Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:19]=[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:11](=[O:18])[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:4](=[C:5]23)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26]([CH:28]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:29]Br)[CH3:27].CN(C)C=O>O>[CH2:26]([CH:28]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:29][O:1][C:2]1[CH:19]=[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:11](=[O:18])[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:4](=[C:5]23)[CH:3]=1)[CH3:27]
Reactant: O=C1c2ccccc2-c2cc(O)cc3cccc1c23
Reactant: CCCCC(CC)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(CC)COc1cc2c3c(cccc3c1)C(=O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A 500 ml three neck flask was equipped with a mechanical stirrer, heating mantle and condenser. To the flask was added 25 g 2-hydroxy-7H-benzo[de]anthracene-7-one, 18 g powdered potassium carbonate, 25 g 2-ethylhexyl bromide and 250 g dimethylformamide (DMF). The mixture was heated to reflux. After seven hours, 4.5 g 2-ethylhexyl bromide was added and the mixture heated at reflux for an additional three hours. The mixture was then cooled to room temperature and 500 g deionized water was added. The solution was extracted twice with 200 g chloroform. The organic layers were combined and washed twice with 250 g water. The solvent was removed on a rotary evaporator, then the crude product was passed through a flash silica gel column using methylene chloride as the elutant. The product fractions were collected and the solvent removed using a rotary evaporator. The yield of 2-[(2-ethylhexyl)oxy]-7H-benzo[de]anthracene-7-one was 28.5 g.
Reaction SMILES: [CH2:1]([N:3]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12]O)=[CH:9]2)=[N:4]1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:33]1(=[O:43])[NH:37][C:36](=[O:38])[C:35]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]12.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>C1COCC1>[CH2:1]([N:3]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][N:37]3[C:33](=[O:43])[C:34]4[C:35](=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:36]3=[O:38])=[CH:9]2)=[N:4]1)[CH3:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCn1cc2cc(CO)ccc2n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCn1cc2cc(CN3C(=O)c4ccccc4C3=O)ccc2n1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of (2-ethyl-2H-indazol-5-yl)methanol (step-2 of Example 13, 132 mg, 0.75 mmol) in THF (10 mL) was added triphenylphosphine (236 mg, 0.90 mmol) and phthalimide (132 mg, 0.90 mmol). The mixture was cooled to 0° C. Then, to the mixture was added 40% DEAD in toluene (0.30 mL, 0.75 mmol) and allowed to warm up to room temperature. The mixture was stirred at room temperature for 4 hrs. The reaction mixture was evaporated. The residual oil was purified by silica gel column chromatography (0-50% EtOAc in hexane) to give the titled compound as a mixture. The mixture was used next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:15]3[CH2:16][CH2:17][S:18][CH2:19][CH:14]3[C:13](=[O:20])[NH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.O.O.[Sn](Cl)(Cl)(Cl)Cl.C(=O)([O-])O.[Na+].CS([O-])(=O)=O>C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[N:15]3[CH2:16][CH2:17][S:18][CH2:19][CH:14]3[C:13](=[O:20])[NH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C1NN=C(c2cccc([N+](=O)[O-])c2)N2CCSCC12
Agent: CS(=O)(=O)[O-]
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CCO
Product: Nc1cccc(C2=NNC(=O)C3CSCCN23)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the compound prepared in Example 3 (537 mg) in ethanol (4 mL) was added tin chloride dihydrate (2.07 g) and the mixture was refluxed for 30 minutes. After cooling to room temperature, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, which was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated. To methanol (2 mL) was added the obtained solid (137 mg) and then 4N hydrogen chloride in dioxane (0.26 mL) was added to the mixture, which was stirred at room temperature for 3 hours. The reaction mixture was concentrated. The residue was recrystallized from a mixture solvent (isopropanol:ethanol=4:1) to give the compound of the present invention (144 mg) having the following physical data. Moreover, the compound was converted to methanesulfonate thereof by conventional method.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([OH:16])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:29].Cl>[Zn].[Cl-].[NH4+].O.C(O)C>[ClH:29].[ClH:29].[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([NH:6][CH2:5][CH:4]([OH:16])[CH2:3][O:2][CH3:1])=[CH:8][CH:9]=1
Reactant: COCC(O)CNc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: COCC(O)CNc1ccc(N)cc1

Procedure:
The 1-methoxy-3-[(4-nitrophenyl)amino]propan-2-ol (13) obtained above was reduced with a boiling zinc/ammonium chloride/water/ethanol mixture. The corresponding amine was isolated in dihydrochloride form.
Reaction SMILES: [S:1]1[C:5]([CH2:6][C:7]2[C:8]([O:26][CH3:27])=[N:9][C:10]3[C:15]([C:16]=2[Cl:17])=[CH:14][C:13]([C:18]([C:20]2[N:24]([CH3:25])[CH:23]=[N:22][CH:21]=2)=[O:19])=[CH:12][CH:11]=3)=[CH:4][C:3]2[CH:28]=[CH:29][CH:30]=[CH:31][C:2]1=2.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[Mg]Br>C1COCC1>[S:1]1[C:5]([CH2:6][C:7]2[C:8]([O:26][CH3:27])=[N:9][C:10]3[C:15]([C:16]=2[Cl:17])=[CH:14][C:13]([C:18]([C:20]2[N:24]([CH3:25])[CH:23]=[N:22][CH:21]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=2)[OH:19])=[CH:12][CH:11]=3)=[CH:4][C:3]2[CH:28]=[CH:29][CH:30]=[CH:31][C:2]1=2
Reactant: COc1nc2ccc(C(=O)c3cncn3C)cc2c(Cl)c1Cc1cc2ccccc2s1
Reactant: Br[Mg]c1ccccn1
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccccn3)c3cncn3C)cc2c(Cl)c1Cc1cc2ccccc2s1
Reaction time: 0.08 h

Procedure:
LaCl3-2LiCl (0.6 M in THF, 0.78 mL, 0.47 mmol) was added dropwise by syringe to a solution of (3-(benzo[b]thiophen-2-ylmethyl)-4-chloro-2-methoxyquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanone (101.4 mg, 0.226 mmol, Intermediate 40: step b) in dry THF (2 mL). After 5 minutes, the solution was cooled in an ice bath and pyridin-2-ylmagnesium bromide (2.8 mL, 0.7 mmol) was added dropwise via syringe. The reaction was stirred for 3 hours, then quenched with saturated aqueous ammonium chloride and removed from the cold bath. The mixture was partitioned between water and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (silica gel, 0-5% MeOH-DCM) followed by reverse-phase chromatography (acetonitrile/H2O+0.05% TFA). The isolated product fractions were basified with saturated aqueous sodium bicarbonate, extracted with DCM, dried (Na2SO4), filtered, and concentrated to dryness to provide the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 8.63-8.59 (m, 1H), 8.13 (d, J=2.0 Hz, 1H), 7.82 (d, J=8.7 Hz, 1H), 7.71-7.60 (m, 4H), 7.49 (d, J=1.1 Hz, 1H), 7.30-7.18 (m, 4H), 7.08 (d, J=1.0 Hz, 1H), 6.32 (d, J=1.1 Hz, 1H), 4.50 (d, J=1.1 Hz, 2H), 4.13 (s, 3H), 3.41 (s, 3H); MS m/e 527.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH:31]([CH3:33])[CH3:32])(=[O:30])=[O:29])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH3:2].[Cl:43][C:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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]>[CH2:1]([O:3][C:4](=[O:42])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:47]3[CH:48]=[CH:49][C:44]([Cl:43])=[CH:45][CH:46]=3)[CH:25]=[C:26]([S:28]([CH:31]([CH3:33])[CH3:32])(=[O:30])=[O:29])[CH:27]=2)[C:10]=1[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH3:2]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(S(=O)(=O)C(C)C)c2)c1CCC(=O)OCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccc(Cl)cc3)cc(S(=O)(=O)C(C)C)c2)c1CCC(=O)OCC
Yield: 79 %

Procedure:
A similar procedure as described in Example 41, step 1 was used, starting from 4-[3-[6-(3-bromo-5-(propane-2-sulfonyl)-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (175 mg, 0.26 mmol), 4-chloro-phenylboronic acid (86 mg, 0.52 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (29 mg, 0.039 mmol), and cesium carbonate (172 mg, 0.52 mmol) to afford 4-[2-(2-ethoxycarbonyl-ethyl)-3-[6-(5-(propane-2-sulfonyl)-4′-chloro-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid ethyl ester (144 mg, 79%) as a colorless viscous oil: ES(+)-HRMS m/e calcd for C38H49ClO8S (M+Na)+ 723.2729, found 723.2731.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][C:13](=O)[NH:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:5])[CH3:2].B.O1CCCC1.Cl.[OH-].[Na+]>O1CCCC1.O>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][CH2:20][CH2:21]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)c[nH]c1CC(=O)NCCN1CCCC1
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(C)c[nH]c1CCNCCN1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
A stirred solution of 4-methyl-2-[(2-pyrrolidin-1-yl-ethylcarbamoyl)-methyl]-1H-pyrrole-3-carboxylic acid ethyl ester (1.843 g, 6 mmol) in 12 ml of anhydrous tetrahydrofuran was added dropwise slowly with borane-tetrahydrofuran in tetrahydrofuran (18 ml, 18 mmol) under an argon atmosphere. Upon completion of the addition, the mixture was stirred for 1 hour at room temperature and heated to reflux for another 5 hours. The reaction mixture was added with cold water (5 ml) and 1N hydrochloric acid (20 ml) dropwise. The mixture was stirred for another 5 minutes, adjusted to pH 10 with 10% aqueous sodium hydroxide solution and extracted with ethyl acetate (20 ml×3). The combined organic extracts were washed with brine (15 ml), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-methyl-2-[2-(2-pyrrolidin-1-yl-ethylamino)-ethyl]-1H-pyrrole-3-carboxylic acid ethyl ester (1.441 g) as a brown oil which was used as such.
Reaction SMILES: [CH3:1][C:2]1[C:26]([CH3:27])=[CH:25][C:5]2[N:6](COCC[Si](C)(C)C)[C:7]([C:9]3[CH:13]=[C:12]([S:14][CH2:15][CH3:16])[NH:11][N:10]=3)=[N:8][C:4]=2[CH:3]=1.CC1C(C)=CC2NC=NC=2C=1>>[CH2:15]([S:14][C:12]1[NH:11][N:10]=[C:9]([C:7]2[NH:8][C:4]3[CH:3]=[C:2]([CH3:1])[C:26]([CH3:27])=[CH:25][C:5]=3[N:6]=2)[CH:13]=1)[CH3:16]
Reactant: CCSc1cc(-c2nc3cc(C)c(C)cc3n2COCC[Si](C)(C)C)n[nH]1
Agent: Cc1cc2nc[nH]c2cc1C
Product: CCSc1cc(-c2nc3cc(C)c(C)cc3[nH]2)n[nH]1

Procedure:
By proceeding in a similar manner to Example 230(a) above but using 5,6-dimethyl-2-(5-ethylsulfanyl-1H-pyrazol-3-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole [Reference Example 1(f)] there was prepared 2:5-ethylsulfanyl-1H-pyrazol-3-yl)-5,6-dimethyl-1H-benzoimidazole. LC-MS (METHOD A): RT=2.32 minutes; 273 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])[O:16][C:12]=2[N:13]=[CH:14][N:15]=1.[OH-].[Na+].Cl.C(OC)(=O)C>O1CCOCC1>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]2[C:11]3[C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:34])=[O:2])=[N:15][CH:14]=[N:13][C:12]=3[O:16][C:17]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])=[CH:20][CH:21]=1
Reactant: COC(=O)CCCCCNc1ncnc2oc(-c3ccccc3C)c(-c3ccc(OC)cc3)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(-c2c(-c3ccccc3C)oc3ncnc(NCCCCCC(=O)O)c23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dissolve 65 mg (0.14 mmol) 6-{[5-(4-methoxyphenyl)-6-(2-methylphenyl)furo[2,3-d]pyrimidin-4-yl]amino}hexanoic acid methyl ester in 2.5 ml dioxan and add 0.50 ml 1 N sodium hydroxide solution. Stir for 16 h at RT, then add 0.50 ml 1 N hydrochloric acid and then 6 ml methyl acetate. Separate the organic phase, dry over sodium sulphate, filter, and concentrate by evaporation. 53 mg (82% of theor.) of the target compound is obtained.
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][N:36]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:34][C:35]1[N:36]=[CH:37][C:38]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:26][CH2:25][CH:24]([N:27]5[CH2:28][CH2:29][O:30][CH2:31][CH2:32]5)[CH2:23][CH2:22]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:4][CH2:3][C:2]([F:1])([F:33])[CH2:7][CH2:6]2)=[O:9])=[CH:39][CH:40]=1
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCOCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1ccc(Cl)nc1)N1CCC(N2CCOCC2)CC1
Yield: 31 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-morpholin-4-yl-piperidin-1-yl)-methanone (example 170), 2-chloropyridine-5-boronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a yellow solid (31%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=O)[CH3:2].S([O-])([O-])(=O)=O.[Na+].[Na+].[NH2:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][O:27][C:28]2=[O:33]>ClCCl>[CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)/[CH:8]=[N:23]/[C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][O:27][C:28]2=[O:33])[CH3:2]
Reactant: Nc1cccc2c1COC2=O
Reactant: CCOC(OCC)c1cccc(C=O)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(OCC)c1cccc(/C=N/c2cccc3c2COC3=O)c1
Temperature: 25 °C
Reaction time: 144 h
Yield: 60.9 %

Procedure:
To a stirred mixture of 3-(diethoxymethyl)benzaldehyde (3.75 g, 18 mmol) and anhydrous sodium sulfate (21.3 g, 150 mmol) in anhydrous dichloromethane (300 mL) was added 4-aminoisobenzofuran-1(3H)-one (2.24 g, 15 mmol) at 0° C. After the addition, the mixture was stirred at room temperature for 6 days. The mixture was filtered and the cake was washed with dichloromethane (50 mL×3). The filtrate was concentrated to give crude product. The crude product was washed with petroleum ether to give (E)-4-(3-(diethoxymethyl)benzylideneamino)isobenzofuran-1(3H)-one (3.1 g, yield 61%) as a white solid. LC-MS (ESI) m/z: 340 (M+1)+.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([C:10]1[N:14]=[C:13]([NH2:15])[S:12][N:11]=1)[C:7]([OH:9])=[O:8])[CH:2]=[CH2:3].[C:16]1([C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N+]=[N-])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[CH2:1]([O:4][N:5]=[C:6]([C:10]1[N:14]=[C:13]([NH2:15])[S:12][N:11]=1)[C:7]([O:9][CH:22]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:8])[CH:2]=[CH2:3]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: C=CCON=C(C(=O)O)c1nsc(N)n1
Solvent: C1CCOC1
Product: C=CCON=C(C(=O)OC(c1ccccc1)c1ccccc1)c1nsc(N)n1
Reaction time: 8 h
Yield: 31.3 %

Procedure:
To a solution of 2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) (10 g) in tetrahydrofuran (230 ml) was added portionwise diphenyldiazomethane (12.76 g) under cooling in an ice bath and stirring and the mixture was stirred for 2 hours at room temperature. The resulting mixture was concentrated under reduced pressure until an crystallization began and stood overnight at room temperature. The precipitates were collected by filtration, washed with ethyl acetate and dried to give diphenylmethyl 2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetate (syn isomer) (5.41 g), mp. 175° to 180° C. (dec.). The filtrate and the washings were combined and evaporated to dryness. The residue was crystallized from methylene chloride-diethyl ether (4:1) to give further crops of the object compound (6.7 g), which was recrystallized from acetonitrile.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:5]=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[N+:43]([O-:45])=[O:44])=[O:34].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N+:43]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[CH2:36][O:35][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][O:1][C:2]1[CH:14]=[C:6]([C:7]([O:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([O-:45])=[O:44]
Reactant: O=C(CCCCCCCCCCBr)OCc1ccccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)c1cc(O)cc(C(=O)OC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)c1cc(OCCCCCCCCCCC(=O)OCc2ccccc2[N+](=O)[O-])cc(C(=O)OC(C)(C)C)c1

Procedure:
Previously prepared di-tert-butyl 5-hydroxyisophthalate (0.597 g, 2.03 mmol) and previously prepared 2-nitrobenzyl 11-bromoundecanoate (1.62 g, 4.06 mmol) were combined and dissolved in acetone (50 mL), producing a light yellow solution. Potassium carbonate (0.505 g, 3.65 mmol) was added and the mixture was heated to reflux for 40 hours. The mixture was filtered using vacuum filtration, and the solvent was removed from the filtrate by rotovap. The crude product was purified with silica gel column chromatography with CH2Cl2: hexanes (v/v 5:1) as eluent to afford the product as a yellow oil, which was dried by vacuum. Yield: 0.152 g (12.2%). 1H-NMR (CDCl3) δ (ppm): 8.2 (s, 1H, Ar) 8.1 (d, 1H, Ar), 7.7 (s, 2H, Ar) 7.6 (t, 1H, Ar), 7.5 (d, 1H, Ar), 7.4 (t, 1H, Ar), 5.5 (s, 2H, O—CH2), 4.0 (t, 2H, CH2—O), 2.4 (t, 2H, CH2—C═O), 1.8 (m, 2H, CH2), 1.6 (m, 2H, CH2), 1.6 (s, 18H, CH3), 1.4 (m, 2H, CH2), 1.3 (m, 10H, CH2). 13C-NMR (CDCl3) δ (ppm): 173.5, 165.4, 159.3, 147.9, 134.1, 133.7, 132.7, 129.4, 129.1, 125.4, 122.9, 119.5, 81.9, 68.8, 63.1, 34.5, 29.9, 29.8, 29.7, 29.6, 29.5, 29.4, 28.5, 26.3, 25.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:19]3[CH2:20][CH2:21][CH2:22][CH:12]2[C:13]2[CH:14]=[N:15][NH:16][C:17]=2[CH2:18]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:23](Cl)(=[O:27])[CH:24]([CH3:26])[CH3:25]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:19]3[CH2:20][CH2:21][CH2:22][CH:12]2[C:13]2[C:17]([CH2:18]3)=[N:16][N:15]([C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[CH:14]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Cl
Reactant: O=S(=O)(c1ccc(Cl)cc1)N1C2CCCC1c1cn[nH]c1C2
Product: CC(C)C(=O)n1cc2c(n1)CC1CCCC2N1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
Prepared by acylation of 12-(4-chloro-benzenesulfonyl)-4,5,12-triaza-tricyclo[6.3.1.02,6]-dodeca-2(6),3-diene using isobutyryl chloride.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl[C:22]1[CH:30]=[C:29]2[C:25]([C:26]([CH3:33])([CH3:32])[C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:22]4[CH:30]=[C:29]5[C:25]([C:26]([CH3:33])([CH3:32])[C:27](=[O:31])[NH:28]5)=[CH:24][CH:23]=4)[N:19]=3)[CH:14]=[CH:15][N:16]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CC1(C)C(=O)Nc2cc(Cl)ccc21
Reactant: CS(=O)(=O)c1ccc(-c2nccn3nc(N)nc23)cc1
Product: CC1(C)C(=O)Nc2cc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)nccn4n3)ccc21

Procedure:
8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine, synthesized as described earlier, is coupled with 6-chloro-3,3-dimethyl-1,3-dihydro-indol-2-one under Buchwald Hartwig conditions using general procedure 2.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][CH2:6][CH:7]1[CH2:20][C:11]2=[N:12][C:13]3[NH:14][CH2:15][CH2:16][CH2:17][C:18]=3[CH:19]=[C:10]2[CH2:9][CH2:8]1)C.[OH-].[Na+]>C1COCC1.O>[NH:14]1[C:13]2[N:12]=[C:11]3[CH2:20][CH:7]([CH2:6][CH2:5][C:4]([OH:21])=[O:3])[CH2:8][CH2:9][C:10]3=[CH:19][C:18]=2[CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)CCC1CCc2cc3c(nc2C1)NCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCC1CCc2cc3c(nc2C1)NCCC3

Procedure:
A solution of 14-3 (0.180 g, 0.62 mmol) and NaOH (1.24 mL of a 1N soln, 1.24 mmol) in THF/H2O (5 mL/5 mL) was stirred at room temperature for 12 h. The solution was concentrated. The residue was triturated with Et2O to give 14-4.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]#[C:6][C:7]1[CH:15]=[CH:14][C:10]2[O:11][CH2:12][O:13][C:9]=2[CH:8]=1)[CH3:2].[C:17]([O:21][C:22]([N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([CH2:34][CH2:35][O:36][C:37]3[CH:38]=[C:39]4[C:43](=[CH:44][CH:45]=3)[NH:42][CH:41]=[CH:40]4)[N:32]=2)[CH2:27][CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([CH2:34][CH2:35][O:36][C:37]3[CH:38]=[C:39]4[C:43](=[CH:44][CH:45]=3)[N:42]([C:6]([C:7]3[CH:15]=[CH:14][C:10]5[O:11][CH2:12][O:13][C:9]=5[CH:8]=3)=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[O:16])[CH:41]=[CH:40]4)[N:32]=2)[CH2:27][CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOC(=O)C#Cc1ccc2c(c1)OCO2
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4[nH]ccc4c3)nc21
Product: CCOC(=O)C=C(c1ccc2c(c1)OCO2)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21
Yield: 39 %

Procedure:
The title compound was synthesized from benzo[1,3]dioxol-5-yl-propynoic acid ethyl ester and 7-[2-(1H-Indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using the procedure described in Example 16, step (c1), in 39% yield as an E/Z mixture. 1H NMR (CDCl3) δ 7.32 (d, 1H, J=7.6 Hz), 7.10-7.04 (m, 2H), 7.00-6.90 (m, 2H), 6.85-6.71 (m, 4H), 6.56-6.49 (m, 1H), 6.10 (s, 0.6H), 6.04 (s, 0.4H), 6.03 (s, 0.8H), 6.00 (s, 1.2H), 4.40-4.35 (m, 2H), 4.13 (q, 0.8H, J=7.1 Hz), 3.98 (q, 1.2H, J=7.1 Hz), 3.76 (t, 2H, J=5.9 Hz), 3.20 (t, 2H, 6.8 Hz), 2.73 (t, 2H, 6.7 Hz), 1.95-1.89 (m, 2H), 1.519 (s, 5.4H), 1.516 (s, 3.6 H), 1.22 (t, 1.2H, J=7.1 Hz), 1.01 (t, 1.8H, J=7.1 Hz). Mass Spectrum (LCMS, ESI) calculated for C30H29N3O5 512.3 (M-Boc +1); found 512.3.
Reaction SMILES: [CH:1]12[NH:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([NH2:13])=[CH:3][C:2]2=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C@@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]2[NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[C:18]([Cl:33])=[CH:17][N:16]=1>>[CH:1]12[NH:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([NH:13][C:15]3[N:20]=[C:19]([NH:21][C@@H:22]4[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]4[NH:28][S:29]([CH3:32])(=[O:30])=[O:31])[C:18]([Cl:33])=[CH:17][N:16]=3)=[CH:3][C:2]2=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)C1CCC(C2)N1
Product: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Nc2ccc3c(c2)C2CCC(C3)N2)ncc1Cl

Procedure:
Following a procedure analogous to 61e, 12-Aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamine (200 mg, 1.15 mmol) and N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (389 mg, 1.15 mmol) were converted to the title compound isolated as an ivory solid (430 mg, 78%) %), isolated as a mixture of diastereomers. 1HNMR (400 MHz, DMSO-d6) δ 9.1 (s, 1H), 7.9 (s, 1H), 7.5 (s, 0.5H), 7.4 (s, 0.5H), 7.3 (appt t, 1H, J=7.8 Hz), 7.2 (d, 0.5H, J=8.1 Hz), 7.1 (d, 0.5H, J=8.3 Hz), 6.9 (d, 1H, J=8.3 Hz), 6.7 (d, 1H, J=7.3 Hz), 4.1 (d, 0.5H, J=4.0 Hz), 4.0 (d, 0.5H, J=3.4 Hz), 3.9-3.8 (m, 1H), 3.7 (m, 1H), 3.4 (m, 1H), 3.0 (d, 1H, J=4.5 Hz), 2.9 (d, 3H, J=7.3 Hz), 2.5-2.4 (m, 2H), 2.1-2.0 (m, 2H), 1.9 (m, 2H), 1.8-1.6 (m, 3H), 1.5-1.2 (m, 5H); MS (m/e) 477 (M+1); mp 150-154° C.