Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C[O:9][C:10](=[O:44])[CH2:11][NH:12][CH2:13][C:14](=[O:43])[NH:15][C:16]1[CH:21]=[C:20]([N:22]2[C:26](=[O:27])[C:25]([CH3:29])([CH3:28])[N:24]([CH2:30][C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[C:23]2=[O:37])[CH:19]=[CH:18][C:17]=1[O:38][C:39]([F:42])([F:41])[F:40].[OH-].[Li+]>O1CCOCC1.O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:28][C:25]1([CH3:29])[C:26](=[O:27])[N:22]([C:20]2[CH:19]=[CH:18][C:17]([O:38][C:39]([F:40])([F:41])[F:42])=[C:16]([NH:15][C:14]([CH2:13][NH:12][CH2:11][C:10]([OH:44])=[O:9])=[O:43])[CH:21]=2)[C:23](=[O:37])[N:24]1[CH2:30][C:31]1[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=1
Reactant: COC(=O)CNCC(=O)Nc1cc(N2C(=O)N(Cc3ccncc3)C(C)(C)C2=O)ccc1OC(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)c(NC(=O)CNCC(=O)O)c2)C(=O)N1Cc1ccncc1
Temperature: 50 °C

Procedure:
100 mg (0.16 mmol) ({[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy-phenylcarbamoyl]-methyl}-amino)-acetic acid methyl ester trifluoro acetate were dissolved in 5 ml dioxane/water (9/1) and treated with 9.3 mg (0.39 mmol) lithium hydroxide. After stirring for 1H at 50° C., the solvent was evaporated and the residue was purified by preparative HPLC. (C18 reversed phase column, elution with a water (0.1% trifluoracetic acid)/acetonitrile gradient) Yield: 10 mg.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH2:15])=[O:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:24]=1[CH2:25]Cl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:24]=1[CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH2:15])=[O:14])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Fc1cccc(Cl)c1CCl
Reactant: NC(=O)c1cc(-c2ccc(O)cc2)no1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccc(OCc3c(F)cccc3Cl)cc2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.8 %

Procedure:
3-(4-Hydroxy-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 2; 50 mg, 0.24 mmol), K2CO3 (37 mg, 0.27 mmol) and tetrabutylammonium iodide (9 mg, 0.024 mmol) were taken up in DMF (2.4 mL). 2-Chloro-6-fluorobenzyl chloride (45 mg, 0.24 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by high-throughput purification to give 3-[4-(2-chloro-6-fluoro-benzyloxy)-phenyl]-isoxazole-5-carboxylic acid amide (12.3 mg, 15%). HRMS Calcd. for C17H13ClFN2O3 (M+H)+, 347.0593. Found: 347.0591.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([CH3:20])[CH2:19][CH2:18][CH2:17][C:12]2(OCC[O:13]2)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>O.C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][C:10]1([CH3:20])[CH2:19][CH2:18][CH2:17][C:12](=[O:13])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(COCc2ccccc2)CCCC2(C1)OCCO2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC1(COCc2ccccc2)CCCC(=O)C1
Temperature: 80 °C
Yield: 88.4 %

Procedure:
To a solution of 7-benzyloxymethyl-7-methyl-1,4-dioxaspiro[4.5]decane (5.3 g, 19 mmol) in a mixed solvent of acetone (42 ml) and water (11 ml) was added pyridinium p-toluenesulfonate (4.8 g, 19 mmol), and the mixture was stirred with heating at 80° C. for 2 hr. After cooling, to the reaction mixture were added ethyl acetate and water, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (3.9 g, yield 88%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:26]([Cl:27])=[CH:25][N:24]=[CH:23][C:22]=1[Cl:28].[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][NH:35][CH3:36]>>[Cl:27][C:26]1[CH:25]=[N:24][CH:23]=[C:22]([Cl:28])[C:21]=1[NH:20][C:14]1[C:13]2[C:18](=[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:35]([CH2:34][CH2:33][N:32]([CH3:37])[CH3:31])[CH3:36])[C:10]([O:29][CH3:30])=[CH:11][CH:12]=2)[NH:17][C:16](=[O:19])[CH:15]=1
Reactant: CNCCN(C)C
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCCl
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCN(C)CCN(C)C

Procedure:
The title compound was prepared from 8-(6-chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (Intermediate 4) and N1,N1,N2-trimethylethane-1,2-diamine following the procedure outlined in Example 18, Step 2 (modifications: 40° C., 24 h then 60° C., 4 h). 1H NMR (400 MHz, DMSO-d6, bis HCl salt): δ 10.91 (br, 2H), 10.26 (s, 1H), 9.11 (s, 1H), 8.81 (s, 2H), 7.98 (d, 1H), 7.14 (d, 1H), 4.90 (s, 1H), 4.01 (t, 2H), 3.94 (s, 3H), 3.63-3.42 (br m, 4H), 3.25-3.00 (br m, 2H), 2.90-2.78 (m, 9H), 1.85-1.69 (m, 4H), 1.52-1.32 (m, 4H); MS (ESI): 536.4.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:18])[CH2:14][O:15][CH2:16][CH3:17])[CH2:9]1)=O)(C)(C)C.F[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.[H-].[Na+].CCO>CN(C=O)C.Cl>[CH2:16]([O:15][CH2:14][C@@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[O:18][C:28]1[C:29]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[CH:26][CH:27]=1)[CH3:17]
Reactant: Fc1cccc2ccccc12
Reactant: CCOC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC[C@H](Oc1cccc2ccccc12)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(S)-3-((R)-2-Ethoxy-1-hydroxyethyl)pyrrolidine-1-carboxylic acid t-butyl ester (200 mg, 0.8 mmol) and 1-fluoronaphthalene were dissolved in DMF (2.7 mL). NaH (27.8 mg, 1.2 mmol) was added and the mixture was stirred at room temperature for 15 minutes, then heated at 120° C. for 4 hours. The mixture was then cooled to room temperature. The mixture was concentrated then dissolved in 1.2M HCl in EtOH (19 mL, 23 mmol) and stirred overnight at room temperature. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt (125 mg, 94% purity). MS m/z: [M+H]+ calcd for C18H23NO2, 286.17; found 286.2.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:12]([O:15][Si](CC)(CC)CC)([CH3:14])[CH3:13])=[C:10]([F:11])[C:5]2=[N:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][C:25]=1[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1>Cl>[F:11][C:10]1[C:5]2[N:6]([C:2]([C:27]3[CH:28]=[CH:29][C:24]([F:23])=[C:25]([C:33]4[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=4)[CH:26]=3)=[CH:3][N:4]=2)[CH:7]=[CH:8][C:9]=1[C:12]([OH:15])([CH3:13])[CH3:14]
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(Br)cnc2c1F
Reactant: OB(O)c1ccc(F)c(-c2cccnc2)c1
Agent: Cl
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cccnc4)c3)cnc2c1F
Reaction time: 18 h

Procedure:
3-Bromo-8-fluoro-7-[2-(triethylsilyloxy)prop-2-yl]imidazo[1,2-α]pyridine was coupled with 4-fluoro-3-(pyridin-3-yl)phenylboronic acid as described in Example 1 and then deprotected by treatment with an ethanolic solution of 37% hydrochloric acid (5 drops in 2 ml of ethanol). After 18 h, the solution was concentrated in vacuo and purified by column chromatography on silica, to afford the title compound as a white amorphous solid: δH (360 MHz, CDCl3) 1.74 (6H, s), 7.20 (1H, t, J 7.0), 7.26-7.44 (2H, m), 7.54-7.62 (2H, m), 7.71 (1H, s), 7.90-7.93 (2H, m), 8.05 (1H, d, J 7.3), 8.65-8.66 (1H, m), 8.85 (1H, s); m/z (ES+) 366 (100%, [MH]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[O:14]>C1(C)C=CC=CC=1>[OH:14][CH:13]([CH2:10][C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:11])[C:12]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C=O
Reactant: COc1ccc(C(C)=O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(O)CC(=O)c1ccc(OC)cc1
Yield: 82 %

Procedure:
15.02 g (0.10 mol) of 4′-methoxyacetophenone and a 45% toluene solution (25 ml) of ethyl glyoxalate were stirred overnight at 100° C. The reaction liquid was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain 20.62 g (yield: 82%) of ethyl 2-hydroxy-4-(4-methoxyphenyl)-4-oxo-butyrate as a yellow oily substance.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:6])[CH2:4][Cl:5].C([N-]C(C)C)(C)C.F[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22]>C1COCC1.O>[Cl:1][CH2:2][CH:3]([CH2:4][Cl:5])[O:6][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22]
Reactant: OC(CCl)CCl
Reactant: O=[N+]([O-])c1ccccc1F
Agent: CC(C)[N-]C(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccccc1OC(CCl)CCl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 1,3-dichloro-propan-2-ol (1.29 g, 10 mmoles) in THF, under nitrogen, was cooled to 0° C., treated dropwise with llithium diisopropylamide (LDA) (5 ml, 2M solution in hexanes, 10 mmoles), while maintaining the temperature constant at 0° C., stirred at 0° C. for 15 minutes, treated with 1-fluoro-2-nitro-benzene (1.2 g ml, 8.5 mmoles) and stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with EtOAc. The extracts were combined, washed with brine, dried over Na2SO4, and concentrated under vacuum, to afford the title compound as an off-white solid (2.0 g, 8 mmoles), identified by HNMR analysis.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[N:12]=[C:11]2[N:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH2:26][CH3:27])[NH:15][C:16](=[O:17])[C:10]2=[CH:9][N:8]=1.ClC1C=C(C=CC=1)C(OO)=[O:33]>ClCCl>[CH3:1][S:2]([CH2:3][CH2:4][CH2:5][NH:6][C:7]1[N:12]=[C:11]2[N:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH2:26][CH3:27])[NH:15][C:16](=[O:17])[C:10]2=[CH:9][N:8]=1)=[O:33]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCOc1ccccc1-c1nc2nc(NCCCSC)ncc2c(=O)[nH]1
Solvent: ClCCl
Product: CCCOc1ccccc1-c1nc2nc(NCCCS(C)=O)ncc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 240 h

Procedure:
A cool (0° C.) solution of 7-(3-methylthiopropylamino)-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (1.84 g) and m-chloroperoxybenzoic acid (0.97 g) in dichloromethane (180 ml) was allowed to warm to ambient temperature with stirring. The solution was then stirred for 18 hours at ambient temperature and allowed to stand for 10 days . The reaction mixture was evaporated under reduced pressure and the residue eluted from a silica column with chloroform:methanol (gradient elution). The combined fractions containing product were evaporated under reduced pressure and the residue was recrystallized from isopropanol to yield the title compound, 1.73 g, m. p. 188-9° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH:4]=[CH:5][O:6][CH3:7].[I:9]N1C(=O)CCC1=O.C(O)(=O)C.C(N(CC)CC)C>O.ClCCl>[I:9][C:4](=[CH:5][O:6][CH3:7])[C:3]([O:2][CH3:1])=[O:8]
Reactant: COC=CC(=O)OC
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC=C(I)C(=O)OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of methyl-3-methoxypropenoate, 37-f, (13.92 g, 120 mmol), N-iodosuccinimid (32 g, 140 mmol), glacial acetic acid (18 mL, 240 mmol), and dichloromethane (150 mL) was stirred at room temperature for 24 h. Triethylamine (50 mL, 36 mmol) was added, and the reaction mixture was stirred at room temperature for 12 h before water was added. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were washed with saturated aqueous sodium thiosulfate, saturated aqueous sodium bicarbonate, and water, and were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography (PE:EA=1:5) to afford compound, 37-g (30.5 g, crude). 1H NMR (300 MHz, CDCl3) δ 7.69 (s, 1H), 4.01 (s, 3H), 3.80 (s, 3H); LC-MS (ESI): 243 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9](O)[CH2:8][CH2:7]1)[CH3:2].[I:14]I.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([I:14])[CH2:8][CH2:7]1)[CH3:2]
Reactant: II
Reactant: CCOC(=O)CC1CCC(O)CC1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)CC1CCC(I)CC1
Reaction time: 15 h
Yield: 71.1 %

Procedure:
To a mixture of 2-(4-hydroxycyclohexyl)acetic acid ethyl ester (3 g, 16.1 mmol), iodine (6.13 g, 24.2 mmol), imidazole (1.64 g, 24.2 mmol), and triphenylphosphine (6.34 g, 24.2 mmol) was added dichloromethane (100 mL) at room temperature under nitrogen atmosphere. The resulting brown suspension was stirred for 15 h at which time TLC analysis indicated the absence of starting material. Then, the solvent was removed under vacuum and most of the residue was dissolved in ethyl acetate (˜500 mL) and some of the residue was not dissolved which was found to be Ph3PO by 1H NMR. The ethyl acetate solution was washed two times with a solution of water and methanol (3:1) to remove the remaining triphenylphosphineoxide and then washed with brine solution. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated to give the crude residue which was purified using an ISCO (120 g) column chromatography eluting with ethyl acetate in hexanes (0-50%). The desired fractions were combined and the solvent was removed under vacuum to obtain 2-(4-iodocyclohexyl)acetic acid ethyl ester (3.39 g, 71.1% yield) as a viscous light yellow oil. 1H NMR of this product indicated that it contained 30-40% of elimination product (olefin) which was not separable on TLC.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([NH:13][C:14](=[O:22])OC3C=CC=CC=3)=[CH:11][C:10]([C:23]([F:26])([F:25])[F:24])=[N:9]2)=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH2:40][CH2:41][O:42][CH3:43])[N:35]=[CH:34][N:33]=[C:32]2[O:44][C:45]1[CH:46]=[C:47]([CH:49]=[CH:50][CH:51]=1)[NH2:48]>CN(C)C1C=CN=CC=1.C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([NH:13][C:14]([NH:48][C:47]3[CH:49]=[CH:50][CH:51]=[C:45]([O:44][C:32]4[C:31]5[C:36](=[CH:37][C:38]([O:39][CH2:40][CH2:41][O:42][CH3:43])=[C:29]([O:28][CH3:27])[CH:30]=5)[N:35]=[CH:34][N:33]=4)[CH:46]=3)=[O:22])=[CH:11][C:10]([C:23]([F:24])([F:25])[F:26])=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(Nc1cc(C(F)(F)F)nn1-c1ccc(F)cc1)Oc1ccccc1
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(F)(F)F)nn4-c4ccc(F)cc4)c3)c2cc1OC
Yield: 68 %

Procedure:
The title compound was prepared as described in Example 162B, using phenyl 1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate described in Example 171B (0.146 g, 0.4 mmol), 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (0.137 g, 0.4 mmol), and 4-(dimethylamino)pyridine (0.025 g) in THF (6 mL), to afford 1-[1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}urea as solid (0.166 g, 68%). 1H NMR (300 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.79 (s, 1H), 8.55 (d, 1H), 7.67 (m, 2H), 7.54 (m, 2H), 7.44 (m, 4H), 7.20 (d, 1H), 6.97 (d, 1H), 6.86 (s, 1H), 4.35 (m, 2H), 3.98 (s, 3H), 3.77 (m, 2H), 3.35 (s, 3H); LC-MS (ESI) m/z 613 (M+H)+.
Reaction SMILES: N#N.[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([C:28]4[CH:33]=[CH:32][C:31](I)=[CH:30][CH:29]=4)([C:22]4[N:26]([CH3:27])[CH:25]=[N:24][N:23]=4)[NH2:21])[CH:18]=3)[N:13]3[N:35]=[N:36][N:37]=[C:12]3[N:11]=2)[CH:7]=[CH:8][CH:9]=1.[CH3:38][N:39](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[NH2:21][C:20]([C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]1[N:35]=[N:36][N:37]=[C:12]1[N:11]=[C:10]2[C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=1)([C:22]1[N:26]([CH3:27])[CH:25]=[N:24][N:23]=1)[C:28]1[CH:33]=[CH:32][C:31]([C:38]#[N:39])=[CH:30][CH:29]=1
Reactant: Cn1cnnc1C(N)(c1ccc(I)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)nc1nnnn12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: [C-]#N
Product: Cn1cnnc1C(N)(c1ccc(C#N)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)nc1nnnn12
Temperature: 80 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
N2 was bubbled at room temperature in a solution of 5-(3-chlorophenyl)-α-(4-iodophenyl)-α-(4-methyl-4H-1,2,4-triazol-3-yl)-tetrazolo[1,5-a]quinazoline-7-methanamine (0.0024 mol) in DMF (15 ml) for 1 hour. Zn(CN)2 (0.0036 mol) and Pd(PPh3)4 (0.0002 mol) were added. The mixture was stirred at 80° C. for 1 hour, cooled, poured out into ice water and extracted with EtOAc. The precipitate was filtered off (secondary product). The organic layer was washed twice with water then with saturated NaCl, separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 95/5/0.2 to 80/20/2; 15–35 μm). The pure fractions were collected and the solvent was evaporated, yielding 0.425 g (35%) of 4-[amino[5-(3-chlorophenyl)tetrazolo[1,5-a]quinazolin-7-yl](4-methyl-4H-1,2,4-triazol-3-yl)methyl]-benzonitrile which were crystallized from CH3CN. The precipitate was filtered off and dried, yielding 0.19 g (16%) of 4-[amino[5-(3-chlorophenyl)tetrazolo[1,5-a]quinazolin-7-yl](4methyl-4H-1,2,4-triazol-3-yl)methyl]-benzonitrile, mp. 194° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][CH:26]=1>>[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([S:31][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5]/[C:4](=[C:12]3/[C:13]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[N:14][NH:15][C:16]/3=[O:17])/[CH:3]=2)=[CH:27][CH:26]=1
Reactant: O=C1NN=C(C2CCCCC2)/C1=C1\C=C(Cl)c2ccccc2N1
Reactant: Nc1ccc(S)cc1
Product: Nc1ccc(SC2=C/C(=C3/C(=O)NN=C3C3CCCCC3)Nc3ccccc32)cc1

Procedure:
The title compound was prepared from (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-cyclohexyl-1H-pyrazol-5(4H)-one and 4-aminothiophenol using the procedure described in Example 48. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08-1.19 (m, 3H) 1.29-1.40 (m, 2H) 1.58-1.65 (m, 4H) 1.67 (d, J=9.60 Hz, 2H) 2.37 (t, J=10.23 Hz, 1H) 6.76 (d, J=8.59 Hz, 2H) 6.90 (s, 1H) 7.33 (d, J=8.34 Hz, 2H) 7.63 (t, J=7.33 Hz, 1H) 7.85-7.93 (m, 2H) 8.16 (d, J=8.34 Hz, 1H); ESI-MS: m/z calc'd for C24H24N4OS 416.54. found m/z 417.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([C:15]3[C:16]([SH:21])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:10][CH:9]=2)=[CH:4][N:3]=1.Cl[C:23]1[N:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C>[F:14][C:13]1[CH:12]=[C:11]([C:15]2[C:16]([S:21][C:23]3[N:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:10]=[CH:9][C:8]=1[C:5]1[CH:6]=[N:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(-c2ccc(-c3ccccc3S)cc2F)cn1
Reactant: Clc1ncccn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Nc1ncc(-c2ccc(-c3ccccc3Sc3ncccn3)cc2F)cn1
Temperature: 25 °C
Yield: 45.3 %

Procedure:
A solution of 4′-(2-aminopyrimidin-5-yl)-5′-fluorobiphenyl-2-thiol (300 mg, 1.00 mmol), 2-chloropyrimidine (229 mg, 2.00 mmol), PPh3 (262 mg, 1.00 mmol) and TEA (0.38 mL) in DMF (10 mL) was stirred at 120° C. under a N2 atmosphere over-night. The reaction mixture was then cooled to rt, concentrated to dryness, and the residue subjected to FCC purification to give the title compound (170 mg, 45%). MS (ESI): mass calcd. for C20H14FN5S, 375.10; m/z found, 375.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 2H), 8.56 (d, J=4.9, 2H), 7.79-7.73 (m, 1H), 7.63-7.56 (m, 2H), 7.55-7.48 (m, 2H), 7.33-7.24 (m, 2H), 7.21 (t, J=4.9, 1H), 6.23 (s, 2H).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13](#[N:15])[CH3:14].[CH:16](=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].Cl>CCCCCC.O1CCCC1>[OH:22][CH:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][C:13]#[N:15]
Reactant: CCCCCC=O
Reactant: CC#N
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCCC(O)CC#N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 92.1 %

Procedure:
A 1.9 M solution (21 ml., 40 millimole) of n-butyl lithium in hexane is added cautiously to a stirred solution of freshly distilled diisopropylamine (4.04 g., 40 millimole) in anhydrous tetrahydrofuran (60 ml.) maintained at 0° C. under a nitrogen atmosphere. The resulting solution is stirred at ambient temperature for 15 minutes, cooled to -78° C. and treated with a solution of anhydrous acetonitrile (1.64 g., 40 millimole) in anhydrous tetrahydrofuran (5 ml.). The resulting turbid suspension is stirred and maintained at -78° C. for 30 minutes and then treated with a solution of 1-hexanal (4.0 g., 40 millimole) in anhydrous tetrahydrofuran (5 ml.). After attaining a clear, yellow, reaction solution, cooling at -78° C. is maintained for an additional 15 minutes. The cold reaction solution is treated with 2 N hydrochloric acid (50 ml.) and extracted with ether (100 ml.). The organic extract is washed with water (50 ml.) and 5% aqueous sodium bicarbonate (50 ml.), dried over magnesium sulfate, filtered, and evaporated in vacuo, leaving the title compound as a pale yellow oil (5.2 g., 92%) pmr (CDCl 3) δ 0.97 (3H, t), 2.55 (2H, d), 3.10 (H, s) and 3.93 (H, bs).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]=[C:13]([NH2:16])[S:14][CH:15]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)[CH2:20][CH2:19]1.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:2]3[CH:3]=[C:4]4[C:10]([C:11]5[N:12]=[C:13]([NH2:16])[S:14][CH:15]=5)=[CH:9][NH:8][C:5]4=[N:6][CH:7]=3)=[CH:27][CH:26]=2)[CH2:20][CH2:19]1
Reactant: CN1CCN(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Nc1nc(-c2c[nH]c3ncc(Br)cc23)cs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CN1CCN(Cc2ccc(-c3cnc4[nH]cc(-c5csc(N)n5)c4c3)cc2)CC1
Temperature: 175 °C

Procedure:
In a personal chemistry microwave reaction vial 4-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazol-2-ylamine (0.2 g, 0.67 mmol) and 1-Methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-piperazine (0.23 g, 0.74 mmol), bis(triphenylphosphine)-palladium(II) dichloride (0.004 g, 0.006 mmol) in acetonitrile (2 mL), and 1 M Na2CO3 (2 mL) were added. The resulting mixture was de-gassed with N2 for 10 min, after which it was heated at 175° C. for 30 min in a Personal Chemistry Optimizer. The mixture was diluted with DMF (3 mL), and concentrated in vacuo and purified on silica gel column using dichloromethane and methanol to afford 4-{5-[4-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-thiazol-2-ylamine.