Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][S:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C@H:27]2[CH2:44][C@@:42]3([CH3:43])[C@@H:38]([CH2:39][CH2:40][C@@H:41]3[OH:45])[C@H:37]3[C@H:28]2[C:29]2[CH:30]=[CH:31][C:32]([OH:46])=[CH:33][C:34]=2[CH2:35][CH2:36]3)=[CH:23][CH:22]=1.I([O-])(=O)(=O)=[O:48]>O.CO>[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][S:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([C@H:27]2[CH2:44][C@@:42]3([CH3:43])[C@@H:38]([CH2:39][CH2:40][C@@H:41]3[OH:45])[C@H:37]3[C@H:28]2[C:29]2[CH:30]=[CH:31][C:32]([OH:46])=[CH:33][C:34]=2[CH2:35][CH2:36]3)=[CH:25][CH:26]=1)=[O:48]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C[C@]12C[C@H](c3ccc(OCCCCCSCc4ccccn4)cc3)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@]12C[C@H](c3ccc(OCCCCCS(=O)Cc4ccccn4)cc3)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Reaction time: 0.5 h

Procedure:
3.7 cm3 of a 0.1M solution of sodium metaperiodate in water is added to a solution of 172 mg of the product obtained in Example 4 in 12 cm3 of methanol. The reaction medium is agitated for 1 hour 30 minutes and 3.4 cm3 of methanol and 0.6 cm3 of the metaperiodate solution are added, after 3 hours 30 minutes of agitation the reaction medium is poured into water, extracted with ethyl acetate, washed with salt water and evaporated to dryness under reduced pressure. 176 mg of residue is obtained which is chromatographed on silica twice (eluant methylene chloride-methanol (92.5-7.5)). 107 mg of desired product is collected.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH:12]=[O:13])[C:6]=2[C:5](=[O:14])[NH:4][C:3]1=[O:15].N1([C:27](=[O:28])[C:26]2N(CC=O)C=NC=2N(C)C1=O)C.C(O)CO.C1(C)C=CC=CC=1>O>[CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH:12]3[O:28][CH2:27][CH2:26][O:13]3)[C:6]=2[C:5](=[O:14])[NH:4][C:3]1=[O:15]
Reactant: Cn1c(=O)c2c(ncn2CC=O)n(C)c1=O
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2CC=O
Solvent: Cc1ccccc1
Solvent: O
Solvent: OCCO
Product: Cn1c(=O)[nH]c(=O)c2c1ncn2CC1OCCO1
Yield: 55 %

Procedure:
20.8 g 2-(3-methyl-xanthine-7-yl)-acetaldehyde (Formula IV)-prepared similarly like 7-theophyllinyl acetaldehyde Il Farmaco, Ed. Sc. 17, 73; (1962), 40.0 ethylene glycol (Formula II) 2.5 g DOWEX 50 W synthetic resin and 1,000.0 cm3 toluene are heated under stirring in a flask equipped with a water condenser and a cooler until water condensation ceases. The reaction mixture is filtered hot and the precipitate is washed with hot toluene and the filtrate is washed upon cooling with 5% sodium hydrogen carbonate and the organic layer is evaporated after drying. The residue is crystallized three times from propanol and 2-[(3-methyl-xanthine-7-yl)methyl]-1,3-dioxolane is obtained with a yield of 55%, melting point 276°-278° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH3:21][C:22]1[C:26]([C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[C:25]([CH3:36])[NH:24][C:23]=1[CH:37]=O>C(O)C.N1CCCCC1>[CH3:21][C:22]1[C:26]([C:27]([N:29]2[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]2)=[O:28])=[C:25]([CH3:36])[NH:24][C:23]=1[CH:37]=[C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[CH:17][C:9]=2[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=2)[NH:13][C:12]1=[O:18]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Reactant: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(C(F)(F)F)c4)c32)c(C)c1C(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 75.9 %

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25 mmol) and 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The solvent was evaporated and the solid was washed by ether for three times to provide pure product 3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (96.5 mg, 76%).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[C:5]([N:21]=1)=[CH:6][C:7]1[C:8]([CH3:20])([CH3:19])[C:9](=[O:18])[N:10]([CH2:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)[C:11]=1[CH:12]=2.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(CC)CC>C1COCC1.C(Cl)Cl>[CH:15]1([CH2:14][CH2:13][N:10]2[C:11]3[CH:12]=[C:4]4[NH:3][C:2]([NH:1][C:22](=[O:29])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)=[N:21][C:5]4=[CH:6][C:7]=3[C:8]([CH3:19])([CH3:20])[C:9]2=[O:18])[CH2:17][CH2:16]1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1(C)C(=O)N(CCC2CC2)c2cc3[nH]c(N)nc3cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)C(=O)N(CCC2CC2)c2cc3[nH]c(NC(=O)c4ccccc4)nc3cc21

Procedure:
A solution of D8 (120 mg), benzoic acid chloride (87 μl), NEt3 (150 μl) in THF (1 ml) and CH2Cl2 (3 ml) is stirred at RT for 3 h. After evaporation EtOAc is added and the organic phase is washed with saturated NaHCO3 solution and brine, dried over MgSO4 and evaporated again. The residue is purified by preparative RP-HPLC to give the desired compound (13.4 mg).
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:6]2[CH:20]=[CH:19][C:9]([CH2:10][CH2:11][NH:12]C(=O)C(F)(F)F)=[CH:8][CH:7]=2)[NH:4][CH:5]=1.[OH-].[Na+]>C1COCC1.CO.O>[N:1]1[N:2]=[C:3]([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][CH2:11][NH2:12])=[CH:19][CH:20]=2)[NH:4][CH:5]=1
Reactant: O=C(NCCc1ccc(-c2nnc[nH]2)cc1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: NCCc1ccc(-c2nnc[nH]2)cc1

Procedure:
A solution of N-(4-(4H-1,2,4-triazol-3-yl)phenethyl)-2,2,2-trifluoroacetamide (83 mg, 0.292 mmol) and NaOH (29 mg, 0.73 mmol) in a mixed solvent (THF/MeOH/H2O=2 mL/5 mL/1 mL) was stirred at RT for 2 h. The solvent was evaporated to dryness and the residue was submitted to flash chomatography (SiO2, EtOAc to EtOAc/2M NH3 in MeOH=100:20 to 100:50) to give 2-(4-(4H-1,2,4-triazol-3-yl)phenyl)-ethanamine as a colorless oil.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][N:3]=1.C(OP([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])(OCC)=O)C.[H-].[Na+].[C:26]1(C)C=CC=CC=1>>[CH3:26][C:4]1[C:5]([CH:8]=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:6][CH:7]=[CH:2][N:3]=1
Reactant: Cc1ccccc1
Reactant: Cc1ccc(C=O)cn1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C=Cc1cccnc1C
Yield: 87.6 %

Procedure:
A solution of 0.55 g (4.54 mmol) of 2-methylpyridine-5-carboxaldehyde in toluene was added dropwise into a cool suspension of 1.12 g (5 mmol) of ethyl diethylphosphonoacetate and 0.12 g (5 mmol) of NaH in toluene and the resulting solution was allowed to react at 65° C. for 30 min. After cooling, the mixture was filtered through SUPERCEL™ (wash SUPERCEL™ with ether) and concentrated in vacuo to yield 0.71 g (87.6%) of ethyl β-(2-methylpyridin-3-yl)acrylate (cis/trans mixture), which was further purified through a silica plug (hexane/ethyl acetate, 1:1).
Reaction SMILES: C(N(CC1C=CC=CC=1)[C:9]1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=CC=C(C)[CH:24]=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[S:30](=[O:39])(=[O:38])[CH2:29][CH2:28]3)[CH:17]=2)CCOC1)C1C=CC=CC=1.[OH:47][C@@H:48]1[CH2:52][NH:51][CH2:50][C@H:49]1[NH:53][C:54](=[O:60])[O:55][C:56]([CH3:59])([CH3:58])[CH3:57].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CC(C)([O-])C.[Na+]>O1CCOCC1>[O:38]=[S:30]1(=[O:39])[C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[CH2:33][N:27]([C:18]2[CH:17]=[C:24]([N:51]3[CH2:50][C@@H:49]([NH:53][C:54]([O:55][C:56]([CH3:57])([CH3:59])[CH3:58])=[O:60])[C@H:48]([OH:47])[CH2:52]3)[C:25]3[C:20](=[CH:9][CH:14]=[N:15][CH:16]=3)[N:19]=2)[CH2:28][CH2:29]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(N(Cc4ccccc4)Cc4ccccc4)CCOC3)c2c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H]1O
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H]1CN(c2cc(N3CCS(=O)(=O)c4ccccc4C3)nc3ccncc23)C[C@H]1O
Temperature: 120 °C
Reaction time: 2 h
Yield: 10.2 %

Procedure:
To a solution of -(4-chloro-1,6-naphthyridin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (300 mg, 0.84 mmol, prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4-dichloro-1,6-naphthyridine) in 1,4-dioxane (5 mL) was added tert-butyl (trans-4-hydroxypyrrolidin-3-yl)carbamate (204 mg, 1.02 mmol), tri(dibenzylideneacetone)dipalladium(0) (39 mg, 0.042 mmol), (2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (24 mg, 0.063 mmol) and sodium tert-butoxide (114 mg, 1.17 mmol) under Ar protection. The reaction mixture was heated with stirring in a 10 mL of microwave process vial for 2 hours at 120° C. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC to give 45 mg of the desired product (yield was 10%).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([O:12][C:13]([C:15]1[C:19]2[CH:20]=[C:21]([C:30]3[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=3)[C:33]([OH:35])=O)[C:22]([N:24]([CH3:29])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][C:18]=2[O:17][C:16]=1[C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1)=[O:14])[CH3:11].[C:46]1([C:52]([NH2:55])([CH3:54])[CH3:53])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[F:45][C:42]1[CH:41]=[CH:40][C:39]([C:16]2[O:17][C:18]3[CH:23]=[C:22]([N:24]([CH3:29])[S:25]([CH3:28])(=[O:27])=[O:26])[C:21]([C:30]4[CH:38]=[CH:37][CH:36]=[C:32]([C:33](=[O:35])[NH:55][C:52]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)([CH3:54])[CH3:53])[CH:31]=4)=[CH:20][C:19]=3[C:15]=2[C:13]([O:12][CH2:10][CH3:11])=[O:14])=[CH:44][CH:43]=1
Reactant: CC(C)(N)c1ccccc1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cccc(C(=O)O)c3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
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: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cccc(C(=O)NC(C)(C)c4ccccc4)c3)cc12
Reaction time: 1 h
Yield: 81.2 %

Procedure:
DIEA (51 μL, 0.293 mmol) was added to a stirring solution of 3-(3-(ethoxycarbonyl)-2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)benzoic acid (50 mg, 0.098 mmol), 2-phenylpropan-2-amine (26 mg, 0.195 mmol), HATU (56 mg, 0.147 mmol) in DMF (1 mL) at 25° C. It was allowed to stir for 1 hour. The mixture was diluted with EtOAc and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give the titled compound (50 mg, 81%). LC-MS retention time: 1.82 min; m/z (MH+): 629. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:37](COCC[Si](C)(C)C)[C:16]2[N:17]=[CH:18][C:19]3[N:20]([C:21]([C@@H:24]4[CH2:28][CH2:27][C@H:26]([NH:29]C(=O)OC(C)(C)C)[CH2:25]4)=[N:22][CH:23]=3)[C:15]=2[CH:14]=1.[C:46]([OH:52])([C:48](F)(F)F)=[O:47].[NH4+].[OH-]>C(Cl)Cl>[C:46]([OH:52])(=[O:47])[CH3:48].[C:46]([OH:52])(=[O:47])[CH3:48].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[NH:37][C:16]2[N:17]=[CH:18][C:19]3[N:20]([C:21]([C@@H:24]4[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25]4)=[N:22][CH:23]=3)[C:15]=2[CH:14]=1
Reactant: COc1ccc2c(c1)c(-c1cc3c(ncc4cnc([C@@H]5CC[C@H](NC(=O)OC(C)(C)C)C5)n43)n1COCC[Si](C)(C)C)cn2C
Reactant: O=C(O)C(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)O
Product: COc1ccc2c(c1)c(-c1cc3c(ncc4cnc([C@@H]5CC[C@H](N)C5)n43)[nH]1)cn2C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.2 %

Procedure:
tert-Butyl cis-3-(7-(5-methoxy-1-methyl-1H-indol-3-yl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentylcarbamate (0.331 g, 0.524 mmol, prepared using J.1 from Preparation #I.1 with cis-3-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid [Peptech], and L.1 with mercury(II) trifluoroacetate) in DCM (8 mL) was treated with TFA (2.0 mL, 26 mmol) then stirred for about 1.5 h at rt. The solvents were removed under reduced pressure then the material was dissolved in 1,4-dioxane (4 mL) and treated with concentrated aqueous NH4OH (2.5 mL, 24 mmol). The mixture was heated at about 60° C. for about 30 min. The mixture was concentrated under reduced pressure then dissolved in AcOH (1 mL) and DMF (3.5 mL) then the material was purified by preparative reverse phase HPLC (Table 2, Method i) to give cis-3-(7-(5-methoxy-1-methyl-1H-indol-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentanamine diacetate (0.145 g, 53%): LC/MS (Table 2, Method a) Rt=1.73 min; MS m/z 401.2 (M+H)+. Syk IC50=A.
Reaction SMILES: C(O)(C(F)(F)F)=O.[O:8]=[C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:16]=2)[CH:12]=[CH:11][N:10]1[CH2:28][C:29]1[N:30](C(OC(C)(C)C)=O)[C:31]2[C:36]([CH:37]=1)=[CH:35][CH:34]=[CH:33][CH:32]=2.C([O-])(O)=O.[Na+].CC#N>ClCCl>[NH:30]1[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:37]=[C:29]1[CH2:28][N:10]1[CH:11]=[CH:12][C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:16]=2)=[CH:14][C:9]1=[O:8]
Reactant: CC(C)(C)OC(=O)n1c(Cn2ccc(-c3ccnc(NC4CCOCC4)n3)cc2=O)cc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1cc(-c2ccnc(NC3CCOCC3)n2)ccn1Cc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.7 %

Procedure:
TFA (2 mL) was added to a solution of tert-butyl 2-((2-oxo-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-1(2H)-yl)methyl)-1H-indole-1-carboxylate (130 mg, 0.32 mmol) in dichloromethane (3 mL) at 20° C. The mixture was stirred at room temperature for 2 hours. LC-MS showed the tert-butyl 2-((2-oxo-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-1(2H)-yl)methyl)-1H-indole-1-carboxylate had disappeared. The reaction mixture was adjusted to a pH of around 8-9 with saturated NaHCO3 solution, extracted with dichloromethane, and dried with Na2SO4. The organic phase was evaporated, and the residue was purified with prep-HPLC (A: H2O including 0.5% NH3HCO3, B: CH3CN) to afford 1-((1H-indol-2-yl)methyl)-4-(2-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one (60 mg, 60% yield). 1H NMR (500 MHz, (CD3)2SO) δ 11.07 (s, 1H), 8.41 (d, J=4.5 Hz, 1H), 7.88 (d, J=7.5 Hz, 1H), 7.47 (d, J=8 Hz, 1H), 7.37-7.36 (m, 2H), 7.15-7.14 (m, 2H), 7.06 (m 1H), 6.96 (m, 1H), 6.88 (d, J=6 Hz, 1H), 6.35 (s, 1H), 5.26 (s, 2H), 3.97 (m, 1H), 3.88-3.86 (m, 2H), 3.42-3.37 (m, 2H), 1.85-1.83 (m, 2H), 1.56-1.48 (m, 2H); LCMS (ESI) m/z 402.3 [M+H+].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]([O:16]CC)=O)[C:8]([C:19]([O:21]CC)=O)=[C:7]2[OH:24])([O-:3])=[O:2].[C:25]1([NH:31][NH2:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[NH2:31][NH2:32].[OH:16][C:14]1[C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=3[C:7](=[O:24])[C:8]=2[C:19](=[O:21])[N:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:32]=1
Reactant: CCOC(=O)c1nc2ccc([N+](=O)[O-])cc2c(O)c1C(=O)OCC
Reactant: NNc1ccccc1
Solvent: CCO
Product: NN
Product: O=c1c2cc([N+](=O)[O-])ccc2[nH]c2c(O)nn(-c3ccccc3)c(=O)c12
Temperature: 25 °C

Procedure:
To a stirred suspension of diethyl 6-nitro-4-hydroxy-quinoline-2,3-dicarboxylate (1.670 g, 5.00 mM) in ethanol (30 mL) was added phenyl hydrazine (3.44 mL, 35.00 mM) to give a deep red solution. The solution was heated to reflux for 1 hour and concentrated to about 15 mL. Continued heating gave a thick suspension which was diluted with ethanol (5 mL) and refluxed for 16 additional hours. The mixture was cooled to room temperature and filtered to give thephenyl hydrazine salt of the title compound as a tan solid. This material was refluxed in glacial acetic acid (25 mL) for 2 hours and cooled to roomtemperature. Filtration gave the title compound (1.01 g, 58%) as a tan powder, mp 368° C. (decomp.); MS(CI): 351 (M+H). Analysis for C17H10N4O5 : Calculated: C, 58.30; H, 2.88; N, 16.00; Found: C, 58.21; H, 3.07; N, 16.15; NMR: 8.91 (d, J=2.76 Hz, 1H), 8.60 (dd, J=2.76, 9.18 Hz, 1H), 8.06 (d, J=9.18 Hz, 1H,), 7.18 (t, J=7.23 Hz, 2H), 6.82 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([O:23][CH3:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[CH3:44][C:45]1[S:49][C:48]([CH:50]([NH2:52])[CH3:51])=[N:47][CH:46]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:52][CH:50]([C:48]2[S:49][C:45]([CH3:44])=[CH:46][N:47]=2)[CH3:51])=[O:42])=[C:18]([O:23][CH3:24])[CH:17]=1
Reactant: Cc1cnc(C(C)N)s1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1NC(=O)NC(C)c1ncc(C)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methoxyaniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of 1-(5-methyl-1,3-thiazol-2-yl)-1-ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (38 mg, yield 83%).
Reaction SMILES: [ClH:1].[NH:2]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:23][N:24]([CH3:32])[C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1.C([OH:35])C.[Cl-]>CO>[OH2:35].[ClH:1].[CH3:23][N:24]([CH3:25])[C:6]1[CH:7]=[CH:8][C:3]([NH:2][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]4[N:21]=[CH:20][NH:19][C:17]4=3)[N:12]=[C:11]([CH3:22])[CH:10]=2)=[CH:4][CH:5]=1.[OH2:35].[OH2:35].[CH3:23][N:24]([C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]4[N:21]=[CH:20][NH:19][C:17]4=3)[N:12]=[C:11]([CH3:22])[CH:10]=2)=[CH:27][CH:26]=1)[CH3:32].[ClH:1]
Reactant: CCO
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Reactant: CN(C)c1ccc(N)cc1
Agent: Cl
Agent: [Cl-]
Solvent: CO
Product: Cc1cc(Nc2ccc(N(C)C)cc2)c2c(ccc3nc[nH]c32)n1
Product: O

Procedure:
A mixture of 33 g. (0.15 mole) of the compound of Example I, C. and 21 g. (0.15 mole) of p-dimethylaminoaniline in 1800 ml. of ethanol was refluxed overnight. The solvent was removed by evaporation in vacuo. The residue was recrystallized from ethanol to give 32 g. of yellow solid. The solid was dissolved methyl alcohol and was acidified with a saturated etherhydrogen chloride solution. The product was collected as a cream colored solid and was recrystallized from methyl alcohol to give a yellow solid melting at 210°-215° in a yield of 22 g. (42%). Recrystallization from methyl alcohol raised the melting point to 215°-217°.
Reaction SMILES: CN(C=O)C.CO.S(Cl)([Cl:10])=O.[CH:12]1[C:17]([CH2:18][CH2:19][CH2:20][C:21](O)=[O:22])=[CH:16][CH:15]=[C:14]([N:24]([CH2:28][CH2:29][Cl:30])[CH2:25][CH2:26][Cl:27])[CH:13]=1>[Pd].C(Cl)Cl>[Cl:27][CH2:26][CH2:25][N:24]([C:14]1[CH:15]=[CH:16][C:17]([CH2:18][CH2:19][CH2:20][C:21]([Cl:10])=[O:22])=[CH:12][CH:13]=1)[CH2:28][CH2:29][Cl:30]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCc1ccc(N(CCCl)CCCl)cc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CCCc1ccc(N(CCCl)CCCl)cc1
Reaction time: 7 h

Procedure:
0.33 g (0.83 mmol) of 1H-2-(3-nitrophenyl)benzimidazole-5-[N-(2-amidinoethyl)]carboxyamide hydrochloride was suspended in a mixed solvent of DMF and methanol, and catalytic hydrogenation was then carried out in the presence of 10% Pd/C as a catalyst to lead the above-mentioned compound to a corresponding amino compound. This DMF solution was stirred under ice cooling and under a nitrogen gas stream, and a methylene chloride solution of 4-[4-[N,N-bis(2-chloroethyl)amino]phenyl]butyryl chloride {which was prepared by adding 0.55 g (4.6 mmols, 5.0 eq.) of thionyl chloride to 0.28 g (0.92 mmol) of chlorambucil, removing thionyl chloride under reduced pressure after 5 minutes, and then carrying out azeotropic distillation with benzene twice} was added dropwise. The temperature of the suspension was returned to room temperature, followed by stirring for 7 hours. Next, the suspension was concentrated under reduced pressure, and the resulting residue was then purified through silica gel column chromatography (ethyl acetate/IPA/water=6/2/1), and then solidified with ethanol to obtain 0.23 g (0.36 mmols, 43.4%) of the desired compound in the state of light yellowish white crystals.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][C:7](=[O:9])[CH:6]([C:10](=[O:12])[CH3:11])[C:5](=[O:13])[CH2:4]1)=O.[NH2:14]OS(O)(=O)=O>O>[O:13]=[C:5]1[CH:6]([C:10](=[O:12])[CH3:11])[C:7](=[O:9])[CH2:8][CH:3]([C:1]#[N:14])[CH2:4]1
Reactant: CC(=O)C1C(=O)CC(C=O)CC1=O
Reactant: NOS(=O)(=O)O
Solvent: O
Product: CC(=O)C1C(=O)CC(C#N)CC1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 58.3 %

Procedure:
19.3 g (0.11 mol) of 5-formyl-2-acetylcyclohexane-1,3-dione in 200 ml of distilled water were initially taken, and 14.7 g (0.13 mol) of hydroxylamine-O-sulfonic acid were added at room temperature. The mixture was then stirred for 17 hours at room temperature. The precipitate was filtered off under suction, washed with water and dried. 11.5 g (61% of theory) of 3,5-dioxo-4-acetylcyclohexanenitrile of melting point 66-69° C. were obtained.