Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[O:10]1[CH:14]=[CH:13][CH2:12][CH2:11]1>C1C=CC=CC=1>[O:10]1[CH2:11][CH2:12][CH2:13][CH:14]1[N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[N:4]([CH:11]2[CH2:12][CH2:13][CH2:14][O:10]2)[C:5]1=[O:8]
Reactant: C1=COCC1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: c1ccccc1
Product: O=c1c(F)cn(C2CCCO2)c(=O)n1C1CCCO1
Yield: 48.1 %

Procedure:
In a closed tubular reactor, 1.3 g of 5-fluorouracil, 5 ml of benzene and 14 g of 2,3-dihydrofuran were heated together at 200° C. for 6 hours. After cooling, the reaction mixture was concentrated to dryness under reduced pressure and the residue was separated and purified by column chromatography on 25 g silica gel. From the chloroform eluate, the fractions rich in the contemplated compound were collected. The solvent was distilled off and the residue was recrystallized from petroleum ether. By the above procedure was obtained 1.3 g of 1,3-bis-(tetrahydro-2-furyl)-5-fluorouracil.
Reaction SMILES: [Br:1][C:2]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=2)[CH:17]=1)=[C:3]1[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[Br:1][C:2](=[C:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][N:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=C(Br)c2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1ccc(Oc2cccc(C(Br)=C3CCNCC3)c2)nc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 54 %

Procedure:
To a solution of tert-butyl 4-(bromo(3-(5-(trifluoromethyl)pyridin-2-yloxy)phenyl)methylene)piperidine-1-carboxylate (0.42 g, 0.82 mmol) in CH2Cl2 (10 mL) was added TFA (3 mL). The pale yellow solution went to a darker yellow solution. The reaction was stirred at room temperature for 5 h. The reaction was concentrated to give the title compound as a solid (235 mg, 54% yield).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:7]([OH:9])=O)=[CH:5][CH:6]=1.S(Cl)(Cl)=O.[NH2:14][C:15]1[CH:25]=[CH:24][CH:23]=[C:17]2[C:18]([O:20][C:21](=[O:22])[C:16]=12)=[O:19]>N1C=CC=CC=1>[Cl:1][C:2]1[S:3][C:4]([C:7]([NH:14][C:15]2[C:16]3[C:21](=[O:22])[O:20][C:18](=[O:19])[C:17]=3[CH:23]=[CH:24][CH:25]=2)=[O:9])=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: Nc1cccc2c1C(=O)OC2=O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1cccc2c1C(=O)OC2=O)c1ccc(Cl)s1
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
To prepare the required acid chloride, 27.77 g of 2-chloro-5-thiophenecarboxylic acid (0.171 mol) are suspended in 50 ml of thionyl chloride (0.685 mol) and stirred at 90° C. for 90 min (after 15 min, a clear solution is formed). The resulting solution is concentrated under reduced pressure, twice subjected to azeotropic distillation with toluene, dissolved in 60 ml of toluene and, over a period of 40 min and at 20° C., added dropwise to a solution of 17.98 g (110.2 mmol) of 3-aminophthalic anhydride in 200 ml of pyridine. The mixture is stirred at RT overnight, the pyridine is evaporated under reduced pressure and the residue is twice stirred with toluene and re-evaporated. 1 l of ethyl acetate and 0.5 l of KH2PO4 buffer (pH=4-5) are added and the mixture is then shaken vigorously and filtered off with suction, and the solids are washed with ethyl acetate, pressed thoroughly dry and dried under reduced pressure over P2O5. The mother liquor is extracted three times with ethyl acetate and evaporated and the residue is stirred with ethyl acetate and filtered off with suction. This gives a total of 19.77 g (58.3% of theory) of the target compound of m.p. 195° C.
Reaction SMILES: Cl[C:2]([C@H:4]1[C@H:6]([CH:7]=[C:8]([Cl:13])[C:9]([F:12])([F:11])[F:10])[C:5]1([CH3:15])[CH3:14])=[O:3].N1C=CC=CC=1.[C:22]([CH:24]([OH:38])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:26]=1)#[N:23]>O>[Cl:13][C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C@@H:6]1[C@H:4]([C:2]([O:38][CH:24]([C:22]#[N:23])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:26]=2)=[O:3])[C:5]1([CH3:15])[CH3:14]
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Reactant: CC1(C)[C@@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the residue of (+)-cis/trans-1-chlorocarbonyl-3-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropane (obtained in Example 18) was added a mixture of pyridine (0.12 g) and (+)-α-cyano-3-phenoxybenzyl alcohol (0.33 g) and the mixture thus obtained was stirred for a period of 16 hours at the ambient temperature. Water (20 ml) was added and the mixture extracted with diethyl ether (3×10 ml). The combined extracts were washed with water, saturated sodium bicarbonate solution, and water and dried over anhydrous sodium sulphate. After removal of the ether by evaporation under reduced pressure the residual oil was subjected to preparative thick-layer chromatography, using 2 mm thick silica on glass with chloroform as eluent, to yield (+)-α-cyano-3-phenoxybenzyl (+)-cis-3-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropane carboxylate (Rf 0.52), and the corresponding trans isomers (Rf 0.42), each containing about 90-95% of the Z-isomer. Spectral data: infra red (CHCl3) 1740, 1660, 1590, 1480, 1460 cm-1 ; n.m.r. (CCl4): 6.90-7.50π, 1.60-2.70π, 1.50-1.00τ, and specific peaks at 6.3 τ (benzylic H), 6.85, 6.50, 6.11 and 5.84 π (vinylic H) tentatively assigned to the Z-cis, E-cis, Z-trans and E-trans isomers respectively.
Reaction SMILES: [H-].[Na+].[S:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[S:13])[CH2:4]1.I[CH3:15]>O1CCCC1>[CH3:15][S:13][C:5]1[CH2:4][S:3][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=1
Reactant: CI
Reactant: S=C1CSc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSC1=Nc2ccccc2SC1
Reaction time: 0.25 h

Procedure:
To 17 parts of sodium hydride in 1500 parts of tetrahydrofuran at room temperature under nitrogen is added, portionwise with stirring during approximately 15 minutes, 90 parts of 2H-1,4-benzothiazine-3(4H)-thione [J. Med. Chem. 12, 290 (1969)]. After the addition is complete, stirring under nitrogen is continued for 10 minutes, whereupon a solution of 85 parts of iodomethane in 70 parts of tetrahydrofuran is rapidly stirred in and stirring continued thereafter for a still further 15 minutes. Removal of solvent by vacuum distillation under nitrogen affords 3-methylthio-2H-1,4-benzothiazine as the residue. Since the product is subject to spontaneous hydrolytic decomposition, it is not usually isolated for the purposes of this invention but instead is employed as the solution in tetrahydrofuran preparable via the foregoing procedure.
Reaction SMILES: [Na].Br[C:3]1[N:4]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:5]2[C:10]([N:11]=1)=[C:9]([NH2:12])[N:8]=[C:7]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])[N:6]=2.[CH3:24][OH:25]>>[CH2:14]([O:13][C:7]1[N:6]=[C:5]2[C:10]([N:11]=[C:3]([O:25][CH3:24])[N:4]2[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[C:9]([NH2:12])[N:8]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CO
Reactant: CCCCOc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Agent: [Na]
Product: CCCCOc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Temperature: 65 °C
Reaction time: 9 h

Procedure:
Sodium (3.7 g) was added to absolute methanol (400 ml) under a nitrogen atmosphere. To this solution was added the product (28.5 g) from step (iii) and the mixture was stirred at 65° C. for 9 h. The mixture was concentrated in vacuo and 500 ml of water added. The aqueous phase was extracted with EtOAc and washed with brine and dried. The subtitle compound was obtained after crystallisation from diethyl ether. Yield 14.2 g.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH2:18][CH2:19][Cl:20])=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:10]=1)=[O:5])[CH3:2].Cl.[F:22][C:23]1[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=1)[CH:26]=[C:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(CC)C(C)C)(C)C>C(O)C>[ClH:20].[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH2:18][CH2:19][N:30]2[CH2:31][CH2:32][C:27](=[CH:26][C:25]3[CH:33]=[CH:34][CH:35]=[C:23]([F:22])[CH:24]=3)[CH2:28][CH2:29]2)=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(-c2ccc(F)cc2)c(CCCl)s1
Reactant: Fc1cccc(C=C2CCNCC2)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1nc(-c2ccc(F)cc2)c(CCN2CCC(=Cc3cccc(F)c3)CC2)s1
Yield: 47.2 %

Procedure:
1.50 g of 2-ethoxycarbonyl-4-(4-fluorophenyl)-5-(2-chloroethyl)thiazole, 1.10 g of 4-(3-fluorobenzylidene)piperidine hydrochloride and 2.50 g of N,N-diisopropylethylamine were stirred in 3 ml of ethanol at 80° C. for 40 hours. The reaction solution was concentrated under reduced pressure, and the residue was treated with ethyl acetate and saturated aqueous sodium bicarbonate to effect separation of layers. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the drying agent was removed by filtration. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by a flash column chromatography (Wako Gel C200 (manufactured by Wako Pure Chemical Industries), eluant: hexane-ethyl acetate-5.1) and then Chromatolex NH NHDM1020 (manufactured by Fuji Division Chemical), eluant: hexane-ethyl acetate=10.1). This product was treated with 4 N hydrogen chloride/1.4-dioxane solution and then recrystallized from ethanol to obtain 1.14 g of 2-ethoxycarbonyl-4-(4-fluorophenyl)-5-[2-[4-(3-fluorobenzylidene)piperidin-1-yl]ethyl]thiazole hydrochloride
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].C([O-])([O-])=O.[Na+].[Na+].[I:16]I.Cl>O.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([I:16])[C:5]([OH:8])=[CH:4][C:3]=1[F:9]
Reactant: II
Reactant: Oc1cnc(Cl)c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1cc(F)c(Cl)nc1I
Reaction time: 2 h

Procedure:
To a solution of 6-chloro-5-fluoropyridin-3-ol (307.8 mg, 2.08 mmol) in water (11 mL) was added Na2CO3 (441 mg, 4.16 mmol) and I2 (549 mg, 2.08 mmol). After 2 hours, the reaction mixture was acidified with 1 N HCl to pH 3, diluted with EtOAc (100 mL), and washed with aq. NaHSO3 and brine (50 mL each). The organic layer was dried over Na2SO4, filtered and concentrated to afford 6-chloro-5-fluoro-2-iodopyridin-3-ol. LCMS=273.9 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.11 (d, J=8.5 Hz, 1H), 5.47 (d, J=1.4 Hz, 1H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[S:6][C:7]([CH2:10][NH:11][C:12](=[N:15][N+:16]([O-:18])=[O:17])SC)=[CH:8][N:9]=1>C(#N)C>[Cl:4][C:5]1[S:6][C:7]([CH2:10][NH:11][C:12]([N:2]([CH3:3])[CH3:1])=[N:15][N+:16]([O-:18])=[O:17])=[CH:8][N:9]=1
Reactant: CSC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Reactant: CNC
Solvent: CC#N
Product: CN(C)C(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
252 mg of a 50% aqueous dimethylamine solution was dropwise added to a mixture consisting of 600 mg N-(2-chloro-5-thiazolylmethyl)-S-methyl-N'-nitroisothiourea and 20 ml acetonitrile at room temperature. After stirring at room temperature for 2 hours the reaction mixture was concentrated and 20 ml of ethanol was added to the residue, followed by stirring thoroughly. The resultant crystals were collected by filtration and dried to afford 350 mg of N-(2-chloro-5-thiazolylmethyl)-N',N'-dimethyl-N"-nitroguanidine (compound No.17) as a white powder. The mothor liquor after the filtration was concentrated and 5 ml of ethanol was added, followed by stirring thoroughly, then the resultant crystals were collected by filtration and dried to give additional 120 mg of compound No.17 (mp 154-159° C.). Recrystallization of this product from acetonitrile afforded a product having a melting point of 164-166° C.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+:7]([CH3:9])C.C(N(CC)C(C)C)(C)C.[C:19]([C:21]1[N:26]=[CH:25][C:24]([CH:27]([C:42]2C(=O)[CH2:46][CH2:45][CH2:44][C:43]=2[OH:49])[NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=2)=[O:30])=[CH:23][CH:22]=1)#[N:20]>ClCCl>[C:19]([C:21]1[N:26]=[CH:25][C:24]([CH:27]([C:42]2[C:43](=[O:49])[CH2:44][CH2:45][CH2:46][C:6]=2[O:7][CH3:9])[NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:39])[F:40])[CH:33]=2)=[O:30])=[CH:23][CH:22]=1)#[N:20]
Reactant: C[O+](C)C
Reactant: N#Cc1ccc(C(NC(=O)Nc2cccc(C(F)(F)F)c2)C2=C(O)CCCC2=O)cn1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC1=C(C(NC(=O)Nc2cccc(C(F)(F)F)c2)c2ccc(C#N)nc2)C(=O)CCC1
Temperature: 25 °C

Procedure:
Trimethyloxonium tetrafluoroborate (121 mg, 0.82 mmol) is added to a solution of N,N-diisopropylethylamine (276 μL, 1.58 mmol) and 1-((6-cyanopyridin-3-yl)(2-hydroxy-6-oxocyclohex-1-enyl)methyl)-3-(3-(trifluoromethyl)phenyl)urea (intermediate 30, 346 mg, 0.804 mmol) in dichloromethane (10 mL). The mixture is stirred at room temperature over night, and another portion of trimethyloxonium tetrafluoroborate (121 mg, 0.82 mmol) is added. After 1 h the mixture is diluted with dichloromethane, and washed with water and saturated aqueous sodium chloride solution. The organic layer is dried over Na2SO4 and concentrated under reduced pressure. Yield: 300 mg; ESI mass spectrum [M+H]+=445, Retention time HPLC: 1.09 min (V011_S01).
Reaction SMILES: C([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:72]2[N:73]=[C:74]([NH:77]C(OC(C)(C)C)=O)[S:75][CH:76]=2)\[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([OH:34])(=[O:33])=[O:32])[C@@H:27]2[CH2:35][N:36]2[N:40]=[C:39]([CH:41]([N:43](C(OC(C)(C)C)=O)/[C:44](=[N:57]/C(OC(C)(C)C)=O)/[NH:45][CH2:46][CH2:47][CH2:48][NH:49]C(=O)OC(C)(C)C)[CH3:42])[CH:38]=[N:37]2)=[O:24])[CH2:19][CH2:18]1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:49][CH2:48][CH2:47][CH2:46][NH:45][C:44](=[NH:57])[NH:43][CH:41]([C:39]1[CH:38]=[N:37][N:36]([CH2:35][C@@H:27]2[C@H:26]([NH:25][C:23](=[O:24])/[C:22](=[N:21]\[O:20][C:17]3([C:15]([OH:16])=[O:14])[CH2:19][CH2:18]3)/[C:72]3[N:73]=[C:74]([NH2:77])[S:75][CH:76]=3)[C:29](=[O:30])[N:28]2[S:31]([OH:34])(=[O:32])=[O:33])[N:40]=1)[CH3:42]
Reactant: CC(c1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CC3)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)n1)N(C(=O)OC(C)(C)C)/C(=N/C(=O)OC(C)(C)C)NCCCNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(NC(=N)NCCCN)c1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)n1
Temperature: 0 °C
Yield: 39.8 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-((E)-3-(tert-butoxycarbonyl)-4-((tert-butoxycarbonyl)imino)-12,12-dimethyl-10-oxo-11-oxa-3,5,9-triazatridecan-2-yl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidine-1-sulfonic acid (0.133 mmol), TFA (410 μl, 5.32 mmol) anisole (29 μL, 0.27 mmol) and DCM (1.33 mL). The reaction mixture was cooled to 0° C. and diluted with DCM and ice water, Whereupon the layers were separated. The aqueous layer was purified by reverse phase preparative HPLC (XSELECT, C18 5 um 30×100 mm; ACN-water with 0.1% formic acid), affording the title compound (34 mg, 39%) as a white powder. LCMS: Rt=0.52 min, m/z=643.2 (M+1) Method 2m_acidic_polar. 1H NMR (400 MHz, D2O, reported as a 1:1 mixture of diastereomers) δ 7.79 (s, 1H) 7.77 (s, 1H), 7.12 (s, 1H), 7.12 (s, 1H), 5.64 (d, J=5.6 Hz, 1H), 5.61 (d, J=5.6 Hz, 1H), 5.05-4.73 (m, 8H assumed; partially obscured by solvent residual peak), 3.39-3.32 (m, 4H), 3.13-3.05 (m, 4H), 2.00 (p, J=7.0 Hz, 4H), 1.64 (d, J=3.6 Hz, 3H), 1.63 (d, J=3.7 Hz, 3H), 1.37-1.28 (m, 4H), 1.21-1.12 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][O:12][CH2:13][CH3:14])=[CH:9][N:10]=2)[N:7]=1.[O:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][NH2:24])[CH2:17][CH2:16]1.Cl>CCOCC>[ClH:1].[CH2:13]([O:12][CH2:11][C:8]1[N:6]2[N:7]=[C:2]([NH:24][CH2:23][CH2:22][CH2:21][N:18]3[CH2:19][CH2:20][O:15][CH2:16][CH2:17]3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)[CH3:14]
Reactant: NCCCN1CCOCC1
Reactant: CCOCc1cnc2ccc(Cl)nn12
Agent: Cl
Solvent: CCOCC
Product: CCOCc1cnc2ccc(NCCCN3CCOCC3)nn12
Yield: 17 %

Procedure:
Prepared from 6-chloro-3-(ethoxymethyl)imidazo[1,2-b]pyridazine (8b) and 3-morpholinopropylamine according to general procedure 4 (step B). The free-base was converted to the HCl salt with 2N HCl in Et2O to provide the title compound (36 mg, 17%) as a white solid; 1H NMR (500 MHz, CD3OD) δ 7.64 (d, J=9.7 Hz, 1H), 7.50 (s, 1H), 6.77 (d, J=9.7 Hz, 1H), 4.80 (s, 2H), 3.90-3.88 (m, 4H), 3.60 (q, J=7.1 Hz, 2H), 3.50 (t, J=6.4 Hz, 2H), 3.26-3.18 (m, 6H), 2.17-2.11 (m, 2H), 1.20 (t, J=7.0 Hz, 3H); 13C NMR (125 MHz, CD3OD) δ 155.6, 137.5, 130.0, 127.0, 125.3, 115.5, 66.7, 65.5, 61.4, 57.0, 53.5, 39.7, 24.6,15.5; HPLC tR=7.7 min (Luna), 97.6%; ES-MS: (M+H)=320 m/z.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[CH:3]1>CO.CCOC(C)=O.[Pd]>[CH3:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[CH:3]1
Reactant: Cn1cc(-c2ccc([N+](=O)[O-])cc2)c2ncccc21
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cn1cc(-c2ccc(N)cc2)c2ncccc21
Reaction time: 4 h
Yield: 98.7 %

Procedure:
A mixture of 1-methyl-3-(4-nitrophenyl)-1H-pyrrolo[3,2-b]pyridine (85 mg) and 10% Pd—C (50% wet, 100 mg) in MeOH (4 mL) and AcOEt (4 ml) was stirred under H2 atmosphere (balloon) for 4 h. After this time, the reaction was filtered and the filtrate was concentrated under reduced pressure to give the title compound (74 mg).
Reaction SMILES: [CH3:1][O:2][NH:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[N:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12]([NH2:21])[C:11]=2[N:10]=[C:9]1[CH2:22][O:23][CH2:24][CH3:25].C(N(CC)CC)C.[CH:33]([N:36]=[C:37]=[O:38])([CH3:35])[CH3:34]>ClCCl.C(=O)(O)[O-].[Na+]>[NH2:21][C:12]1[C:11]2[N:10]=[C:9]([CH2:22][O:23][CH2:24][CH3:25])[N:8]([CH2:7][CH2:6][CH2:5][CH2:4][N:3]([O:2][CH3:1])[C:37]([NH:36][CH:33]([CH3:35])[CH3:34])=[O:38])[C:20]=2[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1
Reactant: CC(C)N=C=O
Reactant: CCOCc1nc2c(N)nc3cccnc3c2n1CCCCNOC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cccnc3c2n1CCCCN(OC)C(=O)NC(C)C
Temperature: -8 °C
Reaction time: 8 h

Procedure:
The preparation of O-methyl-N-[4-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-hydroxylamine is described in Parts A-C of Example 20. Triethylamine (0.14 mL, 1.01 mmol) was added to a solution of O-methyl-N-[4-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]naphthyrdin-1-yl)butyl]hydroxylamine (0.29 g, 0.84 mmol) in dichloromethane (8 mL) and cooled to −8° C. Isopropyl isocyanate (0.08 mL, 0.84 mmol) was added dropwise to the reaction mixture, allowed to warm to ambient temperature and was stirred overnight. The reaction mixture was then diluted with dichloromethane (40 mL) and saturated aqueous sodium bicarbonate (30 mL) and the phases were separated. The aqueous phase was extracted with dichloromethane (20 mL) and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated to afford a yellow solid. The material was then purified by HPFC (eluting with 0-25% CMA in chloroform) and crystallized from acetonitrile, filtered, dried at 80° C. in a vacuum oven over the weekend to afford 0.178 g of 1-[4-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-3-isopropyl-1-methoxyurea as a white powder, mp 146-147° C. Anal. calcd for C21H31N7O3: C, 58.72; H, 7.27; N, 22.83. Found: C, 58.54; H, 7.27; N, 22.78.
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[C:15]([N:22]1[CH:26]=[CH:25][CH:24]=[C:23]1B(O)O)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:18]([O:17][C:15]([N:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1cnc(-c2cccn2C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 42.5 %

Procedure:
To a suspension of methyl 6-chloro-5-nitronicotinate (0.108 g, 0.499 mmol), 1-Boc-pyrrole-2-boronic acid (0.210 g, 0.997 mmol), and trans-Dichlorobis(triphenylphosphine)palladium (II) (0.350 g, 0.499 mmol) in Dioxane (Volume: 2.3 mL) was added 2M Sodium carbonate (0.798 mL, 1.596 mmol) at 23° C. The reaction was stirred at 100° C. for 1 hr. The resulting suspension was filtered and rinsed with dioxane and H2O. The filtrate was diluted with EtOAc (20 mL) and the layers were separated. The organic phase was washed with saturated NaHCO3 and brine, dried over MgSO4, filtered, rinsed with EtOAc, and dried in vacuo. The resulting crude material was purified via medium pressure chromatography using a gradient eluant of CH2Cl2/MeOH. The appropriate fractions were combined and concentrated via rotary evaporation to provide methyl 6-(1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)-5-nitronicotinate (0.0738 g, 0.212 mmol, 42.6% yield) as an orange gummy solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32 (s, 9 H) 3.96 (s, 3 H) 6.41 (t, J=3.28 Hz, 1 H) 6.65 (dd, J=3.28, 1.77 Hz, 1 H) 7.50 (dd, J=3.28, 1.77 Hz, 1 H) 8.82 (d, J=1.77 Hz, 1 H) 9.33 (d, J=1.77 Hz, 1 H). ESI-MS: m/z 348.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]#[N:20])=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]1([C:10]([NH:12][CH2:13][CH2:14][CH3:15])=[O:11])[CH2:9][CH2:8]1.[S:21](Cl)(=[O:24])(=[O:23])[NH2:22]>>[C:19]([C:3]1[C:2]([NH:1][S:21](=[O:24])(=[O:23])[NH2:22])=[CH:18][CH:17]=[CH:16][C:4]=1[O:5][CH2:6][C:7]1([C:10]([NH:12][CH2:13][CH2:14][CH3:15])=[O:11])[CH2:8][CH2:9]1)#[N:20]
Reactant: CCCNC(=O)C1(COc2cccc(N)c2C#N)CC1
Reactant: NS(=O)(=O)Cl
Product: CCCNC(=O)C1(COc2cccc(NS(N)(=O)=O)c2C#N)CC1
Yield: 78 %

Procedure:
Prepared as in Example 111a from 1-((3-amino-2-cyanophenoxy)methyl)-N-propylcyclopropanecarboxamide (Example 198b) and sulfamoyl chloride in 78% yield as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 9.45 (broad s, 1H), 7.51-7.61 (m, 2H), 7.26 (broad s, 2H), 7.16 (d, J=8.0 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H), 4.24 (s, 2H), 3.04 (q, J=6.4 Hz, 2H), 1.43 (hex, J=7.6 Hz, 2H), 1.08-1.14 (m, 2H), 0.83-0.88 (m, 2H), 0.82 (t, J=7.2 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:19]=[CH:18][C:13]3[O:14][CH2:15][CH2:16][O:17][C:12]=3[CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([SH:22])[N:3]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)(O)[O-].[Na+].O>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:19]=[CH:18][C:13]3[O:14][CH2:15][CH2:16][O:17][C:12]=3[CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1ccc2c(c1)OCCO2
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c(N)nc(SCc2ccccc2)c(C#N)c1-c1ccc2c(c1)OCCO2

Procedure:
100 mg (0.32 mol) of 2-amino-6-sulfanyl-4-(2,3-dihydro-1,4-benzodioxin-6-yl)-3,5-pyridinedicarbonitrile [prepared analogously to Dyachenko et al., Russian Journal of Chemistry 33 (7), 1014–1017 (1997); 34 (4), 557–563 (1998)], 110 mg (0.64 mmol) of benzyl bromide and 108 mg (1.29 mmol) of sodium bicarbonate are stirred in 2 ml of DMF at room temperature for 5.5 h. Water is then added and the mixture is extracted three times with ethyl acetate. The combined organic phases are dried with magnesium sulfate and concentrated under reduced pressure. The residue is taken up in diethyl ether, giving, after reconcentration, a crystalline product.