Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:3]=1[NH2:13].Cl[CH2:15][CH2:16][O:17][CH2:18][CH2:19]Cl.[I-].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:3]=1[NH2:13]
Reactant: ClCCOCCCl
Reactant: Nc1cc(Cl)c(N)c(C(F)(F)F)c1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: Nc1c(Cl)cc(N2CCOCC2)cc1C(F)(F)F
Temperature: 165 °C
Yield: 24 %

Procedure:
2-Chloro-6-trifluoromethyl-benzene-1,4-diamine (2.9 g), bis-(2-chloroethyl)ether (1.7 mL) and sodium iodide (516 mg) were mixed in acetonitrile (45 mL) and heated to 165° C. for 1 hour in a sealed microwave process vessel. The crude mixture was concentrated in vacuo, redissolved in ethyl acetate (100 mL) and washed with water (2×100 mL) and brine (1×100 mL). The organic phase was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography to furnish 940 mg (24%) of the title compound as a black oil. 1H NMR (500 MHz, CDCl3): 3.02 (m, 4H), 3.84 (m, 4H), 4.30 (b, 2H), 6.97 (d, 1H), 7.06 (d, 1H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]([C:11]([C:13]2[N:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:15]3[C:20]([C:21]=2[NH2:22])=[CH:19][CH:18]=[C:17]([Cl:23])[CH:16]=3)=[O:12])[O:9][CH:10]=1)(=[O:3])[CH3:2].[C:29]([O:32][C@@H:33]([CH3:37])[C:34](Cl)=[O:35])(=[O:31])[CH3:30]>>[C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]([C:11]([C:13]2[N:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:15]3[C:20]([C:21]=2[NH:22][C:34](=[O:35])[C@@H:33]([O:32][C:29](=[O:31])[CH3:30])[CH3:37])=[CH:19][CH:18]=[C:17]([Cl:23])[CH:16]=3)=[O:12])[O:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: CCOC(=O)n1c(C(=O)c2cc(COC(C)=O)co2)c(N)c2ccc(Cl)cc21
Product: CCOC(=O)n1c(C(=O)c2cc(COC(C)=O)co2)c(NC(=O)[C@H](C)OC(C)=O)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 2 (Method A) employing 2-(4-acetoxymethyl-2-furoyl)-3-amino-6-chloro-1-(ethoxycarbonyl)indole (Example 373, step 2) and (S)-(−)-2-acetoxypropionyl chloride. 1H-NMR (CDCl3) δ: 10.03 (1H, br s), 8.26 (1H, d, J=1.81 Hz), 8.21 (1H, d, J=8.74 Hz), 7.62 (1H, s),7.30 (1H, dd, J=8.74 Hz, 1.81 Hz), 7.28 (1H, s), 5.38 (1H, q, J=6.92 Hz), 4.99 (2H, s), 4.12 (2H, q, J=7.09 Hz), 2.08 (3H, s), 2.04 (3H, s), 1.59 (3H, d, J=6.92 Hz), 1.26 (3H, t, J=7.09 Hz).
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][C@H:8]([OH:10])[C@@H:7]([CH2:11][OH:12])[O:6][CH2:5]1)=[N+:2]=[N-:3].[CH3:13][O:14][C:15]1[CH:36]=[CH:35][C:18]([C:19](Cl)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[CH:17][CH:16]=1>N1C=CC=CC=1>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([C:19]([O:12][CH2:11][C@H:7]2[O:6][CH2:5][C@H:4]([N:1]=[N+:2]=[N-:3])[CH2:9][C@@H:8]2[OH:10])([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:18]2[CH:35]=[CH:36][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)=[CH:25][CH:24]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: [N-]=[N+]=N[C@H]1CO[C@H](CO)[C@@H](O)C1
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2OC[C@H](N=[N+]=[N-])C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 77.1 %

Procedure:
0.52 g (3.0 mmole) of 1,5-anhydro-2-azido-2,3-dideoxy-D-glucitol (11) were dissolved in 9 ml of pyridine. Thereafter, 1.1 g (3.2 mmole) of 4,4′-dimethoxytritylchloride in 9 ml of pyridine are added at r.t. within 30 min under stirring. The reaction mixture was stirred for another 3 h at r.t. Then pyridine was evaporated and the residue was dissolved in 100 ml of ethyl acetate und washed twice with 60 ml of 5% sodium hydrogencarbonate solution. Organic layer was separated, dried over sodium sulfate, filtered and evaporated to dryness. The residue was dissolved in 5 ml of ethyl acetate and purified by flash-chromatography over silica gel (n-hexane/ethyl acetate/1% triethylamine gradient). Product fractions were combined, evaporated and dried at high vacuum to yield 1.1 g (77%) of a colorless foam.
Reaction SMILES: [C:1]([C@H:6]1[O:10][C@H:9](C(=O)C)[CH2:8][O:7]1)([O:3][CH2:4][CH3:5])=[O:2].C1C=C(Cl)C=[C:16]([C:21]([O:23]O)=[O:22])C=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[C:1]([C@H:6]1[O:10][C@H:9]([O:23][C:21](=[O:22])[CH3:16])[CH2:8][O:7]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)[C@@H]1OC[C@@H](C(C)=O)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1OC[C@@H](OC(C)=O)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
A 2.5:1 mixture of cis and trans-2-carboethoxy-4-acetyl-1,3-dioxolane (406 mg, 2.16 mmol), 85% mCPBA (68 mg, 3.81 mmol) and sodium carbonate (389 mg, 3.67 mmol) in dry dichloromethane (10 mL) was stirred under argon for 16 hours at room temperature. The resultant suspension was diluted with dichloromethane and water and stirred for 10 minutes. The aqueous phase was removed and the organic phase was washed successively with saturated sodium thiosulfate, water, brine and then was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the crude product thus obtained was subjected to flash column chromatography (30% EtOAc-Hexanes) to give the title compound (49% yield) which displayed the following spectral characteristics; 1H NMR (CDCl3):δ 1.29 (t, 3H, J=7.2 Hz), 2.09 (s, 1H), 4.12 (d of d, 1H, J=0.9, 9.1 Hz), 4.19-4.31 (m, 3H), 5.53 (s, 1H), 6.48 (d of d, 1H, J=0.9, 3.9 Hz).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:32]=1[C:33](=[O:42])[C:34]([CH3:41])=[CH:35][NH:36]2>>[CH3:29][O:28][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:13]=1[NH:12][C:4]1[N:3]=[C:2]([NH:30][C:31]2[CH:40]=[CH:39][CH:38]=[C:37]3[C:32]=2[C:33](=[O:42])[C:34]([CH3:41])=[CH:35][NH:36]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=1)[CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]
Reactant: Cc1c[nH]c2cccc(N)c2c1=O
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cccc4[nH]cc(C)c(=O)c34)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 5-amino-3-methylquinolin-4(1 H)-one (Compound 203A). 1H NMR (DMSO-d6, 400 MHz): δ=1.20 (t, J=7.07 Hz, 6 H), 1.98 (s, 3 H), 3.24-3.31 (m, 2 H), 3.75 (s, 3 H), 3.94-4.04 (m, 4 H), 6.90 (d, J=7.83 Hz, 1 H), 7.04 (s, 1 H), 7.08 (d, J=8.34 Hz, 1 H), 7.34-7.44 (m, 1 H), 7.50 (d, J=7.83 Hz, 1 H), 7.94 (s, 1 H), 8.37 (s, 1 H), 8.48 (br. s., 1 H), 8.91 (s, 1 H), 11.86 (br. s., 1 H), 14.41 (s, 1 H). MS (ES+): tniz 592.14 [MH+] (TOF, polar).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.[Si]([O:31][CH2:32][C@@H:33]1[N:40]([C:41](=[O:77])[C@@H:42]2[CH2:46][C@@H:45]([F:47])[CH2:44][N:43]2[C:48]([C:50]2[S:54][C:53]3=[N:55][C@:56]([C:67]4[CH:68]=[N:69][C:70]([Cl:73])=[CH:71][CH:72]=4)([CH3:66])[C@@H:57]([C:58]4[CH:63]=[CH:62][C:61]([Cl:64])=[C:60]([F:65])[CH:59]=4)[N:52]3[C:51]=2[CH:74]([CH3:76])[CH3:75])=[O:49])[CH2:39][C:36]2([CH2:38][CH2:37]2)[N:35](C(=O)C(F)(F)F)[CH2:34]1)(C(C)(C)C)(C)C>C(OCC)(=O)C>[Cl:64][C:61]1[CH:62]=[CH:63][C:58]([C@H:57]2[N:52]3[C:53]([S:54][C:50]([C:48]([N:43]4[CH2:44][C@H:45]([F:47])[CH2:46][C@H:42]4[C:41]([N:40]4[CH2:39][C:36]5([CH2:37][CH2:38]5)[NH:35][CH2:34][C@@H:33]4[CH2:32][OH:31])=[O:77])=[O:49])=[C:51]3[CH:74]([CH3:75])[CH3:76])=[N:55][C@:56]2([C:67]2[CH:68]=[N:69][C:70]([Cl:73])=[CH:71][CH:72]=2)[CH3:66])=[CH:59][C:60]=1[F:65]
Reactant: CC(C)C1=C(C(=O)N2C[C@H](F)C[C@H]2C(=O)N2CC3(CC3)N(C(=O)C(F)(F)F)C[C@@H]2CO[Si](C)(C)C(C)(C)C)SC2=N[C@@](C)(c3ccc(Cl)nc3)[C@@H](c3ccc(Cl)c(F)c3)N21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)C1=C(C(=O)N2C[C@H](F)C[C@H]2C(=O)N2CC3(CC3)NC[C@@H]2CO)SC2=N[C@@](C)(c3ccc(Cl)nc3)[C@@H](c3ccc(Cl)c(F)c3)N21
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.6 %

Procedure:
Tetra-n-butylammonium fluoride (1 M tetrahydrofuran solution) (0.42 ml, 0.42 mmol) was added to a tetrahydrofuran (4 ml) solution of the compound (255 mg, 0.28 mmol) obtained in Step 1 above and the resulting mixture was stirred at room temperature for 3 hours. The solvent was concentrated under reduced pressure, then the residue obtained was diluted with ethyl acetate and the organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by NH-silica gel column chromatography [chloroform:methanol=40:1 (v/v)] to give the title compound (102 mg, 52%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][OH:14].[CH3:15][O:16][C:17]([C:19]1[CH:24]=[CH:23][C:22](O)=[CH:21][N:20]=1)=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:15][O:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:21][N:20]=1)=[O:18]
Reactant: Cc1onc(-c2ccccn2)c1CO
Reactant: COC(=O)c1ccc(O)cn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2c(-c3ccccn3)noc2C)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.2 %

Procedure:
To a solution of (5-methyl-3-pyridin-2-yl-isoxazol-4-yl)-methanol (100 mg, 0.53 mmol) in THF (5 mL) was added 5-hydroxy-pyridine-2-carboxylic acid methyl ester (89 mg, 0.58 mmol) and triphenylphosphine (207 mg, 0.79 mmol) at ambient temperature under an argon atmosphere. Then diethyl azodicarboxylate (362 μL, 40% solution in toluene, 0.79 mmol) was added and the reaction mixture was stirred for 3 h at room temperature. The reaction mixture was evaporated and then purified by chromatography (silica, heptane:ethyl acetate=100:0 to 2:3) to afford the title compound (78 mg, 44%) as a white solid. MS: m/e=326.1 [M+H]+.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].C(C[O:63][C:64](=O)[C@@H:65]([NH:78][C:79]([O:81][C:82]([CH3:85])([CH3:84])[CH3:83])=[O:80])[CH2:66][CH:67]([S:72][S:73][C:74]([CH3:77])([CH3:76])[CH3:75])[CH2:68][N:69]=[N+:70]=[N-:71])#N>O.O1CCCC1>[N:69]([CH2:68][CH:67]([S:72][S:73][C:74]([CH3:77])([CH3:76])[CH3:75])[CH2:66][C@@H:65]([NH:78][C:79]([O:81][C:82]([CH3:83])([CH3:84])[CH3:85])=[O:80])[C:64]([O:40][C@H:39]1[C@@H:38]([OH:41])[C@H:37]([N:42]2[CH:50]=[N:49][C:48]3[C:43]2=[N:44][CH:45]=[N:46][C:47]=3[NH2:51])[O:36][C@H:35]1[CH2:34][O:33][P:30]([O:29][C@H:28]1[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25][C@@H:24]1[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:63])=[N+:70]=[N-:71]
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(CN=[N+]=[N-])SSC(C)(C)C)C(=O)OCC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CC(CN=[N+]=[N-])SSC(C)(C)C)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.7 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (56 mg, 0.088 mmol) in water (1 ml) and a solution of (S)-5-azido-2-tert-butoxycarbonylamino-4-tert-butyldisulfanyl-pentanoic acid cyanomethyl ester (Compound 41) (110 mg, 0.263 mmol) in tetrahydrofuran (1 ml) were added to buffer A (29 mL), and the mixture was stirred at room temperature for 3 hours. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford a crude product of (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 5-azido-2-((tert-butoxycarbonyl)amino)-4-(tert-butyldisulfanyl)pentanoate (Compound 42) (55 mg).
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][CH:13]=2)[N:8]=[C:7]([N:22]2[CH:26]=[C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:24]=[N:23]2)[N:6]=1>C1COCC1>[CH3:1][N:2]([CH3:3])[C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][CH:13]=2)[N:8]=[C:7]([N:22]2[CH:26]=[C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:24]=[N:23]2)[N:6]=1
Reactant: CCOC(=O)c1cnn(-c2nc(Cl)c3ccc(Oc4ccccc4)cc3n2)c1
Reactant: CNC
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(-c2nc(N(C)C)c3ccc(Oc4ccccc4)cc3n2)c1
Reaction time: 1 h
Yield: 62 %

Procedure:
A THF solution of dimethylamine (2M, 0.44 mL, 0.88 mmol) was added to a solution of the above ethyl 1-(4-chloro-7-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylate (70 mg, 0.18 mmol) and THF (1.4 mL). The mixture was stirred 1 h, and then concentrated. The residue was triturated with ethanol, providing the titled compound (45 mg, 63%). MS (ESI/CI): mass calcd. for C22H21N5O3, 403.1; m/z found, 404.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 9.02 (s, 1H), 8.31 (d, J=9.3 Hz, 1H), 8.12 (s, 1H), 7.53 (dd, J=11.1, 4.8 Hz, 2H), 7.32 (t, J=7.4 Hz, 1H), 7.27-7.21 (m, 2H), 7.18 (dd, J=9.3, 2.7 Hz, 1H), 6.96 (d, J=2.7 Hz, 1H), 4.27 (q, J=7.1 Hz, 2H), 3.46 (s, 6H), 1.30 (t, J=7.1 Hz, 3H).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:13]([C:24]([OH:26])=[O:25])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][NH:11][CH2:12][C@H:13]1[C:24]([OH:26])=[O:25])=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C[C@H]1C(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCNC[C@H]1C(=O)O
Reaction time: 2 h

Procedure:
A solution of 4.00 g (10.98 mmole) of (S)-4-(benzyloxycarbonyl)-1-(tert-butyloxycarbonyl)-piperazine-2-carboxylic acid in 40 ml of methanol was hydrogenated over 1.0 g of 10% pd/c with rocking at 25° under 40 psi of hydrogen for 16 hr. The mixture was filtered and the cake was washed with a mixture of 100 ml of dichloromethane, 50 ml of methanol and 1.0 g of diisopropylethyl amine. Concentration in vacuo followed by Pumping in vacuo for 2 hr left 2.39 g (95%) of white solid which was homogeneous by tlc (silica gel, 1:1:1:1 ethyl acetate:n-butanol:acetic acid:water, Rf =0.70).
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:4]=1)=O.Cl.[NH2:19][OH:20].C[O-].[Na+]>CO>[OH:20][N:19]=[CH:1][C:3]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:4]=1
Reactant: NO
Reactant: COC(=O)c1cccc(-n2ccc(C=O)c2)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc(-n2ccc(C=NO)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
Methyl 3-(3-formylpyrrol-1-yl)benzoate (10.2 g) was added to a mixture of hydroxylamine hydrochloride (3.1 g) and 28% methanolic sodium methoxide (8.6 ml) in methanol (100 ml) and the whole was stirred for 3 hours at ambient temperature. The solvent was removed by concentration. To the residue was added a mixture of ethyl acetate, tetrahydrofuran and water, and the mixture was adjusted to pH 2 with 6N-hydrochloric acid. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give methyl 3-[3-(hydroxyiminomethyl)pyrrol-1-yl]benzoate (9.24 g) (oil).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:29][C:30]1[CH:31]=[CH:32][C:33]([OH:38])=[C:34]([CH:37]=1)[CH:35]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:34]3[CH:37]=[C:30]([Br:29])[CH:31]=[CH:32][C:33]=3[OH:38])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1cc(Br)ccc1O
Product: Oc1ccc(Br)cc1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 5-bromo-2-hydroxy-benzaldehyde according to the procedure of Example 66. MS (ES) m/z 560.9.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Br:37]C1C=C2C(=CC=1)OC(C1C=CC=CC=1)=C(I)C2=O>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([Br:37])[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=c1c(I)c(-c2ccccc2)oc2ccc(Br)cc12
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(Br)cc4c3=O)cc2)CCC1
Yield: 74 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 6-bromo-3-iodo-2-phenyl-chromen-4-one was reacted to give the title compound as a pale yellow foam (303 mg, 74%). LCMS (Method A) RT=5.02 min, [M+H]+=546/548.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)(=[O:26])=[O:25])(=[O:17])=[O:16])[CH:5]=[C:6]([CH:13]=1)[O:7][CH2:8][CH2:9][CH2:10][O:11][NH2:12].[ClH:34].[N:35]1([C:40](N)=[NH:41])C=CC=N1>CN(C)C=O>[ClH:34].[CH3:1][C:2]1[CH:3]=[C:4]([O:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24]([N:27]2[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]2)(=[O:25])=[O:26])(=[O:17])=[O:16])[CH:5]=[C:6]([CH:13]=1)[O:7][CH2:8][CH2:9][CH2:10][O:11][NH:12][C:40]([NH2:41])=[NH:35]
Reactant: N=C(N)n1cccn1
Reactant: Cc1cc(OCCCON)cc(OS(=O)(=O)c2ccccc2S(=O)(=O)N2CCN(C)CC2)c1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(OCCCONC(=N)N)cc(OS(=O)(=O)c2ccccc2S(=O)(=O)N2CCN(C)CC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
A mixture of 3-[5-methyl-3-(2-(4-methylpiperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyamine (113 mg, 0.23 mmol), as prepared in the previous step, and 1H-pyrazole-1-carboxamidine hydrochloride (62 mg, 0.42 mmol) in anhydrous N,N-dimethylformamide (10 mL) was stirred at room temperature under nitrogen (balloon) for 18 hours. The solution was concentrated under high vacuum with heating and the residue was purified by flash chromatography (10% to 20% methanol in dichloromethane), then dissolved in dichloromethane, filtered and concentrated to give the title compound (105 mg, 80%) as a white solid. 1H NMR (300 MHz, CDCl3) δ8.20 (m, 2H), 7.83 (td, 1H, J=7.7, 1.3 Hz), 7.70 (td, 1H, J=7.7, 1.2 Hz), 6.59 (m, 2H), 6.52 (m, 1H), 6.28 (m, 3H), 4.04 (t, 2H, J=5.8 Hz), 3.96 (t, 2H, J=5.8 Hz), 3.43 (m, 4H), 2.33 (s, 3H), 2.23 (s, 3H), 2.00 (m, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C22H31N5O7S2: 542.2 (M+H), 564.2 (M+Na). Found: 542.3, 564.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:10](=[O:20])[CH:11]=[C:12]([C:15]([O:17]CC)=[O:16])[O:13][CH:14]=2)=[CH:4][CH:3]=1>O1CCOCC1.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:10](=[O:20])[CH:11]=[C:12]([C:15]([OH:17])=[O:16])[O:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(=O)c(Sc2ccc(Cl)cc2)co1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1cc(=O)c(Sc2ccc(Cl)cc2)co1

Procedure:
A solution of ethyl 5-(4-chlorophenylthio)-4-oxo-4H-pyran-2-carboxylate (5.0 g) in dioxan (40 ml) and concentrated hydrochloric acid (20 ml) was heated under reflux for 2 hours then evaporated under vacuum. The solid residue was dried and recrystallised from ethyl acetate-petroleum spirit (60°-80° C.) to give the title product (mp 165°-167° C. with decomposition).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([CH2:17][CH2:18][CH3:19])=[CH:11]2.CN(C)[CH:22]=[O:23]>>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([CH2:17][CH2:18][CH3:19])=[C:11]2[CH:22]=[O:23]
Reactant: CN(C)C=O
Reactant: CCCc1cc2cc(OC)ccc2[nH]1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCc1[nH]c2ccc(OC)cc2c1C=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 86 %

Procedure:
Dimethylformamide (2 mL) was cooled to 0° C. Phosphorus oxychloride (0.5 mL) was added and the reaction mixture was stirred for 10 minutes. A solution of 5-methoxy-2-propylindole (325 mg, 1.7 mmol) in dimethylformamide (3 mL) was added to the reaction mixture dropwise over 10 minutes. The solution was stirred for an additional 40 minutes. The reaction mixture was added to ice cold 1 N NaOH (50 mL) and stirred for 10 minutes. The precipitate was collected and dried overnight in an oil driven vacuum pump equipped to a vacuum desiccator set at 40° C. yielding a white solid (318 mg, 86%): TLC Rf 0.67 in 4:1 ethyl acetate/hexanes. Melting point=166-168° C. 1H NMR (600 MHz, CDCl3) δ 10.16 (s, 1H), 8.31 (s, 1H), 7.79 (d, 1H, J=2.46 Hz), 7.23-7.22 (d, 1H, J=8.82 Hz), 6.89-6.87 (dd, 1H, J1=2.54, J2=8.76 Hz), 3.89 (s, 3H), 3.06-3.04 (t, 2H, J=7.5 Hz), 1.84-1.80 (m, 2H) 1.05-1.03 (t, 3H, J=7.32 Hz); 13C NMR (150 MHz, CDCl3) δ 184.4, 156.5, 151.4401, 129.6, 126.7, 114.7, 113.5, 111.5, 103.0, 55.8, 28.3, 23.5, 13.8. Elemental analysis calculated for C13H15NO2: C, 71.87; H, 6.96; N, 6.45. Found: C, 71.92; H, 6.97; N, 6.34.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH:8]([C:13]1[CH:18]=[N:17][CH:16]=[CH:15][N:14]=1)[CH2:7][CH2:6]2.B(Br)(Br)Br>ClCCl>[N:14]1[CH:15]=[CH:16][N:17]=[CH:18][C:13]=1[CH:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([OH:2])[CH:4]=2)[O:9]1
Reactant: COc1ccc2c(c1)CCC(c1cnccn1)O2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc2c(c1)CCC(c1cnccn1)O2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 2-(6-methoxy-chroman-2-yl)-pyrazine (663 mg, 2.74 mmol) in 50 ml of anhydrous dichloromethane was cooled to −10° C., and a solution of boron tribromide (9.6 ml of 1M solution in dichloromethane, 9.6 mmol) was added dropwise. After stirring at 0° C. for 1 h, 1 ml of boron tribromide solution was added and the reaction mixture was stirred at 0° C. for 1.5 h. The reaction mixture was quenched by slow addition of water, and after 10 min neutralized by addition of a sodium hydrogencarbonate solution. After decantation and extraction with dichloromethane, the organic layer was dried over sodium sulfate and concentrated in vacuo. After chromatography on silica gel (methanol in dichloromethane), 2-pyrazin-2-yl-chroman-6-ol was obtained as a yellow powder (625 mg, 100%).