Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16](F)[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1.Cl.Cl.[CH3:28][NH:29][CH2:30][CH:31]1[O:36][CH2:35][CH2:34][NH:33][CH2:32]1.N12CCCN=C1CCCCC2>C(#N)C>[F:19][C:17]1[CH:16]=[C:15]([F:21])[CH:14]=[CH:13][C:18]=1[N:9]1[C:3]2[C:4](=[CH:5][C:6]([F:8])=[C:7]([N:33]3[CH2:34][CH2:35][O:36][CH:31]([CH2:30][NH:29][CH3:28])[CH2:32]3)[C:2]=2[F:1])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1
Reactant: CNCC1CNCCO1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CNCC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4F)c3c2F)CCO1

Procedure:
A solution of 710 mg of 1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 487 mg of 2-(methylaminomethyl)morpholine dihydrochloride and 1035 mg of 1,8-diazabicyclo[5.4.0]undec-7-ene in 10 ml of acetonitrile is refluxed for 21 hours. The reaction mixture is concentrated under reduced pressure and to the residue is added 10 ml of methanol. The obtained crystals are collected by filtration and washed with methanol, water and then acetone to give 1-(2,4-difluorophenyl)-7-[2-(methylaminomethyl)morpholino]-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, melting at 224°-227° C. with decomposition.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1.[H-].[Na+]>>[C:1]([O:5][C:6](=[O:13])[N:7]([CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1)[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nn1cccc1
Reactant: BrCc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N(Cc1ccc2ccccc2c1)n1cccc1

Procedure:
Prepared according to the benzylation condition used in Example 1 step b) from pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.), 2-bromomethyl-naphthalene (1.03 eq.) and sodium hydride (1.3 eq.). ESI (m/z): 323 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([C:28]2[O:29][C:30]([CH3:33])=[N:31][N:32]=2)[CH:25]=[CH:24][C:3]=1[O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[C:6]1=[O:23].[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>C(Cl)Cl>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[F:1][C:2]1[CH:27]=[C:26]([C:28]2[O:29][C:30]([CH3:33])=[N:31][N:32]=2)[CH:25]=[CH:24][C:3]=1[O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)[C:6]1=[O:23]
Reactant: Cc1nnc(-c2ccc(O[C@H]3CCN(C4CCN(C(=O)OC(C)(C)C)CC4)C3=O)c(F)c2)o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nnc(-c2ccc(O[C@H]3CCN(C4CCNCC4)C3=O)c(F)c2)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-tert-butyl 4-(3-(2-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (680 mg, 1.48 mmol) was dissolved in CH2Cl2 (10 mL) and TFA (4 mL) was added and stirred at ambient temperature for 1 hour and then concentrated in vacuo to afford crude (S)-3-(2-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy)-1-(piperidin-4-yl)pyrrolidin-2-one 2,2,2-trifluoroacetate as an oil which was taken forward without further purification.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[CH:18]1([NH:17][C:13]2[N:12]=[C:11]([C:10]3[C:9]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)=[N:8][N:7]4[C:2]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[CH:3][CH:4]=[CH:5][C:6]=34)[CH:16]=[CH:15][N:14]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COc1ccc(-c2nn3c(Cl)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Reactant: C1COCCN1
Product: COc1ccc(-c2nn3c(N4CCOCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 120 °C
Yield: 85 %

Procedure:
A mixture of 4-[7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (75 mg, 0.18 mmol) and morpholine (5 mL, 57 mmol) was heated at 120° C. for 4 hours, then cooled and concentrated. Flash chromatography (3:1 to 1:3 hexanes-ethyl acetate) afforded N-cyclopentyl-4-[2-(4-methoxyphenyl)-7-(4-morpholinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine (72 mg, 86%) as a yellow solid. 1H NMR (CDCl3): δ 8.14 (d, 1 H), 7.93 (broad, 1 H), 7.58 (d, 2 H), 7.33 (t, 1 H), 6.97 (d, 2 H), 6.35 (m, 2 H), 4.38 (m, 1 H), 3.99 (m, 4 H), 3.87 (s, 3 H), 3.50 (m, 4 H), 2.08 (m, 2 H), 1.79–1.54 (m, 6 H); MS m/z 471 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:16]O.P(Br)(Br)[Br:19].C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:10]1([CH2:9][O:8][C:6]2[CH:5]=[CH:4][C:3]([CH2:16][Br:19])=[C:2]([CH3:1])[CH:7]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrP(Br)Br
Reactant: Cc1cc(OCc2ccccc2)ccc1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(OCc2ccccc2)ccc1CBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.5 %

Procedure:
To a solution of {2-methyl-4-[(phenylmethyl)oxy]phenyl}methanol (1.49 g, 6.53 mmol) in DCM (20 ml) under nitrogen in an ice-water bath was added a solution of phosphorus tribromide (0.62 ml, 6.57 mmol, Aldrich) in DCM (10 ml). The solution was allowed to warm to ambient temperature and stirred for 3 h. The reaction mixture was poured onto ice-water (70 ml) and saturated aqueous sodium hydrogen carbonate (30 ml). The mixture was diluted with DCM (50 ml) and the phases separated. The aqueous extract was washed with dichloromethane DCM (20 ml). The combined organic extracts were washed with water (50 ml), dried (MgSO4), filtered and the solvent removed in vacuo to leave 4-(bromomethyl)-3-methylphenyl phenylmethyl ether as a yellow oil (1.72 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH2:26][CH2:27]CS([O-])(=O)=O)[CH2:11][CH2:10][N:9]([C:12](=[O:25])[C:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=3)[CH2:8]2)[CH:2]=1.Cl.[C:34]1([C:40]2([C:46]([NH2:48])=[O:47])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH2:26][CH2:27][N:43]3[CH2:42][CH2:41][C:40]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)([C:46]([NH2:48])=[O:47])[CH2:45][CH2:44]3)[CH2:11][CH2:10][N:9]([C:12](=[O:25])[C:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=3)[CH2:8]2)[CH:2]=1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3cccnc3)C2)cc(OC)c1OC
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3cccnc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(pyridin-3-yl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (8 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (12 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][CH3:15])[C:5]([O:7]C)=[O:6].Cl.CCOC(C)=O>C(O)C.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][CH3:15])[C:5]([OH:7])=[O:6]
Reactant: CCCOc1ccc(C(=O)OC)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCOc1ccc(C(=O)O)cc1Cl
Yield: 67.7 %

Procedure:
A solution of methyl 3-chloro-4-(propyloxy)benzoate (D99) (12.22 g, 0.053 mol) in ethanol (40 ml) and 2M NaOH aq. (40 ml) was heated at 60° C. for 3 hours. The reaction was allowed to cool and then left at room temperature over the weekend. The reaction mixture was poured into a mixture of dilute aq. HCl and EtOAc. The organic layer was separated, dried and evaporated to give a solid which was triturated with ether to give the title compound as a white solid (7.7 g). δH (400 MHz, d6-DMSO) 1.00 (3H, t), 1.67-1.87 (2H, m) 4.10 (2H, t), 7.24 (1H, d), 7.84-8.06 (2H, m), 12.97 (1H, br s). MS (ES) C10H1135ClO3 requires 214; found 213 (M−H+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8](Br)[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4].[CH:21]1([NH2:25])[CH2:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([NH:25][CH:21]3[CH2:24][CH2:23][CH2:22]3)[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4]
Reactant: NC1CCC1
Reactant: COC(=O)c1nc2c(s1)C(Br)COc1ccc(Br)cc1-2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1nc2c(s1)C(NC1CCC1)COc1ccc(Br)cc1-2
Temperature: 90 °C
Reaction time: 8 h
Yield: 28.3 %

Procedure:
To a solution of 4,9-Dibromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (400 mg, 0.95 mmol) in DMF (9 mL) were added cyclobutanamine (81.5 mg, 1.15 mmol), DIPEA (370 mg, 2.86 mmol). The reaction mixture was stirred in autoclave at 90° C. overnight. Then the mixture was cooled to room temperature and partitioned between EtOAc and H2O, and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated in vacuo and purified by flash column chromatography (silica gel, EtOAc in hexane from 10% to 20%) to afford 9-Bromo-4-cyclobutylamino-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (110 mg, 28%). NMR (400 MHz, DMSO-d6): δ 8.44 (d, J=2.5 Hz, 1H), 7.47 (dd, J1=8.6 Hz, J2=2.5 Hz, 1H), 7.05 (d, J=8.6 Hz, 1H), 4.42 (m, 2H), 3.96 (m, 1H), 3.14 (m, 1H), 2.15 (m, 1H), 1.74 (m, 2H), 1.55 (m, 2H).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[CH2:17][C:18](=[O:32])[NH:19][C:20]4[CH:26]=[C:25]([N:27]5[CH:31]=[CH:30][CH:29]=[CH:28]5)[CH:24]=[CH:23][C:21]=4[N:22]=3)[CH:11]=2)[O:8][CH:9]=1)=[O:4].[NH3:33]>CO>[O:32]=[C:18]1[CH2:17][C:16]([C:12]2[CH:11]=[C:10]([C:7]3[O:8][CH:9]=[C:5]([C:3]([NH2:33])=[O:4])[N:6]=3)[CH:15]=[CH:14][CH:13]=2)=[N:22][C:21]2[CH:23]=[CH:24][C:25]([N:27]3[CH:28]=[CH:29][CH:30]=[CH:31]3)=[CH:26][C:20]=2[NH:19]1
Reactant: N
Reactant: COC(=O)c1coc(-c2cccc(C3=Nc4ccc(-n5cccc5)cc4NC(=O)C3)c2)n1
Solvent: CO
Product: NC(=O)c1coc(-c2cccc(C3=Nc4ccc(-n5cccc5)cc4NC(=O)C3)c2)n1
Temperature: 20 °C
Reaction time: 72 h

Procedure:
A suspension of 2-[3-(4-oxo-7-pyrrol-1-yl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-phenyl]-oxazole-4-carboxylic acid methyl ester (Example 25) (44mg) in a 5N solution (3 mL) of NH3 in MeOH was stirred at 20° C. for 3 d. Insoluble material was filtered off and the solution was evaporated in vacuum. The residue was triturated with EtOAc to give the title compound (22 mg) as light-yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])=[CH:5][C:6]2[C:12]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])=[N:11][CH2:10][C:9](=[O:21])[NH:8][C:7]=2[CH:22]=1.[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([N:8]1[C:7]2[CH:22]=[C:3]([O:2][CH3:1])[C:4]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[CH:5][C:6]=2[C:12]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])=[N:11][CH2:10][C:9]1=[O:21])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1ccccc1-c1cc2c(cc1OC)NC(=O)CN=C2c1cccc(C#N)c1
Reactant: BrCc1ccccc1
Product: COc1ccccc1-c1cc2c(cc1OC)N(Cc1ccccc1)C(=O)CN=C2c1cccc(C#N)c1
Yield: 90 %

Procedure:
Prepared from 3-[8-methoxy-7-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl]-benzonitrile Example 10 using the same method described for Example 35 using benzyl bromine instead of hexyl bromine, we. The title compound (95 mg) was obtained as a yellow solid, (yield=90%).
Reaction SMILES: Cl[C:2]1[C:3]([C:15]#[N:16])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([CH3:8])[N:7]=1.Cl.[CH2:18]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH2:22][CH2:21][NH:20][CH2:19]1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH3:8][C:6]1[N:7]=[C:2]([N:20]2[CH2:19][CH2:18][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][CH2:21]2)[C:3]([C:15]#[N:16])=[N:4][C:5]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1nc(Cl)c(C#N)nc1-c1ccccc1
Reactant: c1ccc2c(c1)CCNCC2
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N2CCc3ccccc3CC2)c(C#N)nc1-c1ccccc1

Procedure:
In analogy to the procedure described in example 12 1-phenyl-1,2-propanedione and 2-aminomalonamide were heated in an aqueous solution to give 5-methyl-3-oxo-6-phenyl-3,4 -dihydro-pyrazine-2-carboxylic acid amide. Then, the 5-methyl-3-oxo-6-phenyl-3,4-dihydro-pyrazine-2-carboxylic acid amide was treated with triethylamine and phosphorus pentachloride in phosphorus oxychloride at reflux to give the 3-chloro-5-methyl-6-phenyl-pyrazine-2-carbonitrile. The 3-chloro-5-methyl-6-phenyl-pyrazine-2-carbonitrile was finally treated with 2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride (J. Heterocycl. Chem. 1971, 8(5), 779-83) and N-ethyldiisopropylamine in N,N-dimethylformamide at room temperature to yield the 5-methyl-6-phenyl-3-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-pyrazine-2-carbonitrile as yellow amorphous solid; MS: 341 (M+H)+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[N:11]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:10][C:9](=[O:20])[NH:8][C:5]2=[N:6][CH:7]=1.C[Sn](C)(C)[C:23]1[CH:24]=[CH:25][C:26]([C:29]([OH:32])([CH3:31])[CH3:30])=[N:27][CH:28]=1>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:32][C:29]([C:26]1[N:27]=[CH:28][C:23]([C:2]2[N:3]=[C:4]3[N:11]([CH2:12][CH2:13][N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[CH2:10][C:9](=[O:20])[NH:8][C:5]3=[N:6][CH:7]=2)=[CH:24][CH:25]=1)([CH3:31])[CH3:30]
Reactant: O=C1CN(CCN2CCOCC2)c2nc(Br)cnc2N1
Reactant: CC(C)(O)c1ccc([Sn](C)(C)C)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(O)c1ccc(-c2cnc3c(n2)N(CCN2CCOCC2)CC(=O)N3)cn1
Temperature: 100 °C
Yield: 27 %

Procedure:
6-Bromo-4-(2-morpholinoethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (0.228 g, 0.666 mmol) and 2-(5-(trimethylstannyl)pyridin-2-yl)propan-2-ol (0.220 g, 0.733 mmol) were combined in dimethylformamide (3 mL). Solution was purged with nitrogen gas followed by the addition of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane (0.109 g, 0.133 mmol). Solution was heated to 100° C. for 2 h. Solution was condensed under reduced pressure and the resulting oil purified via reverse-phase-preparative HPLC (5-60% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min) and desired fractions were loaded onto a Strata-XC ion exchange column. The column was washed successively with water, acetonitrile, methanol and 5% ammonium hydroxide in methanol. The product eluted with the 5% ammonium hydroxide in methanol and was concentrated under reduced pressure and dried to afford the title compound (0.070 g, 0.18 mmol, 26% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 11.33 (br. s., 1H), 9.05 (d, J=1.56 Hz, 1H), 8.27 (dd, J=8.59, 2.34 Hz, 1H), 8.06 (s, 1H), 7.72 (d, J=8.59 Hz, 1H), 5.27 (s, 1H), 4.29 (s, 2H), 3.71 (t, J=6.44 Hz, 2H), 3.54 (t, J=4.49 Hz, 4H), 2.62 (t, J=6.44 Hz, 2H), 2.40-2.48 (m, 4H), 1.46 (s, 6H); MS (ESI) m/z 399.2 [M+1]+; mp 239-241° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[O:12]([C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[O:12]([C:19]1[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][CH:6]=[CH:5]3)=[O:27])=[CH:23][CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccc2ncccc2c1
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Product: O=C(Nc1ccc(Oc2ccccc2)cc1)Nc1ccc2ncccc2c1

Procedure:
Prepared from 6-aminoquinoline and 4-phenoxyphenyl isocyanate. m/z (ES+) 356 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([NH:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: NCc1ccccc1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: Nc1nc(NCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 91 %

Procedure:
2-Amino-6-benzylamino-3-nitropyridine was prepared from 2-amino-6-chloro-3-nitropyridine as follows: 2-Amino-6-chloro-3-nitropyridine (17.35 g, 0.10 mol), benzyl amine (Fluka) (10.72 g, 0.10 mol) and powdered potassium carbonate (10.4 g, 0.035 mol) in n-butanol (100 mL) were heated under reflux for 2 hours. The suspension was filtered and after cooling to room temperature the solid was collected by filtration, washed with butanol, and dried at 50 C. in vacuo to give 2-amino-6-benzylamino-3-nitropyridine (22.2 g, 91%, m.p. 145-146 C.).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C[O-].[Na+].CO.O.[C:20](OCC)(=[O:22])C>CO>[Cl:1][C:2]1[N:11]=[C:10]([O:22][CH3:20])[C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CCOC(C)=O
Reactant: COC(=O)c1cc(F)c(Cl)nc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(F)c(OC)nc1Cl
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 1.5 g of methyl 2,6-dichloro-5-fluoronicotinate in 12 mL of methanol, a solution of 1.3 g of 28% sodium methoxide/methanol in 3 mL of methanol was dropped, and the mixture was stirred at room temperature for 40 minutes. Thereto were added water and ethyl acetate, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.2 g of methyl 2-chloro-5-fluoro-6-methoxynicotinate as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[N:10][CH:11]=1.[CH3:20][NH2:21]>CO>[CH3:20][NH:21][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=1
Reactant: ClCCCOc1cncc(OCc2ccccc2)c1
Reactant: CN
Solvent: CO
Product: CNCCCOc1cncc(OCc2ccccc2)c1
Temperature: 100 °C
Yield: 71.7 %

Procedure:
The 5-(3-chloropropoxy)-3-(phenylmethoxy)pyridine (1.52 g, 5.49 mmol) was dissolved in methanol (25 mL) and added to a 40 wt % aqueous solution of methylamine (50 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 4 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCl solution (25 mL) was added to the residue. The pH of the solution was adjusted to 6, and impurities were extracted with ether (3×15 mL). The aqueous layer was basified to pH 10 with 10% NaOH solution and extracted with chloroform (4×15 mL). The combined chloroform extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 1.07 g (71.7%) of an oil.
Reaction SMILES: CC([C:5]1[C:6]([S:17]([NH2:20])(=[O:19])=[O:18])=[C:7]([S:11]([N:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[N:8]([CH3:10])[CH:9]=1)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[S:11]([C:7]1[N:8]([CH3:10])[CH:9]=[CH:5][C:6]=1[S:17]([NH2:20])(=[O:19])=[O:18])(=[O:12])=[O:13]
Reactant: CN(C)S(=O)(=O)c1c(S(N)(=O)=O)c(C(C)(C)C)cn1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1c(S(N)(=O)=O)ccn1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6.95 g (21 mmol) of N3 -(1,1-dimethylethyl)N2,N2,1-trimethyl-1H-pyrrole-2,3-disulfonamide in 75 mL of methylene chloride under a nitrogen atmosphere was added 75 mL of TFA. The reaction mixture was allowed to stir at room temperature overnight ca. 16 hours. The reaction mixture was concentrated in vacuo. Three portions of diethyl ether were added to the solid residue and removed by evaporation to remove residual TFA. The solids were suspended in diethyl ether and filtered to yield 4.52 g of the title compound as a solid, m.p. 146°-148° C. 1H NMR (Acetone-d6, 200 MHz.) δ: 7.1(d,1H), 6.59(d,1H), 6.28(bs,2H), 3.95(s,3H), 2.93(s,6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:15]2[CH2:16][CH:11]3[CH2:12][C:13]([C:18]([OH:20])=O)([CH2:17][CH:9]1[CH2:10]3)[CH2:14]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:21]1C=CC=CC=1.C(=O)(O)[O-].[NH4+]>C(#N)C>[C:18]([C:13]12[CH2:14][CH:15]3[CH2:16][CH:11]([CH2:10][CH:9]([N:8]3[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:17]1)[CH2:12]2)(=[O:20])[NH2:21]
Reactant: CC(C)(C)OC(=O)N1C2CC3CC1CC(C(=O)O)(C3)C2
Reactant: c1ccncc1
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C2CC3CC1CC(C(N)=O)(C3)C2
Reaction time: 1 h
Yield: 87 %

Procedure:
A 50 mL RB flask fitted with magnetic stirrer was charged with 5 mL of acetonitrile and 2-(tert-butoxycarbonyl)-2-azatricyclo[3.3.1.13,7]decane-5-carboxylic acid, Intermediate-10 (0.16 g, 0.56 mmol). Under N2 atm, pyridine (60 mg, 0.6 mmol) and Boc-anhydride (0.148 g, 0.6 mmol) was added to the reaction mixture and was stirred for 1 hr. After 1 hr, ammonium bicarbonate solid (75 mg, 0.9 mmol) was added and the reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction (reaction was monitored by TLC), reaction mixture was concentrated under vacuum. The resulted crude material was extracted with ethyl acetate (25 ml×3). The organic layer was washed with ammonium chloride solution and saturated sodium bi carbonate solution. It was then dried over anhydrous sodium sulfate and concentrated to give Intermediate-11, as an oily mass (0.14 g, yield=87%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[CH:14]=[CH:15][N:16]([CH2:23][C@@H:24]2[CH2:28][CH2:27][CH2:26][N:25]2C(OC(C)(C)C)=O)[C:17]3=[O:22])=[O:10])=[CH:4][C:3]=1[C:36]([F:39])([F:38])[F:37].O1CCOCC1.Cl>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[CH:14]=[CH:15][N:16]([CH2:23][C@@H:24]2[CH2:28][CH2:27][CH2:26][NH:25]2)[C:17]3=[O:22])=[O:10])=[CH:4][C:3]=1[C:36]([F:39])([F:37])[F:38]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1Cn1ccc2c(NC(=O)Cc3ccc(Cl)c(C(F)(F)F)c3)cccc2c1=O
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=C(Cc1ccc(Cl)c(C(F)(F)F)c1)Nc1cccc2c(=O)n(C[C@@H]3CCCN3)ccc12
Reaction time: 8 h

Procedure:
Into a 20 ml reaction vessel was combined (S)-tert-butyl 2-((5-(2-(4-chloro-3-(trifluoromethyl)phenyl)acetamido)-1-oxoisoquinolin-2(1H)-yl)methyl)pyrrolidine-1-carboxylate (20.0 mg, 0.0000355 mol) and 1,4-dioxane (5 mL, 0.06 mol). Hydrogen chloride (0.016 g, 0.00044 mol) as a 2.0M solution in ether was added dropwise. The reaction was allowed to stir overnight. A white preciptate had formed and was filtered, washed with ether, and dried. The product was dissolved in diethylamine and DMSO (1 mL) and was purified by HPLC using a Phenomenex AXIA packed C18 column (100×21.2 10 micron) at pH 10. The combined pure fractions were reduced in vacuo to yield the title compound as a white solid. LC/MS M+H=464.2.