Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[CH2:9][OH:10].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([O:22][CH3:23])=[C:16]([S:18](Cl)(=[O:20])=[O:19])[CH:17]=1>N1C=CC=CC=1>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:9][OH:10])=[C:2]([NH:1][S:18]([C:16]2[CH:17]=[C:12]([Cl:11])[CH:13]=[CH:14][C:15]=2[O:22][CH3:23])(=[O:19])=[O:20])[CH:7]=1
Reactant: Nc1cc(Br)ccc1CO
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1ccc(Cl)cc1S(=O)(=O)Nc1cc(Br)ccc1CO
Temperature: 0 °C
Reaction time: 72 h
Yield: 81.5 %

Procedure:
A solution of (2-amino-4-bromo-phenyl)-methanol (1.53 g, 7.57 mmol) in pyridine (15 mL) was treated with 5-chloro-2-methoxybenzenesulfonyl chloride (1.85 g, 7.57 mmol) at room temperature and stirred for 72 h, then poured upon ice-cold 2 M aq. hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated to produce a gummy residue, from which the product was precipitated by addition of toluene. The precipitate was collected by filtration and dried to afford N-(5-bromo-2-hydroxymethyl-phenyl)-5-chloro-2-methoxy-benzenesulfonamide (2.51 g, 82%). Off-white solid, MS (ISP)=404.2 (M−H)−.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:21](=[O:37])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:31]=[N:32][CH:33]=[N:34][CH:35]=2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][C:11]1[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:13][C:8]2[N:7]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[CH:31]=[N:32][CH:33]=[N:34][CH:35]=4)[CH:25]=3)[CH2:22][C:21](=[O:37])[NH:20][C:9]=2[CH:10]=1
Reactant: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cncnc3)c2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CNc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3cncnc3)c1)=N2

Procedure:
The title compound was prepared from {4-chloro-5-isobutylamino-2-[3-oxo-3-(3-pyrimidin-5-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M88) (0.28 g, 0.52 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (200 mg, 92%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.[CH3:18][C:19]1[C:20]([CH2:26][OH:27])=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:27][CH2:26][C:20]2[C:19]([CH3:18])=[CH:24][C:23]([CH3:25])=[CH:22][N:21]=2)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Reactant: Cc1cnc(CO)c(C)c1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cnc(COc2nc(N)nc(-n3cccn3)c2C#N)c(C)c1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile, 3,5-dimethyl-2-pyridinemethanol and DBU in DME. ES-MS m/e (%): 322 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:4][CH:5]([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:2]=[CH2:3].[CH2:12](O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]C=C>O.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH2:1]([O:4][C@@H:5]([CH3:11])[C:6]([O:8][CH2:9][CH2:10][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=[CH2:12])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCOC(C)C(=O)OCC
Reactant: C=CCCCCCCCCO
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Solvent: O
Product: C=CCCCCCCCCOC(=O)[C@H](C)OCC=C
Temperature: 80 °C
Reaction time: 5 h
Yield: 80.4 %

Procedure:
3.0 g (19 mmol) of ethyl 2-allyloxypropionate are introduced into 4.5 g (28.5 mmol) of 9-decen-1-ol, and 0.56 g (2 mmol) of Ti(OiPr)4 are added. The mixture is then heated to 80° C. and stirred at a reduced pressure of 400 mbar for 5 h. A few drops of water are then added and the crude product is purified by means of flash chromatography (cyclohexane/EtOAc=25:1; Rf=0.21), giving 4.1 g (81%) of a colorless oil.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:6]([C:7]([OH:9])=[O:8])[O:5][C@@H:4]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:3]1[OH:28].[CH2:29]([O:36][C:37]([NH:39][C@H:40]([C:56](O)=[O:57])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[CH:44][CH:43]=1)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:20]([NH:19][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[C:16]=1[N:17]=[CH:18][N:10]2[C@@H:4]1[O:5][C@H:6]([C:7]([OH:9])=[O:8])[C@@H:2]([NH:1][C:56](=[O:57])[C@H:40]([CH2:41][C:42]2[CH:43]=[CH:44][C:45]([O:48][CH2:49][C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)=[CH:46][CH:47]=2)[NH:39][C:37]([O:36][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:38])[C@H:3]1[OH:28])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O
Reactant: O=C(N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O)OCc1ccccc1
Product: O=C(N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O)OCc1ccccc1
Yield: 52.3 %

Procedure:
1-(6-Benzoylamino-9H-purin-9-yl)-3-(N-benzyloxycarbonyl-O-benzyl-L-tyrosylamino)-1,3-dideoxy-β-D-ribofuranuronic acid (210 mg) was prepared by reacting 1-(6-benzoylamino-9H-purin-9-yl)-1,3-dideoxy-3-amino-β-D-ribofuranuronic acid (200 mg) prepared in Example 1 with N-hydroxysuccinimide ester of N-benzyloxycarbonyl-O-benzyl-L-tyrosine (260 mg) according to a similar manner to that of Example 5, mp. 150°-155° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[F:18])=[C:4]([O:19][CH3:20])[CH:3]=1.C(O)CC#C.[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)#[CH:27]>>[F:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][C:5]1[CH:6]=[CH:7][C:2]([C:27]#[C:26][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:3][C:4]=1[O:19][CH3:20]
Reactant: COc1cc(Br)ccc1Oc1ccc([N+](=O)[O-])cc1F
Reactant: C#Cc1ccccn1
Agent: C#CCCO
Product: COc1cc(C#Cc2ccccn2)ccc1Oc1ccc([N+](=O)[O-])cc1F

Procedure:
According to the procedure of example 11(a) except substituting 5-bromo-2-(2-methoxy-4-propylphenoxy)pyridine by 4-bromo-1-(2-fluoro-4-nitrophenoxy)-2-methoxybenzene (0.29 mmol; 100 mg) and 3-butyn-1-ol by 2-ethynylpyridine (0.73 mmol; 73 μL), the title compound was prepared as a yellow solid (81%; 87 mg) after purification on preparative TLC (cyclohexane/ethyl acetate: 7/3).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N#N>C1COCC1.O>[Cl:13][C:14]1[CH:19]=[C:18]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[NH:4][N:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=c1[nH]nc(Cl)c2ccccc12
Agent: N#N
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]nc(-c2cccc(Cl)c2)c2ccccc12
Yield: 85 %

Procedure:
A solution of 1-chlorophthalazine-4-one (1.0 g, 5.5 mmol), 3-chlorophenyl boronic acid (1.3 g, 8.3 mmol), tricyclohexyphosphine (0.058 g, 0.27 mmol), and K3PO4 (2.3 g, 11.0 mmol) in THF (20 mL) and water (5 mL) was degassed with N2 for 30 min then treated with tri(dibenzylideneacetone)-dipalladium (0.050 g, 0.05 mmol) and heated at reflux overnight. The reaction mixture was diluted with water (100 mL) and the product extracted with EtOAc (2×100 mL). The organics were washed with brine, dried over Na2SO4, and concentrated to give 4-(3-chlorophenyl)phthalazin-1(2H)-one (1.2 g), (MS: ESI +ve, 257.12 [M+H]). 1H NMR: (400 MHz, DMSO) δ: 7.58-7.60 (m, 2H), 7.61-7.64 (m, 2H), 7.65-7.67 (m, 1H), 7.90-7.93 (m, 2H), 8.34-8.36 (m, 1H). 12.93 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[N:12]([S:21]([N:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])[CH:13]=[C:14]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[N:15]=2)=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:33][N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[C:36]([NH:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[N:35]1.O>CN(C)C=O.O>[C:51]([O:50][C:49](=[O:55])[NH:48][C:36]1[C:37]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]3[N:12]([S:21]([N:24]([CH3:26])[CH3:25])(=[O:22])=[O:23])[CH:13]=[C:14]([CH2:16][C:17]([CH3:18])([CH3:19])[CH3:20])[N:15]=3)=[O:10])=[CH:4][CH:3]=2)=[CH:38][N:34]([CH3:33])[N:35]=1)([CH3:54])([CH3:53])[CH3:52]
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(=O)Cc1ccc(Br)cc1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c(NC(=O)OC(C)(C)C)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(=O)Cc1ccc(-c2cn(C)nc2NC(=O)OC(C)(C)C)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (23 mg, 0.03 mmol) was added to a degassed, ambient temperature solution of 2-[(4-bromophenyl)acetyl]-4-(2,2-dimethylpropyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (Intermediate 7) (123 mg, 0.28 mmol), sodium carbonate (89 mg, 0.84 mmol) and tert-butyl [1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-3-yl]carbamate (90 mg, 0.28 mmol) in N,N-dimethylformamide/water (2:1) (7.5 mL). After stirring at 80° C. overnight, the reaction mixture was cooled, poured into water and extracted with diethyl ether. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-30% acetone/methylene chloride afforded tert-butyl[4-(4-{2-[1-[(dimethylamino)sulfonyl]-4-(2,2-dimethylpropyl)-1H-imidazol-2-yl]-2-oxoethyl}phenyl)-1-methyl-1H-pyrazol-3-yl]carbamate.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:21][C:22](O)=[O:23])[CH:18]=2)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30]>>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:21][C:22]([NH:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:23])[CH:18]=2)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc2c(c1)CC(NC(=O)OCc1ccccc1)C2
Reactant: COC(=O)CCCN
Product: COC(=O)CCCNC(=O)Cc1ccc2c(c1)CC(NC(=O)OCc1ccccc1)C2

Procedure:
In the same manner as described in Example 1-(1), 2-(benzyloxycarbonylamino)indan-5-acetic acid and methyl γ-aminobutyrate are reacted to give methyl 4-[(2-benzyloxycarbonylaminoindan-5-yl)acetylamino]-n-butyrate.
Reaction SMILES: [O:1]1[CH2:4][C:3](=O)[CH2:2]1.C[Si]([C:10]#[N:11])(C)C.[CH2:12]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)(=O)C>[CH2:20]([N:19]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]1([C:10]#[N:11])[CH2:4][O:1][CH2:2]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: O=C1COC1
Reactant: C[Si](C)(C)C#N
Solvent: CC(=O)O
Product: N#CC1(N(Cc2ccccc2)Cc2ccccc2)COC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.63 ml (10.8 mmol) of oxetan-3-one and 3.6 ml (27.1 mmol) of trimethylsilyl cyanide were added to 10.4 ml (54.1 mmol) of dibenzylamine in 72 ml of acetic acid. The reaction mixture was then stirred at RT overnight. The mixture was then concentrated, the residue was dissolved in water/diethyl ether and the aqueous phase was extracted twice with diethyl ether. The combined organic phases were washed twice with saturated aqueous sodium bicarbonate solution, dried over sodium sulphate, filtered and concentrated. The residue was purified by silica gel chromatography (cyclohexane/ethyl acetate from 40:1 to 30:1). This gave 2.39 g (77% of theory, purity 97%) of the target compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([C@@H:42]2[CH2:47][CH2:46][C@H:45]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:44][CH2:43]2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2.C(O)(C(F)(F)F)=O>>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([C@@H:42]4[CH2:43][CH2:44][C@H:45]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:46][CH2:47]4)=[C:35]4[C:39]=3[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[C:14]([O:28][CH3:29])[CH:15]=1)([O:22][CH2:23][CH3:24])=[O:25])[CH3:21]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CCOC(=O)[C@H]1CC[C@@H](c2ccc(N)c3c2CN(C)C3=O)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H]1CC[C@@H](c2ccc(Nc3nc(Nc4ccc(CP(=O)(OCC)OCC)cc4OC)ncc3C(F)(F)F)c3c2CN(C)C3=O)CC1
Yield: 38.8 %

Procedure:
A solution of diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (119.5 mg, 0.26 mmol) and ethyl cis-4-(7-amino-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)cyclohexanecarboxylate (100 mg, 0.32 mmol) in TFE (2.39 mL, 32.8 mmol) was treated with TFA (90.1 mg, 0.790 mmol) and irradiated on the microwave at 105° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure to a solid. The material was purified on a CombiFlash®Rf 4X Organic Purification System [24 g RediSep® Normal-phase GOLD Silica Flash Column, dry loaded, elution gradient: 0→5% MeOH in 1:1 DCM/EtOAc] to afford 74 mg (38%) of the desired product. 1H NMR (400 MHz, MeOD) δ ppm 8.46 (br. s., 1 H), 8.35 (s, 1 H), 7.89 (d, J=8.08 Hz, 1 H), 7.26 (d, J=8.84 Hz, 1 H), 7.08 (t, J=2.02 Hz, 1 H), 6.94 (dt, 1 H), 4.52 (s, 2 H), 4.26 (q, J=7.07 Hz, 2 H), 4.11 (quin, J=7.26 Hz, 4 H), 3.92 (s, 3 H), 3.36 (br. s., 1 H), 3.30 (br. s., 1 H), 3.20 (s, 3 H), 2.79 (br. s., 1 H), 2.68 (br. s., 1 H), 2.28-2.33 (m, 2 H), 2.30 (d, J=6.82 Hz, 2 H), 1.77 (d, J=5.81 Hz, 6 H), 1.27-1.37 (m, 9 H). MS (ES+): m/z=734.23 [MH+]. HPLC: tR=1.77 min (UPLC TOF, polar—3 min).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.Cl.[N:15]1([C:20](N)=[NH:21])C=CC=N1.CCN(C(C)C)C(C)C>C(O)C>[OH2:9].[OH2:9].[CH3:11][O:10][C:8](=[O:9])[C:7]1[CH:6]=[CH:5][C:4]([CH2:3][NH:2][C:20]([NH2:21])=[NH:15])=[CH:13][CH:12]=1
Reactant: N=C(N)n1cccn1
Reactant: COC(=O)c1ccc(CN)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COC(=O)c1ccc(CNC(=N)N)cc1
Product: O
Reaction time: 1 h
Yield: 233.8 %

Procedure:
To a solution of methyl 4-(aminomethyl)benzoate hydrochloride (5 g) in dry ethanol (25 mL) was added 1H-pyrazole-1-carboxamidine hydrochloride (4.4 g) followed by DIPEA (13.0 mL) and the mixture was refluxed for 3 h. Ethanol was removed under vacuum. To the remaining viscous oil saturated solution of NaHCO3 (50 mL) was slowly added under vigorous stirring followed by addition of 300 ml water (resultant pH 9). A white solid is formed and stirring was continued for 1 h. This material was filtered off, washed with water (200 mL) and tert-butyl methyl ether (50 mL), and dried to give the title compound 24 as a white powder (4.7 g, 91%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.91 (d, J=8.0 Hz, 2H), 7.39 (d, J=8.0 Hz, 2H), 4.39 (s, 2H), 3.83 (s, 3H), 3.80-2.80 [m, 4H+2H2O (determined by elemental analysis]).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1O.[CH3:12][N:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>[Cl-].[Cl-].[Zn+2]>[CH:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[OH:15])[CH:1]=1.[CH3:12][N:13]([C:19]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)N(C)C
Reactant: Oc1ccc2ccccc2c1
Agent: [Cl-]
Agent: [Zn+2]
Product: CCOC(=O)N(C)c1cccc2ccccc12
Product: Oc1cccc2ccccc12
Yield: 2 %

Procedure:
At 150° C. and 100 mm Hg, 14 g of beta-naphthol and 9 g of dimethyl urethane were reacted in the presence of 0.7 g ZnCl2. A conversion of 2% of naphthol to methyl naphthyl urethane was obtained.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][N:37]5[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCl
Reactant: C1CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCN1CCCCC1
Temperature: 60 °C
Yield: 17.1 %

Procedure:
To a solution of 1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-urea from Example 79A (225 mg, 0.426 mmol) in DMF (3 mL) was added piperidine (0.126 mL, 1.278 mmol) followed by diisopropyl ethylamine (0.222 mL, 1.278 mmol) and tetrabutyl ammonium iodide (157.35 mg, 0.426 mmol). The reaction mixture was heated at 60° C. for 2 days. Formation of product was determined by LCMS. The crude reaction mixture was purified by preparative HPLC (using phenylhexyl reverse phase column eluted with gradient of solvent A=0.05% HOAc/H2O and solvent B=0.05% HOAc/CH3CN) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-(piperidin-1-yl)ethoxy)quinazolin-4-ylthio)phenyl)urea (42 mg, 17%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.20 (s, 1H), 8.65 (s, 1H), 7.85 (s, 1H), 7.60-7.22 (m, 5H), 6.45 (s, 1H), 4.30 (m, 2H), 3.95 (s, 3H), 2.85-2.30 (m, 6H), 1.70-1.30 (m, 6H), 1.25 (s, 9H); LC-MS (ESI) m/z 577 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[C:3]=1[CH3:19].[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:31]([NH2:32])=[CH:30][C:29]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:28][N:27]=2)[CH2:22][CH2:21]1.Cl.O1CCOCC1>CO>[N:23]1([C:26]2[C:31]([NH:32][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][C:10]=4[F:12])[N:5]=[C:4]([C:13]4[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=4)[C:3]=3[CH3:19])=[CH:30][C:29]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:28][N:27]=2)[CH2:22][CH2:21][O:20][CH2:25][CH2:24]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2cccnc2)nc2cccc(F)c2c1Cl
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1c(-c2cccnc2)nc2cccc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
Prepared according to general Procedure K using 4-chloro-5-fluoro-3-methyl-2-(pyridin-3-yl)quinoline (83 mg, 0.30 mmol), 2,5-dimorpholinopyridin-3-amine (80 mg, 0.30 mmol) and a 4.0M solution of HCl in dioxane (0.015 mL, 0.061 mmol) in MeOH (1.0 mL) and heating in the microwave for 2 h at 150° C. After purification N-(2,5-di-4-morpholinyl-3-pyridinyl)-5-fluoro-3-methyl-2-(3-pyridinyl)-4-quinolinamine was obtained as a yellow film. 1H NMR (400 MHz, chloroform-d) δ ppm 8.87 (1H, d, J=2.3 Hz), 8.73 (1H, dd, J=4.9, 1.8 Hz), 7.93-8.03 (2H, m), 7.84 (1H, d, J=12.1 Hz), 7.66 (1H, d, J=2.7 Hz), 7.59-7.64 (1H, m), 7.49 (1H, dd, J=7.8, 5.1 Hz), 7.16-7.24 (1H, m), 6.37 (1H, d, J=2.7 Hz), 3.87-3.98 (4H, m), 3.75-3.86 (4H, m), 3.22 (4H, br. s.), 2.95-3.07 (4H, m), 2.19 (3H, s). Mass Spectrum (ESI) m/e=501.2 (M+1).
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.C(Cl)/C=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH2:18]>ClCCl>[C:6]([NH2:3])(=[O:18])[CH:7]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCN(CC)CC
Reactant: ClC/C=C/c1ccccc1
Reactant: O
Solvent: ClCCl
Product: NC(=O)C=Cc1ccccc1
Reaction time: 40 h

Procedure:
Into a dichloromethane solution of a poly(propyleneimine)dendrimer (1.0 g, 3.2 mmol, made by Aldrich Corporation) of the first generation (n=1 in FIG. 8) containing a catalytic quantity of triethylamine, a solution of trans-cinnamyl chloride (0.63 g, 3.7 mmol, made by Aldrich Corporation) was dropped, and the resultant solution was stirred at 0° C. for one hour and then at room temperature for 40 hours. This reaction liquid was diluted with dichloromethane, was cleaned sequentially with ion-exchange water, an aqueous solution of sodium carbonate and an aqueous solution of sodium chloride, and was dried with magnesium sulfate. After filtration, dichloromethane was removed by an evaporator. The crude product was dialyzed and reprecipitated repetitively for three times, and was dried under a reduced pressure. Then, a white solid was obtained.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[N+:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N:40]=[C:41]=[O:42])([O-:33])=[O:32]>C1COCC1>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:41]([NH:40][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[N+:31]([O-:33])=[O:32])=[O:42])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reactant: O=C=Nc1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1)Nc1ccccc1[N+](=O)[O-]
Reaction time: 18 h

Procedure:
A solution of 40 mg (0.11 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF is mixed with 29.8 μl (0.21 mmol) of triethylamine and 35.1 mg (0.21 mmol) of 2-nitrophenyl isocyanate. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 6 mg (11.2% of theory) of the title compound are obtained.