Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Br:13]Br>C(Cl)Cl>[Br:13][C:6]1[CH:5]=[C:4]([O:3][C:2]([F:11])([F:12])[F:1])[CH:9]=[CH:8][C:7]=1[OH:10]
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: BrBr
Solvent: ClCCl
Product: Oc1ccc(OC(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 20 h
Yield: 56.4 %

Procedure:
A solution of 1.78 g (10.0 mmol) of 4-trifluoromethoxyphenol in 5 mL of CH2Cl2 at 0° C. was treated with a solution of 2.20 g (14.0 mmol) of bromine in 5 mL of CH2Cl2. The cooling bath was removed and the resulting mixture was stirred at rt for 20 h. The reaction quenched with 5% aqueous Na2S2O3 and the resulting mixture was partitioned between 150 mL of ether and 150 mL of H2O. The layers were separated; the organic layer was dried over MgSO4 and concentrated in vacuo. Flash chromatography on 125 g of silica gel using 9:1 v/v hexanes/CH2Cl2 as the eluant afforded 1.45 g (56%) of the title compound as an oil. 1H NMR (500 MHz, CDCl3): δ 5.50 (s, 1H), 7.02 (d, J=9.0, 1H), 7.12 (dd, J=9.0, 2.0, 1H), 7.37 (d, J=2.0, 1H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([O:26][C@@H:27]1[C@@:31]2([CH2:51][O:52][C@H:28]1[C@H:29]([N:53]1[C:69]3[N:68]=[CH:67][N:66]=[C:57]([NH:58][CH2:59][C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=4)[C:56]=3[N:55]=[CH:54]1)[O:30]2)[CH2:32][O:33][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[O:70]1CCCC1>>[CH2:19]([O:26][C@@H:27]1[C@@:31]2([CH2:51][O:52][C@H:28]1[C@H:29]([N:53]1[C:69]3[N:68]=[CH:67][N:66]=[C:57]([NH:58][C:59](=[O:70])[C:60]4[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=4)[C:56]=3[N:55]=[CH:54]1)[O:30]2)[CH2:32][OH:33])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)[Si](OC[C@@]12CO[C@@H]([C@H](n3cnc4c(NCc5ccccc5)ncnc43)O1)[C@@H]2OCc1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: O=C(Nc1ncnc2c1ncn2[C@@H]1O[C@@]2(CO)CO[C@@H]1[C@@H]2OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Tetrabutylammonium fluoride (1.0 M in THF, 1.0 ml, 1.0 mmol) was added, at room temperature, to a tetrahydrofuran solution (7.0 ml) of Compound 42 (173.6 mg, 0.244 mmol), and the mixture was stirred for 25 minutes at room temperature. The reaction mixture was distilled under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (CHCl3-MeOH, 15:1) to obtain a white powder, Compound 43 (115.4 mg, 0.244 mmol, quant.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[CH:3]=1.[NH2:19][C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:19][C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[CH:3]=1
Reactant: C[C@H](Nc1cc(Cl)cc(Cl)n1)c1ccc(F)cc1
Reactant: Nc1cnccn1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@H](Nc1cc(Cl)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 19 h
Yield: 73.9 %

Procedure:
To 734 mg of (S)-4,6-dichloro-N-[1-(4-fluorophenyl)ethyl]pyridine-2-amine, 343 mg of 2-aminopyrazine, 1.39 g of tripotassium phosphate, 190 mg of 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene and 170 mg of tris(dibenzylideneacetone)(chloroform)dipalladium was added 17 ml of 1,4-dioxane, the mixture was subjected to degassing and was substituted with argon, and was stirred at 100° C. for 19 hours. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 654 mg of the objective compound as brown powder.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:13]C(=O)OC(C)(C)C)[CH:7]=[C:8]([C:10]([OH:12])=[O:11])[CH:9]=1)([OH:3])=[O:2].O.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28]([OH:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[C:22]1([CH3:32])[CH:23]=[CH:24][C:25]([S:28]([OH:31])(=[O:29])=[O:30])=[CH:26][CH:27]=1.[NH2:13][C:6]1[CH:7]=[C:8]([C:10]([O:12][CH2:1][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:11])[CH:9]=[C:4]([CH:5]=1)[C:1]([O:3][CH2:32][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(C(=O)O)cc(C(=O)O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1cc(C(=O)OCc2ccccc2)cc(C(=O)OCc2ccccc2)c1
Temperature: 80 °C

Procedure:
Carbamate (7.61) (3.75 g, 8 mmol) and p-toluenesulfonic acid monohydrate (1.5 g, 8 mmol) were dissolved in toluene (55 ml) and heated at 80° C. for 45 min. A white precipitate formed during the reaction. This was collected by filtration, washed with hexanes, and dried to give the title compound which recrystallised from toluene as a white crystalline solid (needles) (3.91 g, 96%). M.p. 200°-201° C.; m/z (+ES) 362 (100%, M+H+); δH (250 MHz, d6 -DMSO) 2.5 (3H, s, CH3), 5.35 (4H, s, 2×Ar--CH2), 7.05 (2H, d, J 7.5 Hz 2×Ar--H), 7.25-7.60 (12H, m, 12×Ar--H), 7.75 (2H, d, 2×Ar--H), 8.00 (1H, s, Ar--H); δC (62.5 MHz, δ6-DMSO) 21.24, 67.08, 118.13, 121.94, 122.61, 125.95, 128.63, 128.74, 129.04, 131.52, 136.31, 138.40, 143.88, 145.65, 165.84; RF 0.15 [DCM/methanol (9:1).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:14])[C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[OH:13])[CH2:3][CH2:2]1.[O:15]1[CH2:17][C@H:16]1[CH2:18]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:14])[C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[O:13][CH2:18][CH:16]2[CH2:17][O:15]2)[CH2:2][CH2:3]1
Reactant: O=C(NC1CC1)c1ccc(F)cc1O
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(F)cc1OCC1CO1
Yield: 59.7 %

Procedure:
A mixturte of N-cyclopropyl-4-fluoro-2-hydroxybenzamide (195 mg, 1.0 mmol), (2S)-oxiran-2-ylmethyl3-nitrobenzenesulfonate (259 mg, 1.0 mmol) and Cs2CO3 (390 mg, 1.2 mmol) in DMF (5 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (0-30% ethylacetate in petroleum ether) to give the subtitled compound (150 mg).
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[N:8]1([CH:14]2[CH2:19][CH2:18][CH:17]([O:20][C:21]3[C:22]4[C:23]5[CH2:24][NH:25][CH2:26][CH2:27][C:28]=5[S:29][C:30]=4[N:31]=[CH:32][N:33]=3)[CH2:16][CH2:15]2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C(Cl)(=O)C>C(Cl)Cl>[N:8]1([CH:14]2[CH2:15][CH2:16][CH:17]([O:20][C:21]3[C:22]4[C:23]5[CH2:24][N:25]([C:3](=[O:5])[CH3:2])[CH2:26][CH2:27][C:28]=5[S:29][C:30]=4[N:31]=[CH:32][N:33]=3)[CH2:18][CH2:19]2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: O=C(O)C(F)(F)F
Reactant: c1nc(OC2CCC(N3CCOCC3)CC2)c2c3c(sc2n1)CCNC3
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)N1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c2C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 25.9 %

Procedure:
To a solution of 3-[[4-(morpholin-4-yl)cyclohexyl]oxy]-8-thia-4,6,12-triazatricyclo[7.4.0.0[2,7]]trideca-1(9),2 (7),3,5-tetraene trifluoroacetate (100 mg, crude) in DCM (20 mL) was added TEA (108 mg, 1.07 mmol). The solution was stirred for 10 min at 0° C. under nitrogen. Then acetyl chloride (41.9 mg, 0.53 mmol) was added to the reaction solution at this temperature and the resulting solution was stirred for 1.5 h at room temperature. The reaction was then quenched by the addition of ethanol and concentrated under vacuum. The crude product was purified by preparative HPLC under the following conditions (Waters): Column: Xbridge Prep C18, 5 μm, 19*50 mm; mobile phase: water with 0.05% NH4HCO3 and CH3CN (10% CH3CN up to 35% in 11 min, up to 95% in 1.5 min, down to 10% in 1.5 min); detector: UV 254/220 nm. After concentration in vacuo and lyophilization overnight, the corresponding 1-(3-[[4-(morpholin-4-yl)cyclohexyl]oxy]-8-thia-4,6,12-triazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-12-yl)ethan-1-one (22.1 mg) was obtained as a white solid. MS (ES): m/z 417 (M+H)+ and 429 (M+Na)+. 1H NMR (300 MHz, CD3OD): δ 8.54 (1H, s), 5.33-5.23 (1H, m), 4.91 (2H, s), 3.97, 3.90 (2H, t, t), 3.76-3.69 (4H, m), 3.05, 2.95 (2H, t, t), 2.67-2.58 (4H, t), 2.34-2.25 (3H, m), 2.25, 2.23 (3H, s, s), 2.10 (2H, d), 1.74-1.45 (4H, m).
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8][C:9]([C:11]2[CH:12]=[CH:13][C:14](=[O:17])[NH:15][CH:16]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:25][OH:26].C([O-])(O)=O.[Na+]>>[OH:26]/[N:25]=[C:9](/[C:11]1[CH:12]=[CH:13][C:14](=[O:17])[NH:15][CH:16]=1)\[CH2:8][CH:7]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CC(c1ccccc1)c1ccccc1)c1ccc(=O)[nH]c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=c1ccc(/C(CC(c2ccccc2)c2ccccc2)=N/O)c[nH]1

Procedure:
In analogy to example 151, step 3, 5-(3,3-diphenyl-propionyl)-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing less than 10% of the corresponding Z isomer as a colorless solid, MS (ESI−): m/z=317.1 [M−H]−.
Reaction SMILES: [CH:1]1[C:6]2=[C:7]3[C:16](=[CH:17][CH:18]=[C:5]2[CH:4]=[CH:3][CH:2]=1)[N:15]=[C:14]1[C:9]([C:10]([C:19]([OH:21])=[O:20])=[CH:11][CH:12]=[CH:13]1)=[N:8]3.[CH:22]1C2=C3C(=CC=C2C=CC=1)N=C1C(C=CC=C1C(O)=O)=N3>CO.C(Cl)(=O)C>[CH3:22][O:20][C:19]([C:10]1[C:9]2[C:14](=[N:15][C:16]3[C:7]([N:8]=2)=[C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=[CH:18][CH:17]=3)[CH:13]=[CH:12][CH:11]=1)=[O:21]
Reactant: O=C(O)c1cccc2nc3c(ccc4ccccc43)nc12
Reactant: O=C(O)c1cccc2nc3ccc4ccccc4c3nc12
Solvent: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1cccc2nc3ccc4ccccc4c3nc12

Procedure:
The mixture of benzo[a]phenazine-11-carboxylic acid (II.20) and benzo[a]phenazine-8-carboxylic acid (885 mg), prepared as described in Reference Example 1L above, was heated to reflux in a mixture of methanol (40 mL) and acetyl chloride (920 μL) for 90 minutes. The reaction mixture was then cooled slowly to yield the title compound as a single isomer which was collected by filtration (377 mg).
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N+:7]([O-])=[C:6]([OH:15])[C:5]1=[O:16])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6](=[O:15])[C:5]1=[O:16])([CH3:3])[CH3:2]
Reactant: CC(C)n1c(=O)c(O)[n+]([O-])c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)n1c(=O)c(=O)[nH]c2ccccc21

Procedure:
A solution of 3,4-dihydro-4-isopropyl-2-hydroxy-3-oxo-quinoxaline-1-oxid (15.5 g, 0.07 mole) and triphenylphosphine (26.2 g, 0.1 mole) in dimethylformamide (DMF) (100 ml) was stirred at 120° C. for 12 hours, whereafter the solvent was evaporated in vacuo. The residue was stirred in methylene chloride (150 ml) whereby the formed triphenyl phosphine oxid was dissolved. The product was then collected as pale crystals by filtration followed by wash with methylene chloride. M.p. 227°-228° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:14][CH2:15][O:16][CH2:17][C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:4]2[C:9]([CH3:10])=[C:8]([CH3:11])[N:7]=[C:6]([NH2:12])[C:5]=2[N:13]=1>[Pd].CO>[CH3:1][C:2]1[N:3]([CH2:14][CH2:15][O:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:4]2[C:9]([CH3:10])=[C:8]([CH3:11])[N:7]=[C:6]([NH2:12])[C:5]=2[N:13]=1
Reactant: Cc1nc(N)c2nc(C)n(CCOCC#Cc3ccccc3)c2c1C
Agent: [Pd]
Solvent: CO
Product: Cc1nc(N)c2nc(C)n(CCOCCCc3ccccc3)c2c1C
Reaction time: 4 h
Yield: 57.2 %

Procedure:
2,6,7-Trimethyl-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]pyridin-4-amine (0.55 g, 1.645 mmol) from Part I of Example 7 was combined with 10% palladium on carbon (0.10 g) in a Parr reactor. Methanol (30 mL) was added to the resulting mixture under a nitrogen purge, and then the mixture was placed under hydrogen at a pressure of 310 kPa for 4 hours. The resulting reaction mixture was filtered through a layer of Celite™ filter agent, and the filtrate was concentrated under reduced pressure to a clear oil. The oil was dissolved in 5% methanol in diethyl ether (˜50 mL), and 1M hydrochloric acid in diethyl ether (1.7 mL) was added to the resulting solution. Volatiles were removed under reduced pressure, and the resulting solids were dissolved in water. The aqueous solution was stirred for 10 minutes when the product oiled out of solution. The aqueous portion was washed with dichloromethane (3×). The combined organic portions were washed with water (2×) and brine (3×), dried with magnesium sulfate, filtered, and concentrated to a glassy oil under reduced pressure. The oil was triturated with diethyl ether. The solids that formed after 10 minutes of stirring were filtered off and dried for 18 hours to provide 0.3185 g of 2,6,7-trimethyl-1-[2-(3-phenylpropoxy)ethyl]-1H-imidazo[4,5-c]pyridin-4-amine, m.p. 118.1–119.0° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[C:24]#[N:25])=[CH:4][C:5](=[O:16])[N:6]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:7]=1.FC(F)(F)S(O[CH2:32][CH:33]([CH3:35])[CH3:34])(=O)=O>>[Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[C:24]#[N:25])=[CH:4][C:5](=[O:16])[N:6]([CH:8]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:7]=1
Reactant: CC(C)COS(=O)(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Cn1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O
Product: CC(C)CC(C(=O)OC(C)(C)C)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
416 mg (1.00 mmol) of tert-butyl [5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]acetate in the presence of 0.95 ml (0.95 mmol, 1.2 eq.) of bis(trimethylsilyl)lithium amide (1M in THF) and 326 mg (1.58 mmol, 2.0 eq.) of isobutyl trifluoromethanesulphonate were reacted according to General Method 7B. Yield: 139 mg (purity 85%, 34% of theory)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:3]=1.[OH:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(CC)CC)C>C(O)CCC>[Cl:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[N:7]=[C:2]([N:30]3[CH2:31][CH2:32][CH:27]([OH:26])[CH2:28][CH2:29]3)[CH:3]=[C:4]([NH:18][CH:19]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[N:5]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: COc1ccc(Nc2nc(Cl)cc(NC3CCCCCC3)n2)cc1Cl
Reactant: OC1CCNCC1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: COc1ccc(Nc2nc(NC3CCCCCC3)cc(N3CCC(O)CC3)n2)cc1Cl
Yield: 23 %

Procedure:
To a solution of compound 6-chloro-N2-(3-chloro-4-methoxy-phenyl)-N4-cycloheptyl-pyrimidine-2,4-diamine (0.15 g, 0.39 mmol) in 1-butanol (5 mL) was added 4-hydroxypiperidine (0.12 g, 1.18 mmol) at 25° C. with stirring. To this triethylamine (0.43 mL, 3.15 mmol) was added dropwise and the mixture was stirred at 25° C. for 30 minutes. This was heated and refluxed for 12 hours under nitrogen atmosphere. The mixture was concentrated under vacuum, diluted with cold water (30 mL) and extracted with ethyl acetate (2×30 mL). The organic layers were collected, combined, washed with brine (30 mL), dried over anhydrous sodium sulphate, and concentrated under vacuum to give the desired compound. Yield: 23%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C:17](=[O:40])[NH:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36].[CH2:41]([O:43][C:44]1[C:45](=O)[C:46](=[O:51])[C:47]=1[O:48]CC)[CH3:42]>C(Cl)Cl>[CH2:41]([O:43][C:44]1[C:47](=[O:48])[C:46](=[O:51])[C:45]=1[NH:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C:17](=[O:40])[NH:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])[CH3:42]
Reactant: CC(C)(C)OC(=O)NCCCOCCOCCOCCCNC(=O)CNCCCOCCOCCOCCCN
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: ClCCl
Product: CCOc1c(NCCCOCCOCCOCCCNCC(=O)NCCCOCCOCCOCCCNC(=O)OC(C)(C)C)c(=O)c1=O

Procedure:
0.25 g of tert-butyl 30-amino-15-oxo-4,7,10,21,24,27-hexaoxa-14,17-diazatriacont-1-ylcarbamate is dissolved in 1.5 ml of CH2Cl2. 57.5 μl of 3,4-diethoxy-3-cyclobutene-1,2-dione are added.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][N:5]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][C:14]([O:16][C:17]3[CH:18]=[C:19]([CH:24]=[C:25]([O:27][C@H:28]4[CH2:32][CH2:31][O:30][CH2:29]4)[CH:26]=3)[C:20]([O:22]C)=[O:21])=[CH:15][C:8]=2[O:7][CH2:6]1>O.C1COCC1>[CH3:4][N:5]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][C:14]([O:16][C:17]3[CH:18]=[C:19]([CH:24]=[C:25]([O:27][C@H:28]4[CH2:32][CH2:31][O:30][CH2:29]4)[CH:26]=3)[C:20]([OH:22])=[O:21])=[CH:15][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)c1cc(Oc2ccc3c(c2)OCN(C)C3=O)cc(O[C@H]2CCOC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN1COc2cc(Oc3cc(O[C@H]4CCOC4)cc(C(=O)O)c3)ccc2C1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.1 %

Procedure:
Lithium hydroxide monohydrate (13 mg, 0.3 mmol) in water (2.5 mL) was added to a solution of methyl 3-[(3-methyl-4-oxo-3,4-dihydro-2H-1,3-benzoxazin-7-yl)oxy]-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate (0.12 g, 0.3 mmol) in THF (5 mL) and stirred at RT for 20 hours. The THF was removed in vacuo and the aqueous layer was washed with ethyl acetate (50 mL) to remove any impurities. The aqueous layer was acidified and extracted into ethyl acetate (2×50 mL), washed with brine (50 mL), dried (MgSO4), and the solvent removed in vacuo to give the desired compound as a white solid (110 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:4]=2[O:3]1.CN(C=O)C.C1C(=O)N([Br:27])C(=O)C1>C(Cl)(Cl)Cl>[Br:27][C:10]1[C:11]([CH3:13])=[CH:12][C:4]2[O:3][C:2]([CH3:14])([CH3:1])[C:7](=[O:8])[NH:6][C:5]=2[CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(c1)OC(C)(C)C(=O)N2
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cc1cc2c(cc1Br)NC(=O)C(C)(C)O2
Reaction time: 4 h
Yield: 58 %

Procedure:
A solution of Compound 1A (4.24 g, 22.2 mmol) in 150 mL of chloroform was treated with 5 mL of dry DMF followed by 4.4 g (24.4 mmol) of NBS at room temperature. After 4 hours, the reaction was quenched with 150 mL of a saturated sodium thiosulfate solution. The aqueous layer was extracted with chloroform and the combined organic layers were dried with magnesium sulfate, filtered, and excess solvent removed on the rotary evaporator. The crude product was purified via silica gel chromatography (5% EtOAc/Hexanes) to yield 3.48 g of brominated product (58%). MS (electrospray): mass calculated for C11H12BrNO2, 269.01; m/z found 268, [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH2:9][CH2:8][N:7]4[CH2:15][CH2:16][CH2:17][CH:6]4[C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:20][C:21]1([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:23][O:22]1>CN(C=O)C>[CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[N:11]([CH2:20][C:21]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)([OH:22])[CH3:23])[C:10]3[CH2:9][CH2:8][N:7]4[CH2:15][CH2:16][CH2:17][CH:6]4[C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCN1CC3
Reactant: CC1(c2cccnc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2cccnc2)CCN2CCCC12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 33.5 %

Procedure:
9-Methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6-diaza-cyclopenta[c]fluorene (150 mg, 0.66 mmol) was dissolved in DMF (1 mL), sodium hydride (47 mg, 1.98 mmol) was added and the mixture was stirred at RT for 5 min. 3-(2-Methyl-oxiranyl)-pyridine (143 mg, 1.06 mmol) was added dropwise into the reaction mixture and stirred at RT for 2 h. The reaction was monitored by TLC and LCMS. After consumption of starting material, the reaction mixture was quenched with ice cold water (20 mL) and extracted with EtOAc (2×100 mL). The combined organic layer was washed with water (2×100 mL), dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel 100-200 mesh, Eluent: −15% MeOH in DCM) to obtain 80 mg of 1-(9-methyl-1,2,3,4,5,10c-hexahydro-3a,6-diaza-cyclopenta[c]fluoren-6-yl)-2-pyridin-3-yl-propan-2-ol. 1H NMR (CD3OD, HCl salt) δ (ppm): 8.66 (dd, 2H), 8.56 (s, 1H), 7.92 (t, 1H), 7.20 (s, 1H), 6.77 (t, 2H), 5.04 (t, 1H), 3.75 (dd, 2H),3.72 (m, 2H), 3.6 (m, 1H), 3.44 (m, 2H), 3.22 (d, 1H), 2.75 (m, 1H), 2.73 (s, 3H), 2.16 (m, 3H), 1.8 (s, 3H). Separation by chiral HPLC provided enantiomers II-127a-b.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([C:8]2[NH:9][C:10]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](NC)[N:18]=3)=[C:11]([I:16])[C:12]=2[C:13]([NH2:15])=[O:14])[CH:7]=1.[C:26](C1C=CC(N2CCN(C)CC2)=CC=1)#C>C(#N)C.[Cu]I.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>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([C:8]2[NH:9][C:10]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([CH3:26])[N:18]=3)=[C:11]([I:16])[C:12]=2[C:13]([NH2:15])=[O:14])[CH:7]=1
Reactant: C#Cc1ccc(N2CCN(C)CC2)cc1
Reactant: CNc1nccc(-c2[nH]c(-c3cc(Cl)ccc3C)c(C(N)=O)c2I)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Product: Cc1nccc(-c2[nH]c(-c3cc(Cl)ccc3C)c(C(N)=O)c2I)n1
Yield: 90.6 %

Procedure:
2-(5-Chloro-2-methylphenyl)-4-iodo-5-[2-(methylamino)pyrimidin-4-yl]-1H-pyrrole-3-carboxamide (47 mg, 0.1 mmol) in dry ACN (1 mL) was treated with 1-(4-ethynylphenyl)-4-methylpiperazine (40 mg, 0.2 mmol) and TEA (0.14 mL, 1 mmol). The flask was stirred and purged with nitrogen and then solid CuI (1.0 mg, 0.005 mmol) and Pd(Ph3P)2Cl2 (3.5 mg, 0.005 mmol) were added. The reaction was refluxed for 2 h, then the solvent was evaporated. The crude was purified by flash chromatography on silica gel (DCM/MeOH/7N NH3 in MeOH 95/4/1) to afford the title compound (41 mg, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:33])[NH:22][C@@H:23]([CH2:28][C:29]([O:31]C)=[O:30])[C:24]([O:26]C)=[O:25])=[CH:16][CH:15]=1.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:33])[NH:22][C@@H:23]([CH2:28][C:29]([OH:31])=[O:30])[C:24]([OH:26])=[O:25])=[CH:16][CH:15]=1
Reactant: COC(=O)C[C@H](NC(=O)Nc1ccc(C2CN(C)Cc3c(Cl)cc(Cl)cc32)cc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(NC(=O)N[C@@H](CC(=O)O)C(=O)O)cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of (2S)-dimethyl 2-(3-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)ureido)succinate (100 mg, 0.20 mmol, 1.00 equiv) in methanol (5 mL), water (1 mL), sodium hydroxide (30 mg, 0.75 mmol, 3.71 equiv). The resulting solution was stirred for 3 h at room temperature and then concentrated under vacuum. The pH of the solution was adjusted to 3-4 with 1N hydrochloric acid. The solids were collected by filtration and the residue was lyophilized. This resulted in 16 mg (16%) of (2S)-2-(3-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)ureido)succinic acid as a white solid. 1H-NMR (300 MHz, DMSO, ppm): δ 8.98 (s, 1H), 7.66 (s, 1H), 7.38-7.44 (d, J=17.1 Hz, 2H), 7.12-7.15 (d, J=8.4 Hz, 2H), 6.78 (s, 1H), 6.60-6.63 (s, 1H), 4.48-4.54 (m, 4H), 3.63-3.66 (s, 2H), 3.01 (s, 1H), 2.51-2.84 (m, 2H). MS (ES, m/z): 466 [M+H]+.