Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.CN[C@@H]1CCN(CC(C2CCCCC2O)C2C=CC3C(=CC=CC=3)C=2)C1.[OH:29][C:30]1([CH:36]([C:52]2[CH:61]=[CH:60][C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH:53]=2)[C:37]([N:39]2[CH2:43][CH2:42][C@@H:41]([NH:44][C:45](=O)OC(C)(C)C)[CH2:40]2)=O)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[ClH:1].[ClH:1].[CH3:45][NH:44][C@@H:41]1[CH2:42][CH2:43][N:39]([CH2:37][CH:36]([C:30]2([OH:29])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)[C:52]2[CH:61]=[CH:60][C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH:53]=2)[CH2:40]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)C(c2ccc3ccccc3c2)C2(O)CCCCC2)C1
Agent: CN[C@@H]1CCN(CC(c2ccc3ccccc3c2)C2CCCCC2O)C1
Agent: Cl
Product: CN[C@@H]1CCN(CC(c2ccc3ccccc3c2)C2(O)CCCCC2)C1

Procedure:
In an analogous manner to Example 13, step 2, 1-[2-[(3R)-3-(methylamino)pyrrolidin-1-yl-1-(2-naphthyl)ethyl]cyclohexanol dihydrochloride was prepared from tert-butyl {(3R)-1-[(1-hydroxycyclohexyl)(2-naphthyl)acetyl]pyrrolidin-3-yl}carbamate. MS m/z 353; HRMS: calcd for C23H32N2O+H+, 353.25874; found (ESI, [M+H]+), 353.2583.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH:9]=[N+]=[N-].O1CCCCC1OCCNC(N)=O.CCOCC.[OH:30][C@H:31]1[CH2:51][C@@:50]2([CH3:52])[C@@H:42]([CH2:43][C@@H:44]([OH:54])[C@:45]2([OH:53])[C:46](=[O:49])[CH2:47][OH:48])[C@H:41]2[C@H:32]1[C@:33]1([CH3:56])[C:38]([CH2:39][CH2:40]2)=[CH:37][C:36](=[O:55])[CH:35]=[CH:34]1>CO>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][O:54][C@@H:44]1[CH2:43][C@@H:42]2[C@:50]([CH3:52])([CH2:51][C@H:31]([OH:30])[C@H:32]3[C@H:41]2[CH2:40][CH2:39][C:38]2[C@:33]3([CH3:56])[CH:34]=[CH:35][C:36](=[O:55])[CH:37]=2)[C@@:45]1([OH:53])[C:46](=[O:49])[CH2:47][OH:48]
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C[C@@H](O)[C@]2(O)C(=O)CO
Reactant: [N-]=[N+]=CCOC1CCCCO1
Agent: NC(=O)NCCOC1CCCCO1
Solvent: CO
Solvent: CCOCC
Product: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C[C@@H](OCCOC1CCCCO1)[C@]2(O)C(=O)CO

Procedure:
A solution of 2-(tetrahydropyran-2-yl)oxy-1-diazoethane (prepared from 69.1 g of N-[2-(tetrahydropyran-2-yl-oxy)ethyl]urea by the procedure described in Example 18) in 600 ml of 3:1 ether-pentane is stirred with 200 ml each of ether and methanol at 0°C. 14 g of 11β,16α,17,21-tetrahydroxypregna-1,4-diene-3,20-dione, 16,17-cycloborate is added in portions. After nitrogen evolution ceases the solvents are removed in vacuo and the residue is dissolved in chloroform and chromatographed on a 150 g-silica gel column. Elution with chloroform and then 1:1 chloroform-ethyl acetate gives 4.0 g of TLC pure 16α-[2-(tetrahydropyran-2-yloxy)ethoxy]11β,17,21-trihydroxypregna-1,4-diene-3,20-dione.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:9]=2)[CH:5]=[C:4]([Cl:26])[N:3]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][NH2:36])=[CH:31][CH:30]=1>C(#N)C>[Cl:26][C:4]1[N:3]=[C:2]([NH:36][CH2:35][C:32]2[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([S:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)(=[O:19])=[O:18])[CH:9]=2)[CH:5]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cc(Cl)nc(Cl)c2)c2cccnc21
Reactant: COc1ccc(CN)cc1
Solvent: CC#N
Product: COc1ccc(CNc2cc(-c3cn(S(=O)(=O)c4ccccc4)c4ncccc34)cc(Cl)n2)cc1
Yield: 39.9 %

Procedure:
A mixture of Example 7a (0.500 g, 1.24 mmol) and (4-methoxyphenyl)methanamine (1.018 g, 7.42 mmol) in acetonitrile (7 mL) was heated at 180° C. for 110 minutes The solvent was evaporated. The residue was treated with EtOAc and washed with 20% brine and 5% citric acid. The organic layer was concentrated and purified on a 100 g column using the ISCO Companion flash system eluting with CH2Cl2/EtOAc (98:2 to 95:5) to give 0.250 g of the title compound.
Reaction SMILES: Cl.Cl.[CH2:3]([NH:6][C:7]1=[N:8][C:9](=[O:19])[S:10]/[C:11]/1=[CH:12]\[CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[C:4]#[CH:5].C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:53][C:54]1[C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][C:57]=2[O:56][C:55]=1[C:63](O)=[O:64]>CN(C=O)C.O>[CH3:53][C:54]1[C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][C:57]=2[O:56][C:55]=1[C:63]([N:16]1[CH2:17][CH2:18][CH:13](/[CH:12]=[C:11]2/[C:7]([NH:6][CH2:3][C:4]#[CH:5])=[N:8][C:9](=[O:19])[S:10]/2)[CH2:14][CH2:15]1)=[O:64]
Reactant: Cc1c(C(=O)O)oc2ccccc12
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(C(=O)c2oc3ccccc3c2C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
To a solution of (5Z)-4-(prop-2-yn-1-ylamino)-5-(piperidin-4-ylmethylidene)-1,3-thiazol-2(5H)-one dihydrochloride (500 mg) in DMF (10 mL) were added N-ethyl-N-(1-methylethyl)propan-2-amine (1.40 mL), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (708 mg), and 3-methylbenzofuran-2-carboxylic acid (335 mg). The reaction mixture was stirred at room temperature overnight, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (625 mg).
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@@H:8]([C:16](=[O:19])[NH:17][CH3:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[CH3:18][NH:17][C:16](=[O:19])[C@H:8]([NH:7][CH3:6])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@@H](Cc1ccccc1)NC
Reaction time: 0.75 h
Yield: 23.7 %

Procedure:
N-Methyl-N-((R)1-(methylcarbamoyl)-2-phenylethyl)carbamic acid tert-butyl ester (1.39 g, 7.23 mmol) was dissolved in a mixture of trifluoroacetic acid (5 mL) and methylene chloride (10 mL) and stirred for 45 min. The volatiles were removed in vacuo and the residue was stirred with a mixture of ethyl acetate (100 mL) and water (100 mL). Sodium hydrogen carbonate (50 mL, saturated) was added and the phases were separated. The organic phase was dried (magnesium sulfate) and the solvent removed in vacuo to afford 330 mg of (R)-N-methyl-2-methylamino-3-phenylpropionamide.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#N)=[CH:6][N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[H-].C([Al+]CC(C)C)C(C)C.[O:27]1CCCC1>C(Cl)Cl>[NH2:1][C:2]1[C:7]([CH:8]=[O:27])=[CH:6][N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: C1CCOC1
Reactant: N#Cc1cnc(Nc2ccccc2)nc1N
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: Nc1nc(Nc2ccccc2)ncc1C=O
Temperature: 0 °C
Yield: 68 %

Procedure:
To a 0° C. solution of 4-amino-2-phenylamino-pyrimidine-5-carbonitrile (7.00 g, 33.18 mmol) (literature prep: J Org. Chem., 1960:5711) in 170 mL of tetrahydrofuran was added 45 mL of a 1 M solution of diisobutylaluminum hydride in methylene chloride. The ice bath was removed, and an additional 40 mL of a 1 M solution of diisobutylaluminum hydride in methylene chloride was added. The reaction mixture was cooled to 0° C., and 60 mL of methanol was added dropwise. This mixture was then added to a rapidly stirring mixture of 300 mL of ethyl acetate and 250 mL of 1 N HCl. The layers were separated, and the organic layer was extracted with additional 1 N HCl. The acid layers were combined, treated with 330 mL of 1 N NaOH, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated. Purification by flash chromatography eluting with ethyl acetate gave 4.99 g (68%) of 4-amino-2-phenylamino-pyrimidine-5-carboxaldehyde.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([OH:13])=O)=[CH:4][C:3]=2[O:2]1.C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[CH:28]([C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH2:40])(=[O:39])=[O:38])=[CH:33][CH:32]=1)([CH3:30])[CH3:29].C([Li])CCC>O1CCCC1.CCCCCC>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([NH:40][S:37]([C:34]3[CH:35]=[CH:36][C:31]([CH:28]([CH3:30])[CH3:29])=[CH:32][CH:33]=3)(=[O:38])=[O:39])=[O:13])=[CH:4][C:3]=2[O:2]1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Reactant: CC(C)c1ccc(S(N)(=O)=O)cc1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)c1ccc(S(=O)(=O)NC(=O)Cc2ccc3c(c2)OCO3)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
An oven dried 500 mL three necked round bottom flask was equipped with a magnetic stir bar, a nitrogen inlet, a septum, and a stopper. The flask was purged with nitrogen then charged with a solution of 5.083 g (28.2 mmol) of 3,4-methylenedioxyphenylacetic acid and 220 mL of anhydrous tetrahydrofuran. The contents were stirred at -78° C. and 5.11 mL of triethylamine (36.7 mmol) and 3.82 mL (31.0 mmol) of trimethylacetyl chloride were successively added. The reaction mixture was stirred at -78° C. for 15 minutes, then at 0° C. for one hour. In a separate oven dried flask, a solution of 10.120 g (50.8 mmol) of 4-(i-propyl)benzenesulfonamide dissolved in 110 mL of tetrahydrofuran was treated with 20.31 mL of a 2.5N solution of n-butyllithium in hexane at -78° C. A heavy precipitate of the deprotonated sulfonamide formed during the addition which prevented stirring. The flask and its contents were then warmed to room temperature and 60 mL of dimethylsulfoxide were added which effected solution of the lithiated sulfonamide. The solution of the lithiated sulfonamide was then transferred via cannula to the stirred 0° C. reaction mixture containing the mixed anhydride. After the addition was complete, the reaction mixture was stirred an additional 3 hours, then it was quenched by addition of excess 10% aqueous NaHSO4. The majority of the THF was next removed in vacuo, and the remainder of the mixture was partitioned between EtOAc and saturated brine. The organic layer was extracted, separated, dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 2.5% MeOH--CHCl3. The purified fractions were combined, evaporated and then recrystallized from methylene chloride-hexane to afford 6.623 g (65%) of the title compound as an off-white crystalline solid which had: mp=262°-3° C.
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([CH:29]=[CH2:30])(=[O:28])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1.[NH:38]1[CH2:43][CH2:42][S:41][CH2:40][CH2:39]1>C1COCC1>[F:37][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:21][CH2:22][N:23]([S:26]([CH2:29][CH2:30][N:38]4[CH2:43][CH2:42][S:41][CH2:40][CH2:39]4)(=[O:28])=[O:27])[CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1
Reactant: C=CS(=O)(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Reactant: C1CSCCN1
Solvent: C1CCOC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)CCN3CCSCC3)CC2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 84 %

Procedure:
A mixture of 2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole (Example 3) (180 mg, 0.335 mmol), thiomorpholine (0.17 mL, 1.68 mmol) in THF (50 mL) was stirred at room temperature for 3 days and then at reflux for 3 hrs. The solvent was removed under vacuum and the residue was dissolved in dioxane (30 mL) and additional thiomorpholine (0.17 mL, 1.68 mmol) was added. The reaction mixture was refluxed for 2 days. The solvent was removed under vacuum and the residue diluted with water. The resulting precipitate was filtered, washed with water and dissolved in CH2Cl2. The solution was dried (Na2SO4) and solvent removed under vacuum. Chromatography on silica, eluting with CH2Cl2/MeOH (98:2), followed by recrystallization from CH2Cl2/hexane gave 180 mg (84% yield) of 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(4-thiomorpholinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole: mp (CH2Cl2/hexane) 210-212° C.; 1H NMR (CDCl3) δ7.86 (dd, J=8.3, 0.5 Hz, 1H), 7.43 (t, JHF=53.5 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H), 6.82 (d, J=7.7 Hz, 1H), 4.05 (s, 3H), 4.00 (br s, 4H), 3.89 (br s, 4H), 3.79 (m, 4H), 3.38 (t, J=5.1 Hz, 4H), 3.11 (dd, J=8.3, 6.1 Hz, 2H), 2.87 (dd, J=8.3, 6.1 Hz, 2H), 2.73 (dd, J=6.1, 3.8 Hz, 4H), 2.63 (m, 4H); Anal. Calcd. for C26H35F2N9O4S2.0.5H2O: C, 48.1; H, 5.6; N, 19.4. Found: C, 48.2; H, 5.4; N, 19.3%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[CH3:15][SH:16].CCN(C(C)C)C(C)C>>[I:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13]#[N:14])=[C:2]2[S:16][CH3:15]
Reactant: N#Cc1cnc2ccc(I)cc2c1Cl
Reactant: CS
Solvent: CCN(C(C)C)C(C)C
Product: CSc1c(C#N)cnc2ccc(I)cc12

Procedure:
Similar procedure as described in example 39a was used, starting from 4-chloro-6-iodo-quinoline-3-carbonitrile (example 14c), methanethiol and DIEA to give 6-iodo-4-methylsulfanyl-quinoline-3-carbonitrile. LC-MS m/e 327 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]3[N:16]=[C:17]4[C:23]([CH:24]=[O:25])=[CH:22][N:21]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:18]4=[N:19][CH:20]=3)=[N:7][N:8]2[CH:11]2[CH2:14][O:13][CH2:12]2)=[CH:4][CH:3]=1.S(=O)(=O)([OH:36])N.Cl([O-])=O.[Na+].P([O-])(O)(O)=O.[K+]>O1CCOCC1.O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]3[N:16]=[C:17]4[C:23]([C:24]([OH:36])=[O:25])=[CH:22][N:21]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:18]4=[N:19][CH:20]=3)=[N:7][N:8]2[CH:11]2[CH2:12][O:13][CH2:14]2)=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)O
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(-c3nn(C4COC4)c4cc(F)ccc34)cnc21
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(-c3nn(C4COC4)c4cc(F)ccc34)cnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 111.6 %

Procedure:
To a solution of 2-(6-fluoro-1-oxetan-3-yl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (293 mg, 0.63 mmol) in 1,4-dioxane (20 ml) and water (4 ml) at 0° C. was added sulfamic acid (365 mg, 3.76 mmol). Then a solution of sodium chlorite (80%, 92 mg, 0.82 mmol) and potassium dihydrogen phosphate (1.02 g, 7.52 mmol) in water (16 ml) was added over ˜15 min. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 30 min. THF (20 ml) was added and stirred was continued for 2 h. The reaction mixture was diluted with water and extracted with EtOAc (3×). The combined organic layers were washed with brine then dried over MgSO4 and concentrated to afford 340 mg of 2-(6-fluoro-1-oxetan-3-yl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid as an off-white powder.
Reaction SMILES: [C:1]1([CH2:11][NH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:16](Cl)[N:15]=1.C(N(CC)CC)C>C(#N)C>[Cl:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:16]([NH:12][CH2:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[N:15]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Reactant: NCc1cccc2ccccc12
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Clc1nc(NCc2cccc3ccccc23)c2ncn(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 64 h
Yield: 97.4 %

Procedure:
1-Naphthylmethanamine (5.4 g, 19.7 mmol) was added to a stirred solution of 2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (3.5 g, 22.3 mmol) (Preparation 19) and triethylamine (4 g, 39.6 mmol) in acetonitrile (150 ml) at room temperature. The reaction mixture was stirred at room temperature for 64 hours. The solvent was removed under reduced pressure, ethyl acetate (100 ml) was added and then the solvent was removed under reduced pressure again. The residue was purified by column chromatography on silica gel eluting with pentane: ethyl acetate (1:1 by volume) increasing in polarity to neat ethyl acetate. The solvent was removed under reduced pressure to give the title compound (7.56 g) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:26]([O-])=O)=[C:6]([CH:25]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1)=[O:8].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O1CCCC1.CO.O>[NH2:26][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:25][C:6]=1[C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([S:16]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)(=[O:18])=[O:17])=[CH:14][CH:15]=1)=[O:8]
Reactant: O=C(Nc1ccc(S(=O)(=O)N2CCOCC2)cc1)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(Cl)cc1C(=O)Nc1ccc(S(=O)(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
11.10 g (26.1 mmol) of 5-chloro-N-(4-(morpholine-4-sulfonyl)-phenyl)-2-nitro-benzamide were dissolved in 440 ml of tetrahydrofuran/methanol (1:1) and a solution of 27.23 g (156.4 mmol) of sodium dithionite in 330 ml of water was added dropwise. After stirring for 1 h at room temperature the organic solvents were removed in rotary evaporator, and the precipitated product was filtered off with suction and purified by chromatography over silica with methylene chloride/methanol (9:1). 5.68 g (55%) of the title compound having a melting point of 229-231° C. were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][O:6][C:7]1[CH:35]=[CH:34][C:10]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[O:26][C:25]([CH:27]=[CH:28][C:29]([O:31]CC)=[O:30])=[CH:24][CH:23]=4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][C:8]=1[Cl:36].[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][O:6][C:7]1[CH:35]=[CH:34][C:10]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[O:26][C:25]([CH:27]=[CH:28][C:29]([OH:31])=[O:30])=[CH:24][CH:23]=4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][C:8]=1[Cl:36]
Reactant: CCOC(=O)C=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Yield: 97 %

Procedure:
Prepared according to Procedure H utilizing ethyl 3-(5-{4-[4-(3-fluorobenzyloxy)-3-chloroanilino]-6-quinazolinyl}-2-furyl)-2-propenoate (0.50 g) and aqueous sodium hydroxide (2M, 2 mL) in THF (6 mL) to afford the title compound (0.46 g). Electrospray MS m/z 516 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH:9]#[C:10][CH2:11]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:11][C:10]#[CH:9]
Reactant: C#CCBr
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCOc1ccccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-bromophenol (50.0 g, 289 mmol) and progargyl bromide (41.3 g, 347 mmol) in dry ACN (500 mL) was added K2CO3 (47.9 g, 347 mmol) and the solution was stirred overnight at rt. The solvent was removed and the residue was poured into water and extracted with Et2O. The combined organic layers were dried over Na2SO4, filtered and concentrated to give compound P34a (60 g, 98%) as an oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[Cl:24][C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][NH:26]1>>[Cl:24][C:25]1[CH:30]=[C:29]([C:6]2[N:7]=[C:8]([N:10]3[C:14]4[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=4[N:12]=[CH:11]3)[S:9][C:5]=2[C:3]([OH:2])=[O:4])[CH:28]=[CH:27][N:26]=1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Reactant: OB(O)C1(Cl)C=CC=CN1
Product: COc1cc2ncn(-c3nc(-c4ccnc(Cl)c4)c(C(=O)O)s3)c2cc1OC
Yield: 46.4 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (120 mg, 0.3 mmol) and 2-chloropyridine-2-boronic acid (71 mg, 0.45 mmol) gave 4-(2-Chloro-pyridin-4-yl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid (58 mg, 46.4%) as a white solid. MS 417 m/z (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](O)([C:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=3[O:18][CH3:19])[C:9](=[O:21])[N:8]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=3[O:33][C:34]([F:37])([F:36])[F:35])(=[O:24])=[O:23])[C:5]2=[N:6][CH:7]=1.CS(OS(C)(=O)=O)(=O)=O.FC(F)(F)C(O)=O.[OH:54][C@H:55]1[CH2:59][NH:58][C@H:57]([C:60]([N:62]([CH3:64])[CH3:63])=[O:61])[CH2:56]1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CCN(CC)CC>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([N:58]3[CH2:59][C@H:55]([OH:54])[CH2:56][C@H:57]3[C:60]([N:62]([CH3:64])[CH3:63])=[O:61])([C:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=3[O:18][CH3:19])[C:9](=[O:21])[N:8]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=3[O:33][C:34]([F:35])([F:36])[F:37])(=[O:24])=[O:23])[C:5]2=[N:6][CH:7]=1
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(O)(c3cc(C)ccc3OC)c3cc(Br)cnc32)c(OC(F)(F)F)c1
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(C)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Br)cnc32)c(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 1.7 %

Procedure:
To a solution of 290 mg of the compound obtained in Step 120-5 and 97 mg of Et3N in CHCl3 (2 ml), on ice, was added 101 mg of methanesulfonic acid anhydride and the reaction mixture was stirred at room temperature for one hour. The solution was cooled again under ice cooling, 97 mg of Et3N and 261 mg of (4R)-4-hydroxy-N,N-dimethyl-L-prolinamide trifluoroacetate was added, and the reaction mixture was stirred at room temperature for two hours. A saturated aqueous solution of NaHCO3 was poured, and the solution was extracted with EtOAc. The organic layer was washed with saturated brine, dried over Na2SO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by thin layer chromatography (silicagel 60 F254; 1 mm thick; mobile phase: CHCl3/MeOH=9/1; v/v) to obtain 6 mg of the title compound (amorphous).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[Cl:20])[NH2:16].P(Cl)(Cl)Cl>ClC1C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:6]([C:7]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([Cl:20])=[C:13]([Cl:12])[CH:14]=2)=[O:9])[C:5]([OH:11])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1cc(Br)ccc1O
Solvent: Clc1ccccc1
Solvent: ClP(Cl)Cl
Product: O=C(Nc1ccc(Cl)c(Cl)c1)c1cc(Br)ccc1O
Reaction time: 18 h
Yield: 46.2 %

Procedure:
A slurry of 5-bromosalicylic acid (15 g, 69 mmol) and 3,4-dichloroaniline (19.85 g, 73 mmol) and phosphorous trichloride (4.74 g 34.5 mmol) in 300 ml of chlorobenzene was refluxed for 3 hr. The hot solution was filtered through a glasswool plug and allowed to stand at room temperature for 18 hr. The crystals which deposited were collected by filtration and washed with fresh chlorobenzene and then methylene chloride to give after drying 19 g (76%) of product mp 230-233°. HPLC tr 19.25 min (Vydac HS5215 C18 ODS, 2.1×150 mm, 0.2 mL/min, gradient, A: water−0.1% trifluoroacetic acid B: acetonitrile−0.1% trifluoroacetic acid, 90-10% A during 20 min, UV detection at 214 nm). Recrystallization from chlorobenzene and then acetone gave 11.5 g of crystals, mp 237-2380°. The structure was verified by X-ray crystallography.