Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([C:22]3[CH2:26][CH2:25][CH2:24][CH:23]=3)=[CH:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1>C(O)C.C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)=[CH:14]2)(=[O:11])=[O:12])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)n2cc(C3=CCCC3)c3ccccc32)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(S(=O)(=O)n2cc(C3CCCC3)c3ccccc32)cc1

Procedure:
Dissolve 4-(3-cyclopent-1-enyl-indole-1-sulfonyl)-benzoic acid methyl ester (2.2 g, 5.77 mmol) in ethanol (25 mL) and ethyl acetate (25 mL) and hydrogenate with 10% palladium on carbon (300 mg) at 33 psi for 16 h. Filter the catalyst over celite and back-wash with 1:1 ethanol/ethyl acetate (50 mL). Concentrate to give a dark solid and dissolve in 1:1 ethyl acetate/hexanes (50 mL) and pass through a silica gel plug. Back-wash the plug with 1:1 ethyl acetate/hexanes (100 mL) and concentrate the filtrate to an oil, which solidifies upon standing and found to be pure title compound (2.0 g, 90%); 1H NMR DMSO-d6) δ8.10 (m, 4H), 7.93 (d, J=8.2 Hz, 1H), 7.55 (d, J=7.7 Hz, 1H), 7.53 (s, 1H), 7.36 (t, J=7.1 Hz, 1H), 7.28 (t, J=7.7 Hz, 1H), 3.84 (s, 3H), 3.16 (m, 1H), 2.08 (m, 2H), 1.62 (m, 6H); MS(ESI) m/z 384 (m+H).
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[CH:42]=[CH:41][N:40]=[CH:39]1>N1C=CC=CC=1.CS(C)=O>[F:37][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:21][CH2:22][N:23]([S:26]([CH2:29][CH2:30][N:38]4[CH:42]=[CH:41][N:40]=[CH:39]4)(=[O:28])=[O:27])[CH2:24][CH2:25]3)[N:11]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:13]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1
Reactant: c1c[nH]cn1
Reactant: C=CS(=O)(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)CCn3ccnc3)CC2)n1
Temperature: 137.5 °C
Yield: 26.6 %

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) (150 mg, 0.280 mmol), imidazole (38 mg, 0.558 mmol), and pyridine (2 drops) in DMSO (5 mL) was heated at 135-140° C. for 5 days. The mixture was then poured over ice and extracted with CH2Cl2 (3×). The combined organic extracts were washed with H2O (1×), dried (Na2SO4) and concentrated. Chromatography on silica, eluting with CH2Cl2/MeOH (100:0 to 95:5), followed by recrystallization from CH2Cl2/hexanes gave 2-(difluoromethyl)-1-[4-(4-{[2-(1H-imidazol-1-yl)ethyl]sulfonyl}-1-piperazinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-methoxy-1H-benzimidazole (45 mg, 27%): mp 188-191° C.; 1H NMR (CDCl3) δ 7.84 (dd, J=8.4, 0.6 Hz, 1H), 7.55 (s, 1H), 7.41 (t, JHF=53.5 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 7.10 (t, J=1.0 Hz, 1H), 6.96 (t, J=1.3 Hz, 1H), 6.82 (d, J=7.7 Hz, 1H), 4.46 (t, J=7.0 Hz, 2H), 4.05 (s, 3H), 3.94 (br s, 4H), 3.87 (br s, 4H), 3.78 (m, 4H), 3.35 (t, J=7.1 Hz, 2H), 3.29 (br s, 4H); Anal. Calcd. for C25H30F2N10O4S: C, 49.7; H, 5.0; N, 23.2. Found: C, 49.3; H, 4.9; N, 23.2%.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:17])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:5][CH:4]=1)=O.[O:18]=[C:19]1[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1.N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[O:18]=[C:19]1[CH2:24][CH2:23][S:22][CH2:21][C:20]1=[CH:1][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:17])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:5][CH:4]=1
Reactant: O=C1CCSCC1
Reactant: CC(C(=O)OC(C)(C)C)c1ccc(C=O)cc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CC(C(=O)OC(C)(C)C)c1ccc(C=C2CSCCC2=O)cc1
Yield: 20.1 %

Procedure:
To a solution of tert-butyl 2-(4-formylphenyl)propionate (2.0 g), 4-oxothiane (1.2 g) and piperidine (1.0 ml) in toluene (10.0 ml) was added acetic acid (2.0 ml) at room temperature, and then the mixture was refluxed by heating for 3 hours. The reaction mixture was quenched with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane/ethyl acetate=6/1) to give the title compound (570 mg, 20%).
Reaction SMILES: ClC(OCC(C)C)=O.CN1CCOCC1.[N:16]1([CH2:22][C:23]#[C:24][C:25]([OH:27])=O)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.[Br:28][C:29]1[CH:30]=[C:31]([NH:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[C:43]([NH2:46])[CH:44]=3)[N:39]=[CH:38][N:37]=2)[CH:32]=[CH:33][CH:34]=1>O1CCCC1.N1C=CC=CC=1>[Br:28][C:29]1[CH:30]=[C:31]([NH:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[C:43]([NH:46][C:25](=[O:27])[C:24]#[C:23][CH2:22][N:16]4[CH2:17][CH2:18][O:19][CH2:20][CH2:21]4)[CH:44]=3)[N:39]=[CH:38][N:37]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: O=C(O)C#CCN1CCOCC1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Agent: CC(C)COC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C(C#CCN1CCOCC1)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 32.4 %

Procedure:
Isobutyl chloroformate (0.343 g, 2.5 mmol) and N-methylmorpholine (0.322 g, 3.18 mmol) were added to an ice cold solution of 0.540 g (3.18 mmol) of 4-morpholin-4-yl-but-2-ynoic acid in 50 mL of tetrahydrofuran under nitrogen. After stirring for 30 min, a solution of 0.500 g of N-(3-bromophenyl)-4,6-quinazolindiamine in 10 mL of pyridine was added and the mixture was stirred at 0° C. for 2 hr. The reaction was then quenched with ice water, poured into saturated sodium bicarbonate, and the product was extracted with ethyl acetate. Chromatography of the extract on silica gel, eluting with methanol/ethyl acetate (15:85), gave 0.240 g of 4-morpholin-4-yl-but-2-ynoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide: mass spectrum (m/e): M+H 466.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.[Cl-].[NH3+:45][C:46]([CH3:65])([CH3:64])[CH2:47][O:48][C:49]1[CH:58]=[CH:57][CH:56]=[C:55]2[C:50]=1[C:51]([NH3+:63])=[C:52]([C:60]([OH:62])=[O:61])[C:53]([CH3:59])=[N:54]2.[Cl-]>CN(C=O)C>[NH2:63][C:51]1[C:50]2[C:55](=[CH:56][CH:57]=[CH:58][C:49]=2[O:48][CH2:47][C:46]([NH:45][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])([CH3:65])[CH3:64])[N:54]=[C:53]([CH3:59])[C:52]=1[C:60]([OH:62])=[O:61]
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Reactant: Cc1nc2cccc(OCC(C)(C)[NH3+])c2c([NH3+])c1C(=O)O
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc2cccc(OCC(C)(C)NC(=O)CCCCCNC(=O)OC(C)(C)C)c2c(N)c1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.4 %

Procedure:
A solution of 6-(tert-butoxycarbonylamino)hexanoic acid (0.21 g, 0.90 mmol) in dry DMF (10 mL) was treated with triethylamine (0.46 g, 4.51 mmol, 0.63 mL) and N,N,N′,N′-tetramethyl-O—(N-succinimidyl)uronium tetrafluoroborate (TSTU) (0.30 g, 0.99 mmol) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature over 3 h and then a solution of 5-(2-ammonio-2-methylpropoxy)-3-carboxy-2-methylquinolin-4-aminium chloride (Example 20b) (0.33 g, 0.90 mmol) and triethylamine (0.46 g, 4.51 mmol, 0.63 mL) in dry DMF was added dropwise at room temperature. The obtained mixture was stirred at room temperature over 3 days and the solvent was evaporated. The residue was dissolved in a mixture of MeOH and H2O (50 mL, 1:1) and the product was isolated by preparative HPLC (RPC18, H2O→CH3CN gradient). The appropriate fractions were collected and evaporated under reduced pressure. The residue was dried in a dessicator over phosphorus pentoxide to give 0.21 g (45%) of 4-amino-5-(2-(6-(tert-butoxycarbonylamino)hexanamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylic acid as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.95-12.65 (m, 1H), 12.45-11.95 (m, 1H), 9.05-8.60 (m, 1H), 7.84 (s, 1H), 7.67 (t, J=8.0 Hz, 1H), 7.29 (d, J=8.2 Hz, 1H), 7.02 (d, J=8.1 Hz, 1H), 6.71 (t, J=5.6 Hz, 1H), 4.36 (s, 2H), 2.78 (s, 3H), 2.70 (q, J=6.4 Hz, 2H), 2.05 (t, J=7.3 Hz, 2H), 1.45-1.34 (m, 2H), 1.36 (s, 3H), 1.34 (s, 3H), 1.30-1.19 (m, 2H), 1.14-1.03 (m, 2H). MS 503 (MH+).
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]1[C:5]2[N:6]([C:14]([CH2:17][CH3:18])=[N:15][N:16]=2)[C:7]2[C:12]([N:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2>CN(C)C=O>[CH3:1][NH:2][C:4]1[C:5]2[N:6]([C:14]([CH2:17][CH3:18])=[N:15][N:16]=2)[C:7]2[C:12]([N:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CCc1nnc2c(Cl)nc3ccccc3n12
Reactant: CN
Solvent: CN(C)C=O
Product: CCc1nnc2c(NC)nc3ccccc3n12
Temperature: 0 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
Monomethylamine gas was bubbled through a solution of 4-chloro-1-ethyl-[1,2,4]triazolo[4,3-a]quinoxaline (1.2 g., 0.005 mole), the product of Example 4, in N,N-dimethylformamide (50 ml.) at 0° C. for 2 minutes. The reaction mixture was stirred at 0° C. for 30 minutes, at room temperature for 2 hours, and then poured over ice and stirred another 20 minutes. The precipitate which formed was separated by filtration, washed with water and air dried. Recrystallization from ethanol then afforded 1.0 g. (88% yield) of 4-methylamino-1-ethyl-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 271°-3° C. Mass spectrum: m/e, 227 (P).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6].NC(C1N=NC(N[C:42]2[CH:47]=[C:46]([O:48]C)[C:45](OC)=[C:44](OC)[CH:43]=2)=NC=1)C.O(C1C=C(C=CC=1)C(O)=O)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[O:48]([C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6])[C:46]1[CH:47]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)cc(OC)c1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)c1cccc(Oc2ccccc2)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Oc4ccccc4)c3)nn2)cc(OC)c1OC
Yield: 100 %

Procedure:
In a similar manner as described for Intermediate 18, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (87 mg, 0.28 mmol), 3-phenoxybenzoic acid (80 mg, 0.37 mmol), diisopropylethylamine (0.13 mL, 0.75 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (140 mg, 0.37 mmol) in dimethylformamide (2 mL) gave 3-phenoxy-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (140 mg, 100%) as a yellow oil. MS m/z 501 (M+1).
Reaction SMILES: S(Cl)(C)(=O)=O.[CH:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:41][O:42][CH3:43])[C:15]([NH:17][CH:18]2[C:39](=[O:40])[N:20]3[CH:21]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=4)=[O:27])[CH:22](O)[CH2:23][S:24][C@H:19]23)=[O:16])[N:13]=1)=[O:7].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[CH:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:41][O:42][CH3:43])[C:15]([NH:17][CH:18]2[C:39](=[O:40])[N:20]3[C:21]([C:26]([O:28][CH2:29][C:30]4[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=4)=[O:27])=[CH:22][CH2:23][S:24][C@H:19]23)=[O:16])[N:13]=1)=[O:7]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(O)CS[C@H]12)c1csc(NC=O)n1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1csc(NC=O)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 12.4 %

Procedure:
Mesyl chloride (0.406 g.) was dropwise added to a stirred mixture of 4-nitrobenzyl 7-[2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetamido]-3-hydroxycepham-4-carboxylate (syn isomer, 1 g.), N,N-dimethylformamide (10 ml.) and potassium carbonate (0.732 g.) at 0° to 5° C. over 2 minutes, and the solution was stirred at room temperature for 2.5 hours. After ethyl acetate and water were added to the resultant solution, the solution was extracted with ethyl acetate. The remaining aqueous layer was extracted again with ethyl acetate. The ethyl acetate extract solution was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (30 g.) and eluted with a mixture of chloroform and ethyl acetate. The eluate was concentrated under reduced pressure to give 4-nitrobenzyl 7-[2-(2-formamido-4-thiazolyl)-2-methoxyimino-acetamido]-3-cephem-4-carboxylate (syn isomer, 0.12 g.), mp 224° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][C:13]([C:17]([O:19]C)=[O:18])=[CH:12][C:11]=3[CH:21]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][C:13]([C:17]([OH:19])=[O:18])=[CH:12][C:11]=3[CH:21]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)C1=Cc2cc(-c3ccc(C)s3)ccc2OCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
In THF (10.5 ml) and methanol (5.2 ml) was dissolved methyl 7-(5-methyl-2-thienyl)-2,3-dihydro-1-benzoxepine-4- carboxylate (525 mg), and to the mixture was added 1N sodium hydroxide (10.5 ml). The mixture was stirred at room temperature for 2 hours. Under reduced pressure, the organic solvent was removed, and to the residue was added ethyl acetate. The mixture was extracted with water, and to the aqueous layer was added 6N hydrochloric acid to make the solution pH 4-5, which was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was removed to give 7-(5-methyl-2-thienyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (410 mg).
Reaction SMILES: [N+](C1C=CC(N2CCNCC2)=CC=1)([O-])=O.[N+:16]([C:19]1[CH:20]=[C:21]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:22]=[CH:23][CH:24]=1)([O-])=O.CS(C1N=CC2=CC=C([C:43]3C=CC=[CH:45][C:44]=3[O:49]C)N2N=1)=O.CS([C:54]1[N:59]=[CH:58][C:57]2=[CH:60][CH:61]=[C:62]([C:63]3[CH:68]=[CH:67][C:66]([S:69]([CH3:72])(=[O:71])=[O:70])=[CH:65][CH:64]=3)[N:56]2[N:55]=1)=O>>[CH3:72][S:69]([C:66]1[CH:67]=[CH:68][C:63]([C:62]2[N:56]3[C:57]([CH:58]=[N:59][C:54]([NH:16][C:19]4[CH:20]=[C:21]([N:25]5[CH2:30][CH2:29][N:28]([CH2:43][C@@H:44]([OH:49])[CH3:45])[CH2:27][CH2:26]5)[CH:22]=[CH:23][CH:24]=4)=[N:55]3)=[CH:60][CH:61]=2)=[CH:64][CH:65]=1)(=[O:71])=[O:70]
Reactant: CS(=O)c1ncc2ccc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: O=[N+]([O-])c1cccc(N2CCNCC2)c1
Agent: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Product: C[C@H](O)CN1CCN(c2cccc(Nc3ncc4ccc(-c5ccc(S(C)(=O)=O)cc5)n4n3)c2)CC1

Procedure:
The compound was prepared in an analogous fashion to Example 69 replacing 1-(4-Nitro-phenyl)-piperazine with 1-(3-Nitro-phenyl)-piperazine and 2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine with 2-Methanesulfinyl-7-(4-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazine to afford 44.32 mg of (S)-1-(4-{3-[7-(4-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperazin-1-yl)-propan-2-ol as a lyophilized powder. (M+H)=507.10. 1H NMR (400 MHz, DMSO, d6) δ 9.49 (s, 2H), 9.08 (s, 1H), 8.51 (d, 2H, J=8.56 Hz), 8.03 (d, 2H, J=8.60 Hz), 7.41 (m, 1H), 7.37 (d, 1H, J=4.81 Hz), 7.25 (m, 2H), 7.01 (d, 1H, J=4.84 Hz), 6.67 (d, 1H, J=6.64 Hz), 4.15 (m, 2H), 3.75 (m, 2H), 3.53 (m, 2H), 3.31 (s, 3H), 3.11 (m, 3H), 3.03 (m, 2H), 1.13 (d, 3H, J=6.12 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:8]([C:10]([CH3:12])=O)=[CH2:9]>C(O)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH3:12][C:10]1[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:1]=[CH:9][CH:8]=1
Reactant: C=CC(C)=O
Reactant: Nc1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: Cc1ccnc2ccccc12
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 55 %

Procedure:
To a stirred solution of aniline (1 g. 10 mmol) in acetic acid (10 ml), activated silferc (1.72 g. ferric chloride 10 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred for 5 minutes and methyl vinyl ketone (MVK) (0.83 g, 11.8 mmol) was added slowly over a period of 15 minutes. The reaction mixture was heated to 70° C. and maintained between 70-75° C. for one hour. Anhydrous zinc chloride (1.46 g. 10 mmol) was added and the reaction was further refluxed for two hours. The reaction mixture was cooled, filtered, basified with 10% NaOH solution, extracted with ethyl acetate (3×20 ml), dried over Na2SO4 and evaporated to give the product; Yield 55%.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[S:12]([NH:15][CH3:16])(=[O:14])=[O:13])=[N+]=[N-].[ClH:17]>C(O)C.[Pd]>[ClH:17].[NH2:1][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[S:12]([NH:15][CH3:16])(=[O:13])=[O:14]
Reactant: CNS(=O)(=O)c1cc(F)ccc1CN=[N+]=[N-]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CNS(=O)(=O)c1cc(F)ccc1CN
Reaction time: 14 h
Yield: 100 %

Procedure:
To a solution of 2-azidomethyl-5-fluoro-N-methyl-benzenesulfonamide (560 mg, 2.3 mmol) in ethanol (10 mL) was added 6N HCl (1 mL) and 10% Pd—C (100 mg) and the mixture hydrogenated with 1 atm of H2 for 14 hrs. The catalyst was removed by filtration through Celite® and the filtrate concentrated in vacuo to provide 630 mg (Yield >100%) of the title compound. 1H NMR (500 MHz, DMSO-D6) δ ppm: 4.36 (2H, d, J=5.2 Hz) 7.63-7.70 (2H, m) 7.77-7.83 (1H, m) 8.11 (1H, d, J=4.9 Hz) 8.41 (3H, s); LC/MS m/z 219 (M+H).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13](Br)[C:12]=1[OH:20].Cl>COCCOC.O.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:18][O:17][C:15]1[CH:16]=[C:11]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:12]([OH:20])=[C:13]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:14]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1cc(Br)c(O)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Temperature: 80 °C
Yield: 33.4 %

Procedure:
To a stirred solution of phenylboronic acid (0.0842 g, 0.691 mmol), Ba(OH)2.8H2O (0.396 g, 1.26 mmol), and Pd(OAc)2 (0.0014 g, 0.00628 mmol) in DME:H2O (6:1, 7 mL) at room temperature was added 2,6-dibromo-4-methoxyphenol (0.0885 g, 0.314 mmol)). The mixture was then heated at 80° C. for 18 h. The reaction was 50% complete, and an additional 2.2 eq. of phenylboronic acid and 0.02 eq. Pd(OAc)2 were added and continued heating for another 24 h. At this point, the reaction was acidified to pH 1 with 1 N HCl and diluted with EtOAc (100 mL). The organic layer was washed with H2O (10 mL) and brine (10 mL) and then dried (MgSO4). After concentration, the residue was purified by flash chromatography (1 to 5% EtAOc/petroleum ether gradient) to afford the product (0.029 g, 33%) as a clear oil; 1H NMR (CDCl3) δ 3.83 (s, 3H), 5.04 (s, 1H), 6.86 (s, 2H), 7.37-7.42 (m, 2H), 7.45-7.50 (m, 4H), 7.54-7.68 (m, 4H); IR (film) 3540, 3060, 2930, 2820, 1605, 1580, 1500, 1470, 1425, 1360, 1330, 1210, 1175, 1120, 1060, 1040, 1025, 755, 700, and 500 cm−1; mass spectrum [EI], m/z 276 (M)+; Anal. Calcd. for C19H16O2.0.80H2O: C, 78.49; H, 6.10; N, 0.00, Found: C, 78.19; H, 5.54; N, 0.19.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.C(OC([CH:70]([NH2:77])[CH2:71][C@@H:72]1[CH2:76][CH2:75][CH2:74][NH:73]1)=O)(C)(C)C.FC(F)(F)C(O)=O>CS(C)=O>[NH2:77][CH2:70][CH2:71][C@@H:72]1[CH2:76][CH2:75][CH2:74][N:73]1[C:12]([C:11]1[CH:10]=[C:9]2[C:4]([C:5]([NH:15][CH:16]([C:18]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=4[N:19]=3)[CH3:17])=[N:6][CH:7]=[N:8]2)=[CH:3][C:2]=1[Cl:1])=[O:13]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)C(N)C[C@@H]1CCCN1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCC[C@H]3CCN)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and (2S)-2-(2-tert.-butyloxycarbonyl-aminoethyl)-pyrrolidine in DMSO at ambient temperature and subsequent treatment with trifluoroacetic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH2:14][C:13](=[O:15])[NH:12][C:11]3[CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=[CH:19][C:10]=3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:24]([NH:28][S:29]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([NH:28][S:29]([C:32]1[CH:37]=[C:36]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[CH2:14][C:13](=[O:15])[NH:12][C:11]4[CH:16]=[C:17]([C:20]([F:22])([F:21])[F:23])[CH:18]=[CH:19][C:10]=4[N:9]=3)[CH:3]=2)[CH:35]=[CH:34][CH:33]=1)(=[O:31])=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: O=C1CC(c2cccc(Br)c2)=Nc2ccc(C(F)(F)F)cc2N1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(C3=Nc4ccc(C(F)(F)F)cc4NC(=O)C3)c2)c1

Procedure:
The title compound was prepared from 4-(3-bromo-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example B.2) (200 mg, 0.50 mmol) and commercially available 3-tert-butylsulfamoyl-benzeneboronic acid [CAS-no. 221290-14-8] (161 mg, 0.60 mmol) according to the general procedure II. Obtained as an off-white solid (31 mg, 12%). MS (ISP) 515.9 [(M+H)+]; mp 179-181° C.
Reaction SMILES: C(OCC(COC(=O)C)CCN1C=NC2C1=NC(N)=NC=2)(=O)C.OCC(CO)CCN1C=NC2C(=O)NC(N)=NC1=2.[NH2:42][C:43]1[N:51]=[C:50]2[C:46]([NH:47][CH:48]=[N:49]2)=[C:45]([Cl:52])[N:44]=1.Br[CH2:54][CH2:55][C:56]([C:67]([O:69]CC)=[O:68])([C:62]([O:64][CH2:65][CH3:66])=[O:63])[C:57]([O:59][CH2:60][CH3:61])=[O:58]>>[NH2:42][C:43]1[N:51]=[C:50]2[C:46]([N:47]=[CH:48][N:49]2[CH2:54][CH2:55][C:56]([C:67]([OH:69])=[O:68])([C:57]([O:59][CH2:60][CH3:61])=[O:58])[C:62]([O:64][CH2:65][CH3:66])=[O:63])=[C:45]([Cl:52])[N:44]=1
Reactant: CCOC(=O)C(CCBr)(C(=O)OCC)C(=O)OCC
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: CC(=O)OCC(CCn1cnc2cnc(N)nc21)COC(C)=O
Agent: Nc1nc2c(ncn2CCC(CO)CO)c(=O)[nH]1
Product: CCOC(=O)C(CCn1cnc2c(Cl)nc(N)nc21)(C(=O)O)C(=O)OCC

Procedure:
Nucleosides and Nucleotides, 15(5), 981-994 (1996) and WO 95/28402 disclose a process for the manufacture of the anti-viral agents 9-(4-acetoxy-3-acetoxymethylbut-1-yl)-2-aminopurine (famciclovir) and 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (penciclovir). According to this process, the ‘bromoester’ route, 2-amino-6-chloropurine is reacted with triethyl 3-bromopropane-1,1,1-tricarboxylate in the presence of base to form diethyl 2-[2-(2-amino-6-chloropurin-9-yl)ethyl]-2-carboxymalonate. The crude isolate from this alkylation reaction is then treated with sodium methoxide in methanol to form dimethyl 2-[2-(2-amino-6-chloropurin-9-yl)ethyl] malonate. This product is purified by crystallisation and then successively reduced using sodium borohydride and O-acetylated to give 9-(4-acetoxy-3-acetoxymethylbutyl)-2-amino-6-chloropurine. Famciclovir is produced directly from the latter compound by hydrogenation over a supported palladium catalyst; and penciclovir is produced from this compound by acid hydrolysis of the acetoxy groups.