Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.B([O-])([O-])O[C:6]1[O:7][C:8]2[CH:14]=[C:13]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:9]=2[CH:10]=1.Br[C:25]1[CH:26]=[CH:27][C:28]2[S:34](=[O:36])(=[O:35])[CH2:33][CH2:32][C:31]([C:37]([NH:39][C:40]3[CH:45]=[CH:44][C:43]([CH2:46][N:47]([CH3:54])[CH:48]4[CH2:53][CH2:52][O:51][CH2:50][CH2:49]4)=[CH:42][CH:41]=3)=[O:38])=[CH:30][C:29]=2[CH:55]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[CH3:54][N:47]([CH2:46][C:43]1[CH:44]=[CH:45][C:40]([NH:39][C:37]([C:31]2[CH2:32][CH2:33][S:34](=[O:36])(=[O:35])[C:28]3[CH:27]=[CH:26][C:25]([C:6]4[O:7][C:8]5[CH:14]=[C:13]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:9]=5[CH:10]=4)=[CH:55][C:29]=3[CH:30]=2)=[O:38])=[CH:41][CH:42]=1)[CH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1
Reactant: CCCOCCOc1ccc2cc(OB([O-])[O-])oc2c1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCCOCCOc1ccc2cc(-c3ccc4c(c3)C=C(C(=O)Nc3ccc(CN(C)C5CCOCC5)cc3)CCS4(=O)=O)oc2c1
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
In toluene (15 ml), ethanol (1.5 ml) and water (1.5 ml) were suspended 6-propoxyethoxy-benzofuran-2-yl borate (250 mg), 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) and potassium carbonate (262 mg), and the suspension was stirred under argon atmosphere for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (47 mg), and the mixture was stirred, under argon atmosphere, at 100° C. for 1 day and cooled. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography to give yellow amorphous of N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-7-(6-propoxyethoxybenzofuran-2-yl)-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 142) (200 mg).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].CN(C)C=O.Cl[C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=1>O.C(O)(=O)C>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C(=O)OCC)c1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h

Procedure:
50 g (0.31 mol) of diethyl malonate were added, a little at a time, at not more than 50° C. to a mixture of 7.5 g (0.31 mol) of sodium hydride and 50 ml of dimethylformamide, with ice-cooling. After the mixture had cooled to room temperature (approximately 25° C.), it was treated with g (0.173 mol) of 2-chloro-3-nitropyridine. After approximately 15 hours, the reaction mixture was diluted with water, acidified using acetic acid and extracted using ethyl acetate. The organic phases were combined, washed and dried, and the solvent was removed under reduced pressure. The excess malonic ester was distilled off at elevated temperature and reduced pressure ("high vacuum"). This gave 43 g (66%) of the title compound as a yellow oil (purity approximately 75%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:28]=[CH:29][CH:30]=1)[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[NH:24][CH:23]=[C:22]([C:25]([OH:27])=O)[CH:21]=2)[CH:15]=1)=[O:8].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH:64]1[CH2:68][CH2:67][C@H:66]([OH:69])[CH2:65]1.Cl>CN(C=O)C.O>[OH:69][C@H:66]1[CH2:67][CH2:68][N:64]([C:25]([C:22]2[CH:21]=[C:20]([C:16]3[CH:15]=[C:14]([O:13][C:12]4[CH:11]=[C:10]([NH:9][C:7]([C:3]5[O:4][CH:5]=[CH:6][C:2]=5[CH3:1])=[O:8])[CH:30]=[CH:29][CH:28]=4)[CH:19]=[CH:18][N:17]=3)[NH:24][CH:23]=2)=[O:27])[CH2:65]1
Reactant: Cc1ccoc1C(=O)Nc1cccc(Oc2ccnc(-c3cc(C(=O)O)c[nH]3)c2)c1
Reactant: O[C@H]1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccoc1C(=O)Nc1cccc(Oc2ccnc(-c3cc(C(=O)N4CC[C@H](O)C4)c[nH]3)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylic acid (60 mg, 0.15 mmol), HATU (68 mg, 0.18 mmol) and N,N-diisopropylethylamine (43 mg, 0.33 mmol) in anhydrous DMF (10 ml) was stirred at room temperature for 10 minutes, followed by addition of (S)-3-pyrrolidinol (16 mg, 0.18 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water. 2M HCl was added dropwise until pH=4˜5. The precipitates were filtered, washed with water and dried in vacuo to give N-(3-{[2-(4-{[(3S)-3-hydroxypyrrolidin-1-yl]carbonyl}-1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)-3-methyl-2-furamide as white solid. Yield: 40 mg, 56%.
Reaction SMILES: [NH2-].[Na+].[OH:3][CH2:4][CH:5]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.S(OC)(O[CH3:21])(=O)=O.[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[CH:5]1([CH2:4][O:3][CH3:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: COS(=O)(=O)OC
Reactant: OCC1CCCCCCCCCCC1
Agent: [NH2-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: COCC1CCCCCCCCCCC1
Reaction time: 1 h

Procedure:
25 g (0.65 mol) of sodium amide was introduced into 150 ml of xylene and heated to boiling under agitation. Within one hour, 99 g (0.5 mol) of hydroxymethylcyclododecane, dissolved in 750 ml of xylene, was added dropwise to the boiling suspension. To complete the alcoholate formation the mixture was heated for another two hours under reflux. Thereafter 44 g (0.35 mol) of dimethyl sulfate was added dropwise. The reaction mixture was heated under reflux for another four hours and then poured into a mixture of ice and 35 g of sodium hydroxide. The organic phase was washed with water, dried with Na2SO4, and then distilled.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][CH:11]([C:17]2[N:18]=[CH:19][NH:20][CH:21]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1.Br[CH2:23][C:24]#[C:25][CH3:26].O>CN(C=O)C>[NH2:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][CH:11]([C:17]2[N:18]=[CH:19][N:20]([CH2:23][C:24]#[C:25][CH3:26])[CH:21]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(Cc1ccc(N)nc1)c1c[nH]cn1
Reactant: CC#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCn1cnc(C(Cc2ccc(N)nc2)C(=O)OCC)c1
Reaction time: 1 h
Yield: 39 %

Procedure:
11 mg (0.23 mmol, 50%) of sodium hydride were added to a solution of 60 mg (0.23 mmol) of ethyl 3-(6-aminopyridin-3-yl)-2-(1H-imidazol-4-yl)propionate (example 1g) in 0.5 ml of DMF at RT and stirred for 1 h. Then 31 mg (37 μl, 0.23 mmol) of 1-bromo-2-butine were added, and the mixture was stirred at RT for 1 h. 1 ml of water was then added and the mixture was extracted with EA. The organic phase was dried over Na2SO4, filtered and concentrated. Chromatography of the residue on silica gel afforded 28 mg of the title compound.
Reaction SMILES: N[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[C:13](Cl)(=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[N:21]1C=CC=CC=1>O1CCOCC1>[C:13]([C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([NH2:21])[CH:3]=1)(=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: c1ccncc1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CCCCCC(=O)Cl
Solvent: C1COCCO1
Product: CCCCCC(=O)c1ccc(C(=O)OCC)c(N)c1

Procedure:
Ethyl 4-amino-benzoate (8.5 g) dissolved in dioxane (50 ml) is reacted with hexanoyl chloride (7 g) and pyridine (7 ml) at the reflux temperature for one hour. After cooling and dilution with water, the product is extracted with ethylacetate and the organic layer is washed first with 1 N HCl and then with 5% NaHCO3. Evaporation to dryness yields ethyl 4-hexanoyl-amino-benzoate (10 g) which is dissolved in dry xilene (100 ml) and reacted with ethyl carbamate (6 g) and phosphorus pentoxide (35 g) for 5 hours at the reflux temperature. After cooling, pour in ice-water, neutralize with 2 N NaOH and separate the organic layer. Evaporation to dryness yields raw 6-carbethoxy-2-pentyl-3,4-dihydro-4-oxo-quinazoline (12.1 g) which is hydrolyzed with 2 N NaOH (30 ml) in dioxane (30 ml) for 16 hours at room temperature, to give 6-carboxy-2-pentyl-3,4-dihydro-4-oxo-quinazoline (7.9 g; m.p. 310°- 312° C., after crystallization from ethanol).
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:24])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].C[O:26][C:27]([C:29]1[NH:30]N=C(OCC2C(C3C=CC=CC=3)=NOC=2C)C=1)=O>>[OH:26][CH2:27][CH2:29][NH:30][C:3]([C:5]1[N:6]([CH3:24])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)n[nH]1
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)nn1C
Product: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)NCCO)n(C)n1
Yield: 46 %

Procedure:
As described for example 6, 2-methyl-5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (30 mg, 0.09 mmol), instead of 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester, was converted to the title compound (15 mg, 46%) which was obtained as a colorless oil. MS: m/e=357.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH2:3][C:4](=[O:8])[N:5]=[N:6][CH:7]=1.[CH3:9][O:10][C:11]([C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1)=[O:12].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)(P(C(C)(C)C)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)P(C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C>[O:8]=[C:4]1[NH:5][N:6]=[CH:7][C:2]([C:17]2[CH:18]=[C:13]([CH:14]=[CH:15][CH:16]=2)[C:11]([O:10][CH3:9])=[O:12])=[CH:3]1
Reactant: O=C1CC(Cl)=CN=N1
Reactant: COC(=O)c1cccc(B(O)O)c1
Agent: CN(C)c1ccc([PH](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[PH](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cccc(-c2cn[nH]c(=O)c2)c1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
Dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium (85 mg, 0.12 mmol) was added to a mixture of 5-chloropyridazin-3(4H)-one (0.52 g, 4.0 mmol, Maybridge, Cat. No. MO08305), [3-(methoxycarbonyl)phenyl]boronic acid (0.864 g, 4.80 mmol, Aldrich, Cat. No. 591130) and sodium carbonate (0.85 g, 8.0 mmol) in 1,4-dioxane (9 mL) and water (1 mL). The reaction mixture was vacuumed and refilled with nitrogen 3 times. The reaction was stirred at 95° C. overnight. To this reaction mixture was added dioxane (3.0 ml) and water (10 ml) and then filtered, washed with acetonitrile/water, dried to provide the pure product (0.86 g). LCMS (M+H)+: m/z=231.1
Reaction SMILES: C(OC(N1CCC(NC(C2SC=CC=2NC2C=CN=C3NC=CC=23)=O)C1)=O)(C)(C)C.[C:31]1([C@@H:37]([CH2:39][OH:40])[NH2:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[CH3:41][C:42]1[S:46][C:45]([C:47](O)=[O:48])=[C:44]([NH:50][C:51]2[CH:56]=[CH:55][N:54]=[C:53]3[NH:57][CH:58]=[CH:59][C:52]=23)[CH:43]=1.N1C2=NC=CC(NC3C=CSC=3C(O)=O)=C2C=C1>>[OH:40][CH2:39][C@@H:37]([NH:38][C:47]([C:45]1[S:46][C:42]([CH3:41])=[CH:43][C:44]=1[NH:50][C:51]1[CH:56]=[CH:55][N:54]=[C:53]2[NH:57][CH:58]=[CH:59][C:52]=12)=[O:48])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: N[C@H](CO)c1ccccc1
Reactant: Cc1cc(Nc2ccnc3[nH]ccc23)c(C(=O)O)s1
Agent: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Agent: O=C(O)c1sccc1Nc1ccnc2[nH]ccc12
Product: Cc1cc(Nc2ccnc3[nH]ccc23)c(C(=O)N[C@H](CO)c2ccccc2)s1

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using (S)-2-phenylglycinol instead of 1-BOC-3-aminopyrrolidine and 5-Methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid of 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid. LCMS (ESI) 393 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.51 (1H, br. s.) 10.26 (1H, s) 8.12 (1H, d, J=8.05 Hz) 8.01 (1H, d, J=5.42 Hz) 7.31-7.38 (2H, m) 7.25-7.31 (4H, m) 7.17-7.24 (1H, m) 6.79 (1H, d, J=5.47 Hz) 6.39 (1H, dd, J=3.54, 1.98 Hz) 5.07 (1H, td, J=7.71, 5.76 Hz) 4.90 (1H, t, J=5.76 Hz) 3.56-3.74 (2H, m, J=11.13, 11.13, 10.97, 5.76 Hz) 2.52 (3H, d, J=1.07 Hz)
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][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[C:35]([C:39]1[CH:51]=[CH:50][C:42]([CH2:43][N:44]2[CH2:48][CH2:47][CH:46]([NH2:49])[CH2:45]2)=[CH:41][CH:40]=1)([CH3:38])([CH3:37])[CH3:36].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)(Cl)Cl>[C:35]([C:39]1[CH:51]=[CH:50][C:42]([CH2:43][N:44]2[CH2:48][CH2:47][CH:46]([NH:49][C:27]([NH:20][C:19]3[CH:21]=[CH:22][C:16]([O:15][C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[CH:8][N:7]=4)=[CH:17][CH:18]=3)=[O:33])[CH2:45]2)=[CH:41][CH:40]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1ccc(CN2CCC(N)C2)cc1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)NC4CCN(Cc5ccc(C(C)(C)C)cc5)C4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
Chloroform (10 ml) and triethylamine (2 ml) were added to 4-[(6,7-dimethoxy-4-quinazolinyl)oxy]aniline (100 mg) to prepare a solution. Triphosgene (110 mg) was added to the solution, and the mixture was stirred at room temperature for 30 min. 1-[4-(Tert-butyl)benzyl]-3-pyrrolidinamine (117 mg) was then added thereto, and the mixture was stirred at room temperature for 5 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/acetone for development. Diethyl ether was added to the purification product, and the precipitated crystal was collected by filtration and was washed to give the title compound (76 mg, yield 41%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][CH2:22][CH3:23].[C:24]1([N:33]=[C:34]=[O:35])[CH:29]=[CH:28][CH:27]=[C:26]([N:30]=[C:31]=[O:32])[CH:25]=1>C(Cl)Cl.CO.C(Cl)(Cl)Cl>[C:24]1([NH:33][C:34]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:18]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[N:11]=[C:10]([NH2:19])[C:9]=3[N:8]=[C:7]2[CH2:20][CH2:21][CH2:22][CH3:23])=[O:35])[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:18]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[N:11]=[C:10]([NH2:19])[C:9]=3[N:8]=[C:7]2[CH2:20][CH2:21][CH2:22][CH3:23])=[O:32])[CH:25]=1
Reactant: O=C=Nc1cccc(N=C=O)c1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Solvent: CO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)Nc1cccc(NC(=O)NCCCCn2c(CCCC)nc3c(N)nc4ccccc4c32)c1
Reaction time: 8 h
Yield: 10.2 %

Procedure:
A suspension of 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (3.11 g, 10.0 mmol) in 100 mL of CH2Cl2 was treated with 1,3-phenylene diisocyanate (800 mg, 5.0 mmol) and stirred under N2 overnight. The reaction mixture was then concentrated under reduced pressure to give a white solid. The white solid was then dissolved in 150 mL of hot 15% MeOH/CHCl3. After slow evaporation of the solvent, a white precipitate had formed. The solid was isolated by filtration, washed with 10% MeOH/CHCl3 (3×10 mL) and dried under vacuum to give the desired product (400 mg) as a white powder. M. p. 160.3-165.6° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.34 (s, 2H), 8.01 (d, J=7.9 Hz, 2H), 7.60 (d, J=8.3 Hz, 2H), 7.43 (s, 1H), 7.38 (t, J=7.6 Hz, 2H), 7.22 (t, J=7.0 Hz, 2H), 7.05-6.94 (m, 3H), 6.45 (s, 4H), 6.07 (t, J=5.4 Hz, 2H) 4.53 (t, J=7.4 Hz, 4H), 3.15 (m, 4H), 2.92 (t, J=7.7 Hz, 4H), 1.88-1.74 (m, 8H), 1.66 (m, 4H), 1.43 (m, 4H), 0.92 (t, J=7.3 Hz, 6H);
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[CH:9][C:8]=1[CH2:16][CH2:17][NH:18][S:19]([C:22]1[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][C:23]=1[O:30][CH3:31])(=[O:21])=[O:20])C.[OH-].[Na+]>C(O)C>[C:28]([C:26]1[CH:25]=[CH:24][C:23]([O:30][CH3:31])=[C:22]([S:19]([NH:18][CH2:17][CH2:16][C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:15])[CH3:14])=[CH:12][C:7]=2[O:6][CH2:5][C:4]([OH:32])=[O:3])(=[O:20])=[O:21])[CH:27]=1)#[N:29]
Reactant: CCOC(=O)COc1cc(C(C)C)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C#N)cc1S(=O)(=O)NCCc1ccc(C(C)C)cc1OCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To a solution of 4.52 g of ethyl[2-[2-(5-cyano-2-methoxy-benzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetate in ethanol was added 12.3 mL of 2 mol/L sodium hydroxide solution to neutralize. After being stirred at room temperature for 3 hours, the reaction mixture was concentrated, and 1 mol/L hydrochloric acid was added to the residue. After the mixture was extracted with ethyl acetate, the organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4.16 g of [2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[N:17][N:18]([CH3:21])[C:19]=3[CH3:20])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:22][O:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)=[O:25].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C.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>[ClH:1].[CH3:22][O:23][C:24](=[O:25])[NH:26][C:27]1[CH:28]=[CH:29][C:30]([C:2]2[C:3]([N:8]3[CH2:13][CH2:12][N:11]([CH2:14][C:15]4[CH:16]=[N:17][N:18]([CH3:21])[C:19]=4[CH3:20])[CH2:10][CH2:9]3)=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:31][CH:32]=1
Reactant: Cc1c(CN2CCN(c3nccnc3Cl)CC2)cnn1C
Reactant: COC(=O)Nc1ccc(B(O)O)cc1
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: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)Nc1ccc(-c2nccnc2N2CCN(Cc3cnn(C)c3C)CC2)cc1
Product: Cl
Temperature: 25 °C
Yield: 55.2 %

Procedure:
Stir together 3′-chloro-4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (307 mg, 1.00 mmol), 4-(methoxycarbonylamino)benzene boronic acid (234 mg, 1.2 mmol), potassium carbonate (332 mg, 2.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.006 g, 0.005 mmol) and water (2 mL), in N,N-dimethylacetamide (4 mL) at room temperature under nitrogen, then heat at 120° C. for 5 hr. Cool to room temperature, purify using SCX chromatography and further purify using silica gel chromatography eluting with (5:95 to 15:85 methanol:DCM). Dissolve in acetonitrile, and add 2 M aq. HCl and water then lyophilize to give the title compound as light yellow powder (253 mg, 55%). MS (ES): m/z=422 [M+H].
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[F:32][C:33]([F:79])([F:78])[C:34]1[CH:35]=[C:36]([C:44]([CH3:77])([CH3:76])[C:45]([N:47]([C:49]2[CH:50]=[N:51][C:52]([NH:63][CH:64]([CH2:74][OH:75])[CH2:65][O:66][Si:67]([C:70]([CH3:73])([CH3:72])[CH3:71])([CH3:69])[CH3:68])=[CH:53][C:54]=2[C:55]2[CH:60]=[CH:59][C:58]([F:61])=[CH:57][C:56]=2[CH3:62])[CH3:48])=[O:46])[CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1.[C:80](O)(=[S:82])[CH3:81]>C1COCC1>[F:79][C:33]([F:32])([F:78])[C:34]1[CH:35]=[C:36]([C:44]([CH3:77])([CH3:76])[C:45]([N:47]([CH3:48])[C:49]2[C:54]([C:55]3[CH:60]=[CH:59][C:58]([F:61])=[CH:57][C:56]=3[CH3:62])=[CH:53][C:52]([NH:63][CH:64]([CH2:65][O:66][Si:67]([C:70]([CH3:72])([CH3:73])[CH3:71])([CH3:68])[CH3:69])[CH2:74][O:75][C:80](=[S:82])[CH3:81])=[N:51][CH:50]=2)=[O:46])[CH:37]=[C:38]([C:40]([F:42])([F:43])[F:41])[CH:39]=1
Reactant: CC(O)=S
Reactant: Cc1cc(F)ccc1-c1cc(NC(CO)CO[Si](C)(C)C(C)(C)C)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=S)OCC(CO[Si](C)(C)C(C)(C)C)Nc1cc(-c2ccc(F)cc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Temperature: 25 °C
Yield: 51.9 %

Procedure:
To a solution of 0.19 mg (0.71 mmol) triphenylphosphine in 10 ml dry THF were added 0.12 g (0.71 mmol) diethyl azodicarboxylate at 0° C. under argon. After 30 min a solution of 0.50 g (0.71 mmol) (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-[2-(tert-butyl-dimethyl-silanyloxy)-1-hydroxymethyl-ethylamino]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide in 5 ml dry THF and 0.06 g (0.9 mmol) thioacetic acid were added. The reaction mixture was allowed to warm to room temperature over night. Dilution with a saturated aqueous solution of sodium hydrogencarbonate was followed by extraction with three portions of tert-butyl methyl ether. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. Flash column chromatography gave 0.28 g (52%) of the title compound as a white solid. MS m/e (%): 760 (M+H+, 100)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=O)[CH2:12][C:13](=O)[CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:17]([CH2:19][C:20]([NH2:22])=[S:21])#[N:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[SH:21][C:20]1[C:19]([C:17]#[N:18])=[C:13]([CH3:14])[CH:12]=[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:22]=1
Reactant: N#CCC(N)=S
Reactant: COc1ccc(C(=O)CC(C)=O)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(-c2cc(C)c(C#N)c(S)n2)cc1OC
Yield: 98.4 %

Procedure:
5.0 g (22.5 mmol) 1-(3,4-dimethoxyphenyl)butane-1,3-dione, 2.9 g (29.2 mmol) cyanthioacetamide and 4.0 g (29.2 mmol) potassium carbonate are added by stirring to 170 ml acetone at room temperature for 21 h. Then, the solvent is removed and the residue is just dissolved in ethanol/water (1:1). Following acidification with glacial acetic acid, the resulting precipitate is sucked off, washed with some water, suck dried and dried in vacuo at 50° C. 6.34 g (98%) 2-mercapto-6-(3,4-dimethoxyphenyl)-4-methyl-pyridine-3-carbonitrile is obtained.