chloro-5-nitroaniline (43.1 g, 250 mmol), formic acid (250 mL) was stirred at room temperature for 5 h. The reaction mixture was concentrated in vacuo. The solid residue was taken up in water (350 mL), filtered, washed with water (×2). The solid residue was dried at 50° C. under vacuum to give a crude formanilide as a light brown amorphous. The crude formanilide, thionyl chloride (164 mL) and sulfuryl chloride (58 mL) was combined, and heated at 55° C. for 48 hr. The mixture was concentrated in vacuo. The residue was dissolved in petroleum ether, decanted from a precipitate and the clear solution was evaporated in vacuo to give the title compound (42.2 g, 166 mmol, 67%) as a light brown amorphous.
Reaction SMILES: [CH:1]1([NH:6][C:7](=[O:26])[NH:8][CH:9]([C:11]2[S:15][C:14]([C:16]([NH:18][O:19]C3CCCCO3)=[O:17])=[CH:13][CH:12]=2)[CH3:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>C1COCC1.O1CCOCC1>[CH:1]1([NH:6][C:7](=[O:26])[NH:8][CH:9]([C:11]2[S:15][C:14]([C:16]([NH:18][OH:19])=[O:17])=[CH:13][CH:12]=2)[CH3:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(NC(=O)NC1CCCC1)c1ccc(C(=O)NOC2CCCCO2)s1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CC(NC(=O)NC1CCCC1)c1ccc(C(=O)NO)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 16 %

Procedure:
To a solution of 5-(1-(3-cyclopentylureido)ethyl)-N-(tetrahydro-2H-pyran-2-yloxy)thiophene-2-carboxamide obtained in step 3 was dissolved in THF (1 mL) was added 4.0 M HCl in dioxane (0.25 mL). The reaction was stirred for 4 hours at room temperature, evaporated to dryness, redissolved in DMSO (1 mL) and purified on Agilent 1100 LC/MSD instrument to afford the title compounds as a white solid (2.7 mg, 16%) LC-MS: (FA) ES+ 298.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[N:7]3[CH2:15][C:14]([CH3:17])([CH3:16])[CH2:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.[B-](F)(F)(F)[F:20].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CN(C=O)C.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[N:7]3[CH2:15][C:14]([CH3:16])([CH3:17])[CH2:13][CH:12]([F:20])[C:8]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: F[B-](F)(F)F
Reactant: CC1(C)CCc2nc3cc(Br)ccc3c(=O)n2C1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(F)c2nc3cc(Br)ccc3c(=O)n2C1
Temperature: 90 °C
Reaction time: 3 h
Yield: 75.2 %

Procedure:
To a solution of 3-bromo-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one (0.1 g, 0.327 mmol, 1 equiv) in DMF (5 mL), Selectfluor (0.12 g, 0.327 mmol, 1 eq) was added. The reaction mixture was heated to 90° C. and stirred for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate (3×50 mL), dried over Na2SO4. After filtration and concentration, 80 mg of the desired product was obtained, which was directly used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:20][C:21](=[O:33])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]5([C:31]#[N:32])[CH2:30][CH2:29]5)[CH:23]=4)[CH:15]=[CH:16][C:17]=3[O:18][CH3:19])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1.O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:31]([C:28]1([C:24]2[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=2)[C:21]([NH:20][C:14]2[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:12]([O:11][C:9]3[CH:8]=[CH:7][C:5]4[N:6]=[C:2]([NH:1][C:37]([CH:34]5[CH2:36][CH2:35]5)=[O:38])[S:3][C:4]=4[CH:10]=3)[CH:13]=2)=[O:33])[CH2:30][CH2:29]1)#[N:32]
Reactant: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(N)sc2c1
Reactant: O=C(Cl)C1CC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2c1
Yield: 55.3 %

Procedure:
A solution of N-{3-[(2-amino-1,3-benzothiazol-6-yl)oxy]-4-methoxyphenyl}-3-(1-cyanocyclopropyl)benzamide (91 mg, 0.20 mmol), cyclopropanecarbonyl chloride (105 mg, 1.00 mmol) and N,N-dimethylpyridine-4-amine (122 mg, 1.00 mmol) in pyridine (2 mL) was stirred at room temperature for 18 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent:hexane/ethyl acetate=1:1), and triturated with diethyl ether to give the title compound (58 mg, 55%) as a pale-yellow solid.