Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(OCC[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][C@H:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[F:31])[C:19]4[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[CH3:36][O:37][CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[CH2:46](N(CC)CC)[CH3:47]>>[F:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C@@H:20]1[C:19]2[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=2[C:17]2[N:16]=[C:15]([NH:14][C:11]3[CH:12]=[CH:13][CH:8]=[C:9]([CH2:46][CH2:47][N:43]4[CH2:44][CH2:45][N:40]([CH2:39][CH2:38][O:37][CH3:36])[CH2:41][CH2:42]4)[CH:10]=3)[N:24]=[CH:23][C:22]=2[CH2:21]1
Reactant: COCCN1CCNCC1
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2[C@@H](c2ccccc2F)C3)cc1
Reactant: CCN(CC)CC
Product: COCCN1CCN(CCc2cccc(Nc3ncc4c(n3)-c3ccccc3[C@@H](c3ccccc3F)C4)c2)CC1

Procedure:
This was synthesized by using (S)-4-(6-(2-fluorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate, 1-(2-methoxyethyl)piperazine and triethylamine as described in general procedure 6 to afford the desired product as hydrochloride salt. M.p.=148-150° C. 1H NMR 400 MHz (CDCl3) δ 8.42 (d, J=7.6 Hz, 1 H), 8.15 (s, 1 H), 7.59-7.54 (m, 2 H), 7.46-7.37 (m, 2 H), 7.29-7.25 (m, 1 H), 7.19-7.13 (m, 2 H), 7.09-7.04 (m, 2 ), 6.94-6.87 (m, 2 H), 6.75 (t, J=7.6 Hz, 1 H), 4.67 (t, J=6.4 Hz, 1 H), 3.52 (t, J=5.2 Hz, 2 H), 3.35 (s, 2 H), 3.21-3.08 (m, 2 H), 2.86-2.82 (m, 2 H), 2.69-2.58 (m, 13 H). LCMS m/e 538 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[C:11]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[CH:16][N:15](S(C3C=CC(C)=CC=3)(=O)=O)[C:12]2=[N:13][CH:14]=1.[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[C:11]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[CH:16][NH:15][C:12]2=[N:13][CH:14]=1
Reactant: COc1ccccc1-c1cnc2c(n1)c(-c1ccccc1OC)cn2S(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccccc1-c1cnc2[nH]cc(-c3ccccc3OC)c2n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 31.5 %

Procedure:
To a solution of 2,7-Bis-(2-methoxy-phenyl)-5-(toluene-4-sulfonyl)-5H-pyrrolo[2,3-b]pyrazine (200 mg, 0.412 mmol) in MeOH (5 mL) was added a solution of NaOH (66 mg, 1.65 mmol) in water (200 μL). The mixture was stirred at room temperature for 3.5 hours before the solvents were removed. The resulting yellow residue was then purified by flash silica gel chromatography using a gradient of ethyl acetate in hexanes to afford 2,7-Bis-(2-methoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine (43 mg, 32% yield) as a pale yellow solid. 1H-NMR (500 MHz, CD3OD) δ 12.21 (s br, 1H), 8.80 (dd, 6.0 Hz, 1.75 Hz, 1H), 8.69 (s, 1H), 7.76 (dd, 6.0 Hz, 1.75 Hz, 1H), 7.43 (dt, 7.5 Hz, 1.75 Hz, 1H), 7.20 (m, 2H), 7.13 (m, 2H), 7.04 (t, 7.3 Hz, 1H), 3.92 (s, 3H), 3.85 (s, 3H). MS: m/z 332.1 [MH+].
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([Cl:20])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:23][C:24]1[C:30]([OH:31])=[CH:29][C:27]([NH2:28])=[C:26]([F:32])[CH:25]=1>C(O)(C)C>[ClH:20].[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:28][C:27]3[CH:29]=[C:30]([OH:31])[C:24]([Cl:23])=[CH:25][C:26]=3[F:32])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Nc1cc(O)c(Cl)cc1F
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3cc(O)c(Cl)cc3F)ncnc2cc1OCc1ccccc1
Yield: 85.2 %

Procedure:
A suspension of 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (169 mg, 0.5 mmol), (prepared as described for the starting material in Example 1), and 4-chloro-2-fluoro-5-hydroxyaniline (97 mg, 0.6 mmol), (EP 061741 A2), in isopropanol (5 ml) was heated at reflux for 2 hours. The resulting precipitate was collected by filtration, washed with isopropanol and ether and dried under vacuum to give 7-benzyloxy-4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxyquinazoline hydrochloride (197 mg, 85%). 1H NMR Spectrum: (DMSOd6) 4.0(s, 3H); 5.36(s, 2H); 7.15(d, 1H); 7.4-7.5(m, 4H); 7.52(s, 1H); 7.54(d, 2H); 8.23(s, 1H); 8.8(s, 1H); 10.6(s, 1H); 11.39(br s, 1H) MS-ESI: 426 [MH]+
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])=[O:8])=[CH:5][N:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]=1.N1C=CC=CC=1.[C:28](Cl)(Cl)=[O:29].[C:32]1([C:38]2[CH:39]=[CH:40][C:41]3[O:45][C:44]([CH2:46][OH:47])=[CH:43][C:42]=3[CH:48]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:13][Si:12]([CH2:11][CH2:10][O:9][C:7]([C:6]1[C:2]([NH:1][C:28]([O:47][CH2:46][C:44]2[O:45][C:41]3[CH:40]=[CH:39][C:38]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:48][C:42]=3[CH:43]=2)=[O:29])=[N:3][N:4]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:5]=1)=[O:8])([CH3:15])[CH3:14]
Reactant: O=C(Cl)Cl
Reactant: OCc1cc2cc(-c3ccccc3)ccc2o1
Reactant: C[Si](C)(C)CCOC(=O)c1cn(-c2ccccc2)nc1N
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: C[Si](C)(C)CCOC(=O)c1cn(-c2ccccc2)nc1NC(=O)OCc1cc2cc(-c3ccccc3)ccc2o1
Temperature: 90 °C

Procedure:
To a solution of 2-(trimethylsilyl)ethyl 3-amino-1-phenylpyrazol-4-carboxylate (967 mg, 3.1 mmol) in 11 ml dry toluene and pyridine (504 mg, 0.52 mL, 6.3 mmol) was added a phosgene solution (2.4 mL of a 1.93M toluene solution, 4.62 mmol) under nitrogen. A white precipitate formed immediately, and the mixture was heated at 90° C. for 30 min. The reaction mixture was cooled to room temperature, and filtered. The filtrate was taken to dryness. (5-Phenyl-benzofuran-2-yl)-methanol 1 (556 mg, 2.48 mmol) and DMAP (40 mg, 0.33 mmol) in 15 mL toluene were added to the residue under nitrogen. The reaction mixture was heated at 75° C. for 4 h, then concentrated to dryness. Purification by chromatography afforded 1.28 g of 1-phenyl-3-(5-phenyl-benzofuran-2-ylmethoxycarbonylamino)-1H-pyrazole-4-carboxylic acid trimethylsilylethyl ester, as a pale yellow solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH:4]([CH3:8])[NH:3]1.C(N(CC)CC)C.[CH3:16][N:17]([CH3:21])[C:18](Cl)=[O:19]>C(Cl)Cl>[CH3:16][N:17]([CH3:21])[C:18]([N:3]1[CH:4]([CH3:8])[CH2:5][NH:6][CH2:7][CH:2]1[CH3:1])=[O:19]
Reactant: CC1CNCC(C)N1
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CNCC(C)N1C(=O)N(C)C
Temperature: 0 °C
Yield: 69.7 %

Procedure:
To an ice-cold solution of 2,6-dimethyl piperazine (179 mmol, 20.4 g), methylene chloride (200 mL), and triethylamine (214 mmol, 29.9 mL) was added dropwise dimethylcarbamoyl chloride (179 mmol, 16.4 mL). After 4 hr the reaction was quenched with a saturated sodium bicarbonate solution and the methylene chloride layer was collected, dried, filtered and the filtrate was evaporated to dryness to obtain an orange oil, 2,6-dimethyl-piperazine-1-carboxylic acid dimethylamide (70%, 23.1 g).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:28][NH:29][C@@H:30]([C:32]([O:34][CH3:35])=[O:33])[CH3:31].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:28][N:29]([C@H:30]([CH3:31])[C:32]([O:34][CH3:35])=[O:33])[C:10](=[O:12])[CH:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)[CH2:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7]
Reactant: CC(C)(C)OC(=O)CC(C(=O)O)c1ccc(OCc2ccccc2)cc1
Reactant: CN[C@H](C)C(=O)OC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](C)N(C)C(=O)C(CC(=O)OC(C)(C)C)c1ccc(OCc2ccccc2)cc1
Reaction time: 8 h
Yield: 48.9 %

Procedure:
To a solution of (R/S)-α-t-butoxycarbonylmethyl-4-benzyloxyphenylacetic acid 48b (4.8 g, 13.48 mmol) and methyl N-methyl-D-alaninate hydrochloride (2.9 g, 18.9 mmol) in DMF (30 mL) cooled in an ice bath was added BOP (6.56 g, 14.83 mmol) followed by DIEA (16.5 mL, 94.5 mmol) and the solution was stirred overnight. EtOAc was added and the solution was washed with NaHCO3 and brine, dried over MgSO4, and concentrated. The residue was purified on a silica gel column by eluting with 40% EtOAc/hexane to give the desired product (3.0 g, 49%) as a solid. MS (CI—NH3): (M+H)+=456.
Reaction SMILES: [C:1]1([CH:7]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][NH:9][C:8]2=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][C:21]=1[C:29]([F:32])([F:31])[F:30]>C1COCC1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([N:10]2[CH:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8](=[O:18])[NH:9]2)=[O:28])=[CH:22][C:21]=1[C:29]([F:30])([F:31])[F:32]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=C1NNC(c2ccccc2)C1c1ccccc1
Solvent: C1CCOC1
Product: O=C1NN(C(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)C(c2ccccc2)C1c1ccccc1
Reaction time: 2.3 h
Yield: 85.3 %

Procedure:
4,5-Diphenyl-3-pyrazolidinone (3.00 g, 12.6 mmol) was dissolved in 40 mL THF under nitrogen, then a solution of 4-chloro-3-trifluoromethylphenylisocyanate (2.87 g, 13.0 mmol, 1.03 eq.) in 10 mL THF added over 2 min. After 2.3 hr, solvent was removed in vacuo, and the residue triturated with 25 mL toluene. The resulting solid was pulverized, washed twice with toluene, and dried in vacuo at 65° C. to give 4.94 g (85%) white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]([C:13]([OH:15])=O)=[N:11][CH:12]=1.[NH2:16][CH2:17][C:18]1[CH:23]=[CH:22][N:21]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:20](=[O:34])[CH:19]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.CS(C)=O>[O:34]=[C:20]1[CH:19]=[C:18]([CH2:17][NH:16][C:13](=[O:15])[C:10]2[CH:9]=[CH:8][C:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)=[CH:12][N:11]=2)[CH:23]=[CH:22][N:21]1[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=1
Reactant: NCc1ccn(-c2ccnc(C(F)(F)F)c2)c(=O)c1
Reactant: O=C(O)c1ccc(-c2cnccn2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(NCc1ccn(-c2ccnc(C(F)(F)F)c2)c(=O)c1)c1ccc(-c2cnccn2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-(pyrazin-2-yl)picolinic acid 41-4 (28 mg, 0.14 mmol), 4-(aminomethyl)-1-(2-(trifluoromethyl)pyridin-4-yl)pyridin-2(1H)-one 56-7 (35 mg, 0.13 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (49 mg, 0.13 mmol) in DMF (1.0 mL) was added DIEA (0.09 mL, 0.52 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted into DMSO and purified by HPLC to give N-((2-oxo-1-(2-(trifluoromethyl)pyridin-4-yl)-1,2-dihydropyridin-4-yl)methyl)-5-(pyrazin-2-yl)picolinamide 56 as a white solid. MS m/z 453.2 (M+1). 1H NMR 400 MHz (DMSO-d6) δ 9.57 (t, 1H), 9.40 (d, 1H), 9.36 (dd, 1H), 8.86 (d, 1H), 8.77 (dd, 1H), 8.69 (m, 2H), 8.16 (dd, 1H), 8.07 (d, 1H), 7.84 (dd, 1H), 7.73 (d, 1H), 6.37 (dd, 1H), 6.31 (b, 1H), 4.36 (d, 2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=O>O>[N+:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:6]1[C:5]([C:3]([OH:2])=[O:4])=[CH:10][C:9]([C:11]2[S:13][CH:24]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:12]=2)=[CH:8][CH:7]=1)([O-:22])=[O:21]
Reactant: O=C(CBr)c1ccccc1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Solvent: O
Product: O=C(O)c1cc(-c2nc(-c3ccccc3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 39 %

Procedure:
2′-Nitro-4-(4-phenyl-thiazol-2-yl)-biphenyl-2-carboxylic acid (100 mg, 39%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 2-bromoacetophenone (available from Chem-Impex International, Inc.) using the procedure described for the preparation of Example 18 except that the entire 4 mL of water was added at the beginning of the hydrolysis step rather than being added in two portions. 1H NMR (300 MHz, DMSO-d6) δ 13.16 (br s, 1H), 8.58 (d, J=1.9 Hz, 1H), 8.06-8.28 (m, 5H), 7.36-7.82 (m, 7H).
Reaction SMILES: [CH3:1][N:2]1[CH2:19][C:18](=O)[N:5]2[C:6]3[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=3[CH2:8][N:9]3[CH:13]=[CH:12][CH:11]=[C:10]3[CH:4]2[C:3]1=O.C(O)(=O)C>O1CCCC1.B#B>[CH3:1][N:2]1[CH2:19][CH2:18][N:5]2[C:6]3[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=3[CH2:8][N:9]3[CH:13]=[CH:12][CH:11]=[C:10]3[CH:4]2[CH2:3]1
Reactant: CN1CC(=O)N2c3ccccc3Cn3cccc3C2C1=O
Agent: B#B
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN1CCN2c3ccccc3Cn3cccc3C2C1
Temperature: 25 °C

Procedure:
To the solution of 140 mg of 2-methyl-1,4-dioxo-1,3,4,14b-tetrahydro-10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine in 5 ml of tetrahydrofuran, 2 ml of 1-molar diborane in tetrahydrofuran are added while stirring and cooling in ice. The mixture is allowed to stir at room temperature overnight and is then refluxed for 4 hours. After cooling to room temperature it is combined with 0.5 ml of glacial acetic acid, evaporated and the residue basified with 3 N aqueous sodium hydroxide. The mixture is extracted with methylene chloride, the extract dried, evaporated and the residue dissolved in diethyl ether. The solution is filtered and the filtrate evaporated to yield the 2-methyl-1,3,4,14b-tetrahydro-10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine, which is identical with that obtained according to Example 1; its monomaleate melts at 176°-178°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:22])[C:5](I)=[C:6]2[C:10]=1[N:9]([S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25]>C(N(CC)CC)C.[Cu]I.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>[Br:1][C:2]1[CH:3]=[C:4]([CH3:22])[C:5]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])=[C:6]2[C:10]=1[N:9]([S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(I)c(C)cc(Br)c32)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C#C[Si](C)(C)C)c(C)cc(Br)c32)cc1
Temperature: 25 °C

Procedure:
To a suspension of 7-bromo-4-iodo-5-methyl-1-tosyl-1H-indole (90 mg, 0.184 mmol), CuI (5.60 mg, 0.029 mmol) and Pd(PPh3)4 (16.9 mg, 0.015 mmol) in triethylamine (3 mL) was added trimethylsilylacetylene (0.036 mL, 0.257 mmol) and the mixture was stirred at room temperature. After 3 hours the reaction was purified directly by flash chromatography (0-40% EtOAc in heptanes) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.03 (d, J=3.79 Hz, 1H) 7.70 (d, J=8.34 Hz, 2H) 7.34-7.48 (m, 3H) 6.85 (d, J=3.79 Hz, 1H) 2.38 (s, 3H) 2.37 (s, 3H) 0.27-0.31 (m, 9H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=[C:3]1[CH2:12][O:13][C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:20]2=[O:44])=[CH:16][CH:15]=1.C(O)(=O)C>O>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=[C:3]1[CH2:12][O:13][C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[NH:21][C:20]2=[O:44])=[CH:16][CH:15]=1
Reactant: Cc1ccnc2c1nc(COc1ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc1)n2C
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccnc2c1nc(COc1ccc(CC3SC(=O)NC3=O)cc1)n2C

Procedure:
A procedure similar to that described in Example 12 was repeated, except that 1.07 g of 5-{4-(3,7-dimethylimidazo[5,4-b]pyridin-2-ylmethoxy)benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 41) and 16 ml of a 3:1 by volume mixture of acetic acid and water were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 1:1 to 1:2 by volume as the eluent. The product was crystallized by trituration with ethyl acetate, to give 0.28 g of the title compound, melting at 205-207° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([NH:9][C@@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]2)[C:6]([N+:19]([O-:21])=[O:20])=[CH:5][N:4]=1.S(Cl)(Cl)=O.[CH3:26][C@H:27]1[NH:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]1>C1COCC1>[Cl:2][C:3]1[CH:8]=[C:7]([NH:9][C@@H:10]2[CH2:11][CH2:12][C@H:13]([C:16]([N:32]3[CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28][C@H:27]3[CH3:26])=[O:18])[CH2:14][CH2:15]2)[C:6]([N+:19]([O-:21])=[O:20])=[CH:5][N:4]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C(O)[C@H]1CC[C@@H](Nc2cc(Cl)ncc2[N+](=O)[O-])CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)[C@H]1CC[C@@H](Nc2cc(Cl)ncc2[N+](=O)[O-])CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A suspension of cis-4-(2-chloro-5-nitropyridin-4-ylamino)cyclohexanecarboxylic acid hydrochloride (0.5 g, 1.487 mmol) in thionyl chloride (10.86 mL, 149 mmol) was heated at 70° C. for 1.5 hours. The mixture was concentrated under reduced pressure and dried under high vacuum for 1 hour. The resulting solid was suspended in THF (14.87 mL) and cooled to 0° C. under nitrogen atmosphere. To this mixture was added (R)-tert-butyl 3-methylpiperazine-1-carboxylate (0.357 g, 1.785 mmol) as a solution in THF (5 mL). The ice bath was removed, and the reaction mixture was stirred overnight at RT. The resulting mixture was diluted with DCM (100 mL) and washed with saturated aqueous NaHCO3 solution (30 mL) and then with saturated aqueous ammonium chloride solution (2×). The organic phase was collected, dried over sodium sulfate, and concentrated under reduced pressure to afford (R)-tert-butyl 4-(cis-4-(2-chloro-5-nitropyridin-4-ylamino)cyclohexanecarbonyl)-3-methylpiperazine-1-carboxylate as a light yellow solid (0.55 g, 77% yield). MS m/z=482.2 [M+H]. Calc'd for C22H32ClN5O5: 481.2.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[C:2]([NH2:4])=[NH:3].CS[C:17](=[NH:22])[NH:18][N+:19]([O-:21])=[O:20]>C(O)C>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:17]([NH2:22])=[N:18][N+:19]([O-:21])=[O:20])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CSC(=N)N[N+](=O)[O-]
Reactant: N=C(N)Nc1nc(CCCCN)cs1
Solvent: CCO
Product: N=C(N)Nc1nc(CCCCNC(N)=N[N+](=O)[O-])cs1
Temperature: 25 °C

Procedure:
To a solution of 2-guanidino-4-(4-aminobutyl)thiazole (0.426 g.) in ethanol (10 ml.) was added 2-methyl-1-nitroisothiourea (0.270 g.). The mixture was heated under reflux for 4 hours, allowed to cool to room temperature, evaporated to dryness and the residue triturated with alcohol. The product was filtered off and dried to give 2-guanidino-4-[4-(2-nitroguanidino)butyl]thiazole, m.p. 180°-181° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[C:5]([C:14]#[C:15][CH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])=[CH:4][N:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:14]=[C:15]([CH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])[N:8]([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[C:6]=2[N:7]=1
Reactant: CCOC(C#Cc1cnc(Cl)nc1NC1CCCC1)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(OCC)c1cc2cnc(Cl)nc2n1C1CCCC1
Yield: 75.3 %

Procedure:
To a stirred solution of [2-chloro-5-(3,3-diethoxy-prop-1-ynyl)-pyrimidin-4-yl]-cyclopentyl-amine (7.50 g, 23.3 mmol) in THF (45 mL) is added 1N TBAF in THF (100 mL, 116 mmol) at room temperature. The reaction mixture is heated under reflux overnight. After cooling the mixture is partitioned between H2O and dichloromethane. The phases are separated and the aqueous layer is extracted with dichloromethane (×2). The combined organic extracts are dried (MgSO4), filtered and concentrated. The residue is purified by SiO2 chromatography eluting with a gradient of 10% EtOAc/petrol to 30% EtOAc/petrol to give 2-chloro-7-cyclopentyl-6-diethoxymethyl-7H-pyrrolo[2,3-d]pyrimidine, (5.68 g, 76%). MS (ESI) m/z 324.1 (M+H)+
Reaction SMILES: [Cl-].[CH3:2][NH3+:3].C[Al](C)C.CO[C:10](=[O:26])[CH:11]=[C:12]([C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=1)[N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1.Cl>C1(C)C=CC=CC=1>[CH3:2][NH:3][C:10](=[O:26])/[CH:11]=[C:12](\[C:18]1[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=1)/[N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: C[NH3+]
Reactant: COC(=O)C=C(c1ccc(C#N)cc1)n1ccnc1
Agent: C[Al](C)C
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CNC(=O)/C=C(\c1ccc(C#N)cc1)n1ccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.35 g of methylammonium chloride in 10 ml of toluene is mixed under argon with 7.5 ml of trimethylaluminum in 10 ml of toluene by instillation and stirred for 2 hours at room temperature. 50 mg of the E-methyl ester of example 1 is mixed in 2 ml of toluene with 2 ml of the above-produced reagent. It is stirred for 6 hours at 80° C., then mixed at room temperature with 1M hydrochloric acid and extracted with ether. The acid phase is alkalized with potassium carbonate and extracted with ethyl acetate. After washing with water and drying, the ethyl acetate phase is concentrated by evaporation. 30 mg of the title compound (50%) remains; melting range: 172°-180° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([OH:26])[CH:14]=[CH:13][C:12]=3[N:11]([CH2:27][CH2:28][C:29](O)=[O:30])[C:10]=2[CH:9]=1.[C:32](Cl)(=O)C(Cl)=O.[NH2:38][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([O:26][CH3:32])[CH:14]=[CH:13][C:12]=3[N:11]([CH2:27][CH2:28][C:29]([NH:38][CH2:39][CH2:40][N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[O:30])[C:10]=2[CH:9]=1
Reactant: O=C(O)CCn1c2ccc(O)cc2c2c3c(c(-c4ccccc4Cl)cc21)C(=O)NC3=O
Reactant: NCCN1CCOCC1
Reactant: O=C(Cl)C(=O)Cl
Product: COc1ccc2c(c1)c1c3c(c(-c4ccccc4Cl)cc1n2CCC(=O)NCCN1CCOCC1)C(=O)NC3=O
Yield: 73 %

Procedure:
Reaction of acid (117) prepared as described in example 230 with oxalyl chloride followed by N-(2-aminoethyl)morpholine using the procedure described in example 207 gave the amide (120) (73%) as a yellow powder, mp 174–176° C. 1H NMR δ [(CD3)2SO] 11.12 (br s, 1H), 8.51 (d, J=2.6 Hz, 1H), 7.77 (s, 1H), 7.74 (t, J=5.6 Hz, 1H), 7.68 (d, J=9.0 Hz, 1H), 7.58 (m, 1H), 7.53–7.44 (m, 3H), 7.31 (dd, J=9.0, 2.6 Hz, 1H), 4.71 (t, J=6.3 Hz, 2H), 3.90 (s, 3H), 3.40 (t, J=4.6 Hz, 4H), 2.97 (m, 1H), 2.58 (t, J=6.3 Hz, 2H), 2.11 (br t, J=4.6 Hz, 4H), 2.00 (t, J=6.7 Hz, 2H). Found: C, 60.46; H, 5.26; N, 9.27. C30H29ClN4O5.2H2O requires C, 60.35; H, 5.94; N, 9.38.
Reaction SMILES: CO[C:3]1[CH2:9][CH2:8][CH2:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[N:4]=1.[Cl-:14].[NH4+:15]>CO.C(Cl)Cl>[ClH:14].[NH:4]1[C:5]2[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=2[CH2:7][CH2:8][CH2:9][C:3]1=[NH:15]
Reactant: COC1=Nc2ccccc2CCC1
Reactant: [Cl-]
Reactant: [NH4+]
Solvent: CO
Solvent: ClCCl
Product: Cl
Product: N=C1CCCc2ccccc2N1
Yield: 91.3 %

Procedure:
The product of EXAMPLE 166 (1.9 g, 11.1 mmol) in 15 mL of MeOH and 10 mL of CH2Cl2 was reacted with ammonium chloride (413 mg, 7.8 mmol) by the method of EXAMPLE 27 to yield 1.4 g (88%) of the title material.