Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:16])[CH2:4][NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[C:17]([O:21][CH:22]([N:26](C)C)[N:23](C)[CH3:24])(C)(C)C.C[O-].[Na+].Cl.COC(=N)N>CO.C1(C)C=CC=CC=1>[CH3:17][O:21][C:22]1[NH:26][C:3](=[O:16])[C:4]([NH:5][C:6]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7])=[CH:24][N:23]=1
Reactant: COC(=O)CNC(=O)OCc1ccccc1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Agent: COC(=N)N
Agent: C[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ncc(NC(=O)OCc2ccccc2)c(=O)[nH]1
Temperature: 70 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
Toluene (10 ml) was added to methyl-N-benzyloxycarbonyl-glycinate (1.50 g, 6.73 mmol) and tert-butoxybisdimethylaminomethane (1.83 ml, 8.91 mmol) and the mixture was stirred overnight at 70° C. The mixture was then washed with saturated brine and concentrated under reduced pressure. MTBE (20 ml) and 1N hydrochloric acid (15 ml) were added to the residue in an ice bath and the mixture was stirred at room temperature for 2 hr. Thereafter, the mixture was separated and the organic layer was washed with saturated brine. A solution (1.23 g, 6.39 mmol) of 28% sodium methoxide in methanol was added dropwise and the mixture was concentrated under reduced pressure. Acetonitrile was added and O-methylisourea hydrochloride (0.72 g, 6.50 mmol) was added. The mixture was stirred overnight at 70° C. and concentrated. Water (5 ml) was added and the mixture was stirred for 1 hr. The precipitate was collected by filtration and vacuum dried to give 2-methoxy-6-oxo-5-benzyloxycarbonylamino-1,6-dihydropyrimidine (1.43 g, 5.20 mmol). The property values were the same as in Example 3.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([OH:28])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:35][CH:36]([CH2:39][CH3:40])[CH2:37][CH3:38].C(N(CC)CC)C>C1COCC1.O.CN(C=O)C>[C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([NH:35][CH:36]([CH2:39][CH3:40])[CH2:37][CH3:38])=[O:28])#[N:2]
Reactant: CCC(N)CC
Reactant: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n([C@H]3CCCc4ccccc43)c2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CCC(CC)NC(=O)/C=C/c1c(C#N)c2c(C)cc(C)nc2n1[C@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TO a solution of (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (300 mg, 0.808 mmol) in THF (3 ml) were added DMF (0.03 ml) and oxalylchloride (0.0846 ml, 0.970 mmol), the mixture was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of 3-aminopentane (141 mg, 1.62 mmol), triethylamine (0.451 ml, 3.24 mmol) and THF (3 ml), and the mixture was stirred under ice-cooling for 1 hour and at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give the objective product as oily matter.
Reaction SMILES: C(=O)(O)[O-].[Na+].[Br:6]N1C(=O)CCC1=O.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[C:32]3[N:33]([CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[C:34](=[O:45])[N:35]([CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]#[N:44])[C:31]=3[CH:30]=[CH:29][N:28]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(OCC)(=O)C>C(#N)C.O>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[C:32]3[N:33]([CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[C:34](=[O:45])[N:35]([CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]#[N:44])[C:31]=3[C:30]([Br:6])=[CH:29][N:28]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc3c2n(Cc2ccccc2)c(=O)n3Cc2ccccc2C#N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)c3c2n(Cc2ccccc2)c(=O)n3Cc2ccccc2C#N)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 106.3 %

Procedure:
Sodium bicarbonate (0.029 g) and N-bromosuccinimide (0.044 g) were added to a solution of 4-[3-benzyl-1-(2-cyanobenzyl)-2-oxo-1H-imidazo[4.5-c]pyridin-4-yl]-piperazine-1-carboxylic acid t-butyl ester (0.121 g) in acetonitrile (5 mL). This was then stirred at room temperature for 15 hours. Ethyl acetate (100 mL) and water (50 mL) were added, and the organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by silica gel chromatography, and the hexane:ethyl acetate 7:3 fraction gave the title compound (0.148 g).
Reaction SMILES: Cl.[S:2]([N:12]1[C:16]2=[N:17][CH:18]=[C:19]([NH:21][NH:22]C(OC(C)(C)C)=O)[N:20]=[C:15]2[CH:14]=[CH:13]1)([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].S(N1C2=NC=C(N(C(OC(C)(C)C)=O)N)N=C2C=C1)(C1C=CC(C)=CC=1)(=O)=O.C([O-])(O)=O.[Na+]>O1CCOCC1.CCOC(C)=O>[NH:21]([C:19]1[N:20]=[C:15]2[CH:14]=[CH:13][N:12]([S:2]([C:5]3[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=3)(=[O:3])=[O:4])[C:16]2=[N:17][CH:18]=1)[NH2:22]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NNC(=O)OC(C)(C)C)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2ccc3nc(N(N)C(=O)OC(C)(C)C)cnc32)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
HCl (4 M in 1,4-dioxane, 226 mL, 902 mmol) was added to a mixture of tert-butyl 2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate and tert-butyl 1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate (49.2 g, 122 mmol) in 1,4-dioxane (290 mL). The reaction was heated at about 60° C. for about 2.5 h and then cooled to about 15-20° C. The solid was collected by vacuum filtration, washed with EtOAc (3×50 mL), and then triturated with Et2O (60 mL), collected by vacuum filtration and dried to a constant weight under vacuum to yield 35.6 g of crude solid. The solid was stirred with a mixture of saturated aqueous NaHCO3 and EtOAc (1:1, 400 mL). After about 1 h, the solid was collected by vacuum filtration, washed with ice cold water (3×30 mL) and EtOAc (3×30 mL), and dried in a vacuum oven to a constant weight to afford 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine as a tan solid (21.2 g, 57%): LC/MS (Table 1, Method a) Rt=1.88 min; MS m/z: 304 (M+H)+.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl.[NH2:10][C@H:11]([C:17]([O:19][CH3:20])=[O:18])[CH2:12][C:13]([O:15][CH3:16])=[O:14].Br[C:22]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2>C(#N)C>[CH3:20][O:19][C:17](=[O:18])[C@H:11]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[NH:10][C:33]1[C:34]2[CH:22]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]=2[CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)C[C@H](N)C(=O)OC
Reactant: BrC1(c2ccccc2)c2ccccc2-c2ccccc21
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C[C@H](Nc1cccc2c1C(c1ccccc1)c1ccccc1-2)C(=O)OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.5 %

Procedure:
To a stirred suspension of anhydrous Pb(NO3)2 (45.0 g, 138.7 mmol) and anhydrous K3PO4 (75.0 g, 353.3 mmol) in dry acetonitrile (300.0 mL) was added sequentially L-aspartic acid dimethyl ester hydrochloride of Example 1 (32.0 , 161.9 mmol) and 9-bromo-9-phenylfluorene (62.0 g, 193.2 mmol). The mixture which resulted was stirred for 20 h at room temperature and then filtered through celite. The filter cake was washed with chloroform (3×300.0 mL). The combined organic solvents were removed under reduced pressure and the residue oil was partitioned between ether (800.0 mL) and the solution of citric acid (5%, 200.0 mL). The ether layer was removed and the aqueous phase extracted with ether (3×200.0 mL). The combined organic layers were washed with brine (2×150.0 mL), dried (MgSO4) and then removed under reduced pressure. The residue was purified by a flash chromatograph (600.0 g silica gel, EtOAc/hexane, 1/10 to 1/4 ) to provide the product as a pale yellow oil (64.0 g).
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[C:15]1([C:21]2[O:22][CH:23]=[C:24]([C:26]([N:28]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH:29]3[CH2:41][O:42][C:43]3[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=3)=[O:27])[N:25]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[ClH:1].[ClH:1].[C:15]1([C:21]2[O:22][CH:23]=[C:24]([C:26]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH:29]3[CH2:41][O:42][C:43]3[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=3)=[O:27])[N:25]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2coc(-c3ccccc3)n2)C(COc2cccnc2)C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: CO
Product: O=C(c1coc(-c2ccccc2)n1)N1CCNCC1COc1cccnc1
Reaction time: 8 h
Yield: 67 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(2-phenyloxazole-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate TFA salt (44.8 mg, 0.077 mmol) in MeOH (1 mL). After stirring overnight, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The desired chromatography fractions were concentrated under reduced pressure, dissolved in MeOH (1 mL), and treated with 4 M HCl in 1,4-dioxane (6 mL). This was concentrated under reduced pressure, yielding 22.6 mg (67%) of the desired product as a white solid. LC-MS: RT=4.36 min, [M+H]+=365.0.
Reaction SMILES: C([NH:4][CH2:5][C:6]1[S:10][C:9]([SH:11])=[N:8][N:7]=1)(=O)C.[ClH:12]>>[ClH:12].[NH2:4][CH2:5][C:6]1[S:10][C:9]([SH:11])=[N:8][N:7]=1
Reactant: CC(=O)NCc1nnc(S)s1
Agent: Cl
Product: NCc1nnc(S)s1

Procedure:
Thus obtained 5-acetamidomethyl-1,3,4-thiadiazole-2-thiol (44 g) was suspended in 6 N hydrochloric acid (400 ml) and the mixture was heated to reflux for 2 hours. The reaction mixture was allowed to cool, and the precipitates were collected by filtration and washed with ethanol to give 5-aminomethyl-1,3,4-thiadiazole-2-thiol hydrochloride (28.3 g). m.p. 213° to 217° C. The mother liquid obtained above was concentrated under reduced pressure and the residue was washed with ether to give the same objective product (12.6 g). Total yield is 40.9 g.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[CH:19]=2)[NH:14][C:13]=1[C:28]([OH:30])=[O:29])=O)(C)(C)C.[ClH:31].C(OCC)C>C(Cl)Cl.O1CCOCC1>[ClH:31].[NH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[CH:19]=2)[NH:14][C:13]=1[C:28]([OH:30])=[O:29]
Reactant: CC(C)(C)OC(=O)NCCCc1c(C(=O)O)[nH]c2ccc(-c3ccccc3F)cc12
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCOCC
Product: NCCCc1c(C(=O)O)[nH]c2ccc(-c3ccccc3F)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the above carboxylic acid (13 mg, 0.031 mmol, 1.0 equiv) in methylene chloride (2 mL) at 0° C. was added 0.2 mL of 4 N HCl in dioxane. The reaction was stirred at ambient temperature for 1 h. Then 10 mL of diethyl ether was added to the reaction and the reaction concentrated. To this residue was added 5 mL diethyl ether and the solid was filtered off and washed with diethyl ether several times and air dried for 15 min to provide the title compound (8 mg); MS, electrospray, 313 (M+H).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][O:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:3]1[C:14]([O:16][CH3:17])=[O:15].ClCC(=O)CC(OC)=O.C1(N=C=O)C=CC=CC=1.[NH:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][N:43]=2)[C:38]([CH:45]=O)=[CH:37]1.N1CCCCC1>CC(O)C>[NH:36]1[C:44]2=[N:43][CH:42]=[CH:41][CH:40]=[C:39]2[C:38]([CH:45]=[C:6]2[O:5][C:4]([NH:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:3]([C:14]([O:16][CH3:17])=[O:15])[C:2]2=[O:1])=[CH:37]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: COC(=O)C1=C(Nc2ccccc2)OCC1=O
Agent: COC(=O)CC(=O)CCl
Solvent: CC(C)O
Solvent: C1CCNCC1
Solvent: O=C=Nc1ccccc1
Product: COC(=O)C1=C(Nc2ccccc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 42.9 %

Procedure:
To a solution of methyl 4-oxo-2-(phenylamino)-4,5-dihydrofuran-3-carboxylate (0.047 g, 0.20 mmol) which similarly prepared according to the procedure described in the Example 2, First step using methyl 4-chloroacetoacetate and phenyl isocyanate, and 7-azaindole-3-carboxaldehyde (0.029 g, 0.20 mmol) in 2-propanol (1.0 mL), piperidine (0.022 mL, 0.22 mmol) was added at ambient temperature. The mixture was refluxed for 5 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound as solid (0.031 g, y. 43%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[C:15](Br)[CH:16]=[CH:17][CH:18]=2)[C:13]([O:21][C@@H:22]2[O:48][C@H:47]([CH2:49][O:50][C:51](=[O:56])[C:52]([CH3:55])([CH3:54])[CH3:53])[C@@H:39]([O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C@H:31]([O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C@H:23]2[O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[N:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:57]([O:64][C:65]1[CH:70]=[CH:69][CH:68]=[C:67]([CH:71]=[CH2:72])[CH:66]=1)[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1.C(N(CC)CC)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[C:15](/[CH:72]=[CH:71]/[C:67]3[CH:68]=[CH:69][CH:70]=[C:65]([O:64][CH2:57][C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)[CH:66]=3)[CH:16]=[CH:17][CH:18]=2)[C:13]([O:21][C@@H:22]2[O:48][C@H:47]([CH2:49][O:50][C:51](=[O:56])[C:52]([CH3:55])([CH3:54])[CH3:53])[C@@H:39]([O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C@H:31]([O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C@H:23]2[O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[N:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1cccc(OCc2ccccc2)c1
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2nn(CCOCc3ccccc3)c3cccc(Br)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2nn(CCOCc3ccccc3)c3cccc(/C=C/c4cccc(OCc5ccccc5)c4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
A mixture of 1-(2-benzyloxyethyl)-4-bromo-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indazole (0.85 g), 1-benzyloxy-3-vinylbenzene (0.32 g), triethylamine (2 mL), palladium (II) acetate (11 mg) and tris(2-methylphenyl)-phosphine (30 mg) in acetonitrile (8 mL) was heated for reflux under an argon atmosphere overnight. The reaction mixture was cooled to room temperature and diluted with diethyl ether, and the resulting mixture was stirred for 30 minutes. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1-3/1) to give 1-(2-benzyloxyethyl)-4-[(E)-2-(3-benzyloxyphenyl)vinyl]-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indazole (0.92 g). This material was dissolved in ethyl acetate (10 mL). To the solution was added 10% palladium-carbon powder (0.3 g), and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1-1/1) to give the title compound (0.68 g).
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:16]=[C:17]([CH:28]=[CH:29][CH:30]=2)[C:18]([C:20]2[CH:27]=[CH:26][C:23]([CH2:24]O)=[CH:22][CH:21]=2)=[O:19])[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.C(=O)([O-])O.[Na+].[CH3:48][N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1>ClCCl.C(Cl)(Cl)Cl>[CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:16]=[C:17]([CH:28]=[CH:29][CH:30]=2)[C:18]([C:20]2[CH:27]=[CH:26][C:23]([CH2:24][N:52]3[CH2:53][CH2:54][N:49]([CH3:48])[CH2:50][CH2:51]3)=[CH:22][CH:21]=2)=[O:19])[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1cccc(C(=O)c2ccc(CO)cc2)c1
Reactant: CN1CCNCC1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(C)cc(C)nc2n1Cc1cccc(C(=O)c2ccc(CN3CCN(C)CC3)cc2)c1
Reaction time: 1 h
Yield: 29.9 %

Procedure:
Compound 14 (0.250 g, 0.625 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (0.131 mL, 0.939 mmol) and methanesulfonyl chloride (0.730 mL, 0.943 mmol) was added to the solution at 0° C., followed by stirring for 1 hour. The reaction mixture was added with a saturated aqueous sodium hydrogen carbonate solution, and diluted with chloroform, then washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (5 mL), and 1-methylpiperazine (0.208 mL, 1.87 mmol) and triethylamine (0.870 mL, 0.623 mmol) was added to the solution, followed by stirring at room temperature overnight. The reaction mixture was diluted with chloroform, and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to obtain Compound 15 (0.0900 g, yield 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[N:36]1([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.[C:45]1([C:51]2([C:57]([OH:59])=[O:58])[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(OCC)(=O)C.CCCCCC>CO.ClCCl>[N:36]1([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:54]3[CH2:53][CH2:52][C:51]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)([C:57]([OH:59])=[O:58])[CH2:56][CH2:55]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Agent: Cl
Agent: NC(=O)N1CCOCC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 27.3.1 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (0.22 g, 0.42 mmol) and 4-phenyl-piperidine-4-carboxylic acid morpholine-amide hydrochloride (0.13 mmol, 0.42 mmol). Chromatograph on silica gel eluting sequentially with 50% ethyl acetate/hexane, 3% methanol/dichloromethane, and then 6% methanol/dichloromethane to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10](Cl)=[O:11].[Cl:25][C:26]1[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:27]=1[O:28][CH2:29][C:30]([O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][OH:41])=[O:31].C(N(CC)CC)C.C1COCC1>CCOCC>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:23])([F:24])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([O:41][CH2:40][CH2:39][O:38][CH2:37][CH2:36][O:35][CH2:34][CH2:33][O:32][C:30](=[O:31])[CH2:29][O:28][C:27]1[CH:42]=[CH:43][C:44]([Cl:46])=[CH:45][C:26]=1[Cl:25])=[O:11]
Reactant: O=C(COc1ccc(Cl)cc1Cl)OCCOCCOCCO
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(COc1ccc(Cl)cc1Cl)OCCOCCOCCOC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
5-(2-Chloro-4-trifluoromethylphenoxy)-2-nitrobenzoyl chloride (4.0 g, 0.0105 mole) was added portionwise to a solution of 8-hydroxy-3,6-dioxaoctyl 2,4-dichlorophenoxyacetate (3.5 g, 0.103 mole), triethylamine (1.2 g, 0.103 mole) and THF (40 ml) over 5 mins. The resulting solution was held at reflux for 3 hrs. After the solvent was stripped off, the residue was taken into 2600 ml of ether, washed two times with NaHCO3 solution and two times with water. The ether solution was then dried over MgSO4 and concentrated to 5.9 g of 8-(2,4-dichlorophenoxyacetoxy)-3,6-dioxaoctyl 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoate, a brownish gum; nmr (CDCl3) δ3.30-4.02 (m, 8H), 4.25-4.62 (m, 4H), 4.70 (S, 2H), 6.65-8.24 (m, 9H); ir (CHCl3) 1750, 1770 Cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:17][C:16]3[C:15](O)=[N:14][CH:13]=[N:12][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[Cl:19]CCCl.P(Cl)(Cl)(Cl)=O.N>C(N(CC)C1C=CC=CC=1)C.O1CCCC1>[Cl:19][C:15]1[C:16]2[NH:17][C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[CH:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: COc1ccc(-c2cc3ncnc(O)c3[nH]2)cc1
Reactant: ClCCCl
Agent: N
Solvent: C1CCOC1
Solvent: CCN(CC)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2cc3ncnc(Cl)c3[nH]2)cc1
Temperature: 110 °C

Procedure:
6-(4-Methoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-ol (500 mg) was suspended in N,N-diethylaniline (1.11 mL)/1,2-dichloroethane (3.73 mL), phosphorus oxychloride (2.29 mL) was added, and the mixture was stirred with heating at 110° C. for 2 hrs. After cooling to room temperature, the reaction mixture was treated with ice water (20 mL), and adjusted to pH 7 or above with aqueous ammonia. After diluting with tetrahydrofuran (500 mL), the mixture was washed with saturated brine (50 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→20:80) to give the title compound (25 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9](C=O)[NH:8][C:7]=1[CH2:19][CH2:20][NH:21]C(OC(C)(C)C)=O)=[O:5])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:9][NH:8][C:7]=1[CH2:19][CH2:20][NH2:21])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CCNC(=O)OC(C)(C)C)[nH]c(C=O)c1-c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(-c2ccccc2)c[nH]c1CCN
Reaction time: 3 h

Procedure:
A stirred solution of 2-(2-tert-butoxycarbonylamino-ethyl)-5-formyl-4-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester (1.120 g, 3 mmol) in dichloromethane (32 ml) was added dropwise slowly with trifluoroacetic acid (3.2 ml) at room temperature. Upon completion of the addition, the mixture was stirred for 3 hours, and concentrated to give 2-(2-amino-ethyl)-4-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester which Was used as such.