Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.[CH2:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1Br)[CH3:25]>>[CH2:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:6]1[CH:5]=[CH:4][C:3]([C:17]2[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=2)=[C:2]([F:1])[CH:7]=1)[CH3:25]
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: CCc1ccccc1Br
Product: CCc1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 2-ethylbromobenzene. MS (ESI): mass calcd. for C18H16FN3, 293.13; m/z found, 294.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.03 (d, J=1.3, 1H), 7.92 (m, 1H), 7.36 (d, J=3.9, 2H), 7.32-7.19 (m, 4H), 6.71 (s, 2H), 2.60 (q, J=7.5, 2H), 1.06 (t, J=7.5, 3H).
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:3]=1[C:4]([CH:6](C(OCC)=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].O>O1CCOCC1>[F:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:3]=1[C:4](=[O:5])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(F)cc1F
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CC(=O)c1cc(F)c(F)cc1F
Temperature: 102 °C
Reaction time: 7 h
Yield: 58.7 %

Procedure:
A solution of 23.8 g of (2,4,5-trifluorobenzoyl)propanedioic acid, diethyl ester, 2.7 ml of water and 740 ml of p-dioxane was placed in an oil bath and stirred at 102° C. for 7 hours. The solution was then evaporated to dryness, heptane was added and the mixture refrigerated overnight. The resulting crystals were collected, washed with 10 ml of cold heptane and dried, giving 10.8 g of 2,4,5-trifluoro-β-oxobenzenepropanoic acid, ethyl ester.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:22]([O:24]C(C)(C)C)=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[CH2:16][C:17]1([CH3:20])[N:19]=[N:18]1)=O)(C)(C)C.[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30]>>[F:32][C:31]([F:34])([F:33])[C:29]([OH:35])=[O:30].[CH3:20][C:17]1([CH2:16][C:15]([NH:14][CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]([C:22]([OH:24])=[O:23])[NH2:8])=[O:21])[N:18]=[N:19]1
Reactant: CC1(CC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)N=N1
Solvent: O=C(O)C(F)(F)F
Product: CC1(CC(=O)NCCCC[C@H](N)C(=O)O)N=N1
Yield: 100 %

Procedure:
A solution of the lysine derivative 9 (174 mg, 0.44 mmol) in TFA (1.4 mL) was stirred at room temperature for 45 minutes and then evaporated in vacuo. The residue was co-evaporated four times with MeOH (4×5 mL) and to give the title compound 10 (160 mg, ˜100%) as a brown oil that was used in the subsequent biochemical studies without any further purification.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=2[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4]1)[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=2[N:33]2[CH:37]=[CH:36][CH:35]=[N:34]2)[C:21]([Cl:38])=[CH:20][N:19]=1>>[Cl:38][C:21]1[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=2[N:33]2[CH:37]=[CH:36][CH:35]=[N:34]2)=[N:23][C:18]([NH:14][C:11]2[CH:12]=[CH:13][C:8]3[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:9]=3[CH:10]=2)=[N:19][CH:20]=1
Reactant: CCN1CCN(CC)c2cc(N)ccc2C1
Reactant: COc1ccc(Nc2nc(Cl)ncc2Cl)c(-n2cccn2)c1
Product: CCN1CCN(CC)c2cc(Nc3ncc(Cl)c(Nc4ccc(OC)cc4-n4cccn4)n3)ccc2C1

Procedure:
The title compound was prepared from 1,4-Diethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-(4-methoxy-2-pyrazol-1-yl-phenyl)-amine in an analogous manner to example 730. Product was isolated as a tan solid (0.043 g, 39%). Mp 82-87° C. LCMS (m/e) 519 (M); 1H-NMR (DMSO, 400 MHz) δ 9.83 (s, 1H), 9.17 (s, 1H), 8.29 (s, 1H), 8.16-8.13 (d, 1H, J=8.59 Hz), 8.09 (s, 1H), 7.85 (s, 1H), 7.20 (s, 1H), 7.20-7.15 (br, 1H), 7.10-7.05 (br, 1H), 7.00-6.95 (q, 1H, J=7.08 Hz), 6.95-6.90 (br, 1H), 6.55 (s, 1H), 3.85 (s, 3H), 3.70-3.50 (br, 1H), 3.17-3.16 (d, 1H, J=5.30 Hz), 3.05-2.70 (m, 6H), 1.15-1.00 (m, 6H).
Reaction SMILES: [C:1]([CH:3]=[C:4]([NH:15][C:16](=[O:20])OCC)[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)#[N:2].[F:21][C:22]([F:28])([F:27])[C:23]([NH:25][NH2:26])=O.C(OCC)(=O)C.O>CN1C(=O)CCC1>[F:21][C:22]([F:28])([F:27])[C:23]1[N:2]=[C:1]2[N:26]([C:16]([OH:20])=[N:15][C:4]([C:5]3[CH:6]=[CH:7][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:9][CH:10]=3)=[CH:3]2)[N:25]=1
Reactant: CCOC(=O)NC(=CC#N)c1ccc(C(F)(F)F)cc1
Reactant: NNC(=O)C(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Oc1nc(-c2ccc(C(F)(F)F)cc2)cc2nc(C(F)(F)F)nn12
Temperature: 160 °C
Reaction time: 4 h

Procedure:
2.42 g (8.5 mmol) of ethyl {2-cyano-1-[4-(trifluoromethyl)phenyl]ethenyl}carbamate (Example 129A) and 1.09 g (8.5 mmol) of 2,2,2-trifluoroacetohydrazide are dissolved in NMP (10 ml) and stirred in a flask with a calcium chloride drying tube at an oil-bath temperature of 160° C. for 4 h. The reaction mixture is cooled to RT and ethyl acetate (150 ml) and water (100 ml) are added. The organic phase is separated off, dried with magnesium sulphate and concentrated. The residue is stirred with diethyl ether (25 ml), and the solid is filtered off and dried. 0.67 g (23% of theory) of the product is obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[Cl:18][C:19]1[C:25]([O:26][CH3:27])=[CH:24][C:22]([NH2:23])=[C:21]([CH3:28])[CH:20]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:18][C:19]1[C:25]([O:26][CH3:27])=[CH:24][C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]4[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=4[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])=[C:21]([CH3:28])[CH:20]=1
Reactant: N#Cc1cnc2cc3ccccc3cc2c1Cl
Reactant: COc1cc(N)c(C)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc(Nc2c(C#N)cnc3cc4ccccc4cc23)c(C)cc1Cl
Yield: 71 %

Procedure:
Following the procedure of Example 3, the reaction mixture of 141.8 mg (0.60 mmol) of 4-chlorobenzo[g]quinoline-3-carbonitrile, 102.9 mg (0.60 mmol) of 4-chloro-5-methoxy-2-methylaniline (can be prepared by the procedure disclosed in WO 85/01939, which is hereby incorporated by reference) and 57.8 mg (0.50 mmol) of pyridine hydrochloride in 8.0 mL of 2-ethoxyethanol is heated at 130–135° C. for 1.5 hours to yield the crude product. Purification of the crude product on preparative TLC (developing solvent: 95:5 methylene chloride/methanol) yields 159.3 mg (72.2%) of the pure product as a yellow solid, mp 195–197° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:3][C:4]([OH:6])=O.[CH2:12]([CH:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:21][NH2:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>CCCCCCC>[CH3:1][CH:2]([CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:3][C:4]([NH:22][CH2:21][CH:20]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:6]
Reactant: CCCCCCCCCCC(CN)CCCCCCCC
Reactant: CC(CC(=O)O)CC(C)(C)C
Solvent: CCCCCCC
Product: CCCCCCCCCCC(CCCCCCCC)CNC(=O)CC(C)CC(C)(C)C
Yield: 70.3 %

Procedure:
3.6 g of 3,5,5-trimethylhexanoic acid and 6.8 g of 2-octyldodecylamine were mixed together in the tube of a microwave machine (Maxidigest™ MX 350 from the company Prolabo; frequency 2450±50 MHz, modulable power 300 W). After irradiation for about 50 minutes at 170° C.±10° C., the reaction mixture was dissolved in heptane and then purified on silica. 7 g of the desired amide were obtained.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:19]2[CH2:24][CH2:23][C:22](=O)[CH2:21][CH:20]=2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:11][N:12]=1.[CH2:26]([NH2:28])[CH3:27].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl.C1COCC1.CS(C)=O>[CH2:26]([NH:28][CH:22]1[CH2:23][CH2:24][C:19]([C:5]2[N:6]=[C:7]([C:8]3[O:9][C:10]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)=[N:11][N:12]=3)[C:2]([NH2:1])=[N:3][CH:4]=2)=[CH:20][CH2:21]1)[CH3:27]
Reactant: Nc1ncc(C2=CCC(=O)CC2)nc1-c1nnc(-c2ccccc2)o1
Reactant: CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CCNC1CC=C(c2cnc(N)c(-c3nnc(-c4ccccc4)o3)n2)CC1
Reaction time: 0.08 h
Yield: 12.3 %

Procedure:
To a solution of 4-[5-amino-6-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]cyclohex-3-en-1-one (15 mg, 0.045 mmol) in DCE (500 μL) was added a solution of ethaneamine (34 μL, of 2 M, 0.07 mmol) in THF and the reaction mixture was stirred for 5 min. Thereafter Na(OAc)3BH (15 mg, 0.07 mmol) was added followed by addition of AcOH (3 mg, 3 μL, 0.05 mmol) and the reaction mixture was stirred for 2 h at room temperature. The crude material was dissolved in DMSO and purified via reverse phase HPLC using 1-99 MeOH/H2O (0.05% HCl modifier) to obtain 5-[4-(ethylamino)cyclohexen-1-yl]-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-amine (2 mg, 9%) as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.56 (s, 1H), 8.12 (d, J=7.9 Hz, 2H), 7.68 (d, J=7.0 Hz, 3H), 7.60 (s, 1H), 6.58 (s, 1H), 3.05 (dd, J=13.2, 6.6 Hz, 2H), 2.76 (m, 3H), 2.38 (m, 1H), 2.27 (d, J=10.9 Hz, 1H), 1.78 (m, 1H), 1.26 (t, J=7.2 Hz, 3H). LC/MS m/z 363.05 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].[N:39]1[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=1.CS(C)(=O)=O>O1CCOCC1>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14]([NH:45][C:42]3[CH:43]=[CH:44][N:39]=[CH:40][CH:41]=3)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Reactant: Nc1ccncc1
Agent: CS(C)(=O)=O
Solvent: C1COCCO1
Product: CS(=O)(=O)N1CCC[C@H](Nc2nc(Nc3ccncc3)ncc2-c2cnc3[nH]ccc3n2)C1

Procedure:
In a dioxane solution of ((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methanesulfonyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine derived from Example 84, step 1, pyridin-4-ylamine was used to displace the methylsulfone similar to examples above and the de-protection step was similar to step 5, Example 76, to give N*4*-((S)-1-methanesulfonyl-piperidin-3-yl)-N*2*-pyridin-4-yl-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidine-2,4-diamine. MS (ES+): 466.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:16])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH:13]([F:15])[F:14])[CH:8]=[N:7]2.[F:17][C:18]1([F:30])[O:22][C:21]2[CH:23]=[CH:24][CH:25]=[C:26](B(O)O)[C:20]=2[O:19]1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C.CCCCCC>COCCOC.O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:30][C:18]1([F:17])[O:19][C:20]2[CH:26]=[CH:25][CH:24]=[C:23]([C:2]3[CH:3]=[C:4]([CH3:16])[CH:5]=[C:6]4[C:11]=3[N:10]=[C:9]([O:12][CH:13]([F:15])[F:14])[CH:8]=[N:7]4)[C:21]=2[O:22]1
Reactant: OB(O)c1cccc2c1OC(F)(F)O2
Reactant: Cc1cc(Br)c2nc(OC(F)F)cnc2c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: Cc1cc(-c2cccc3c2OC(F)(F)O3)c2nc(OC(F)F)cnc2c1
Temperature: 25 °C

Procedure:
To a solution of the title compound of Step E (1.65 g, 5.73 mmol) in ethylene glycol dimethyl ether (25 mL) was added the title compound of Step F (1.73 g, 8.59 mmol), a solution of sodium carbonate (1.82 g, 17.2 mmol) in water (15 mL) and bis(triphenylphosphine) palladium (II) chloride (201 mg, 0.286 mmol). The mixture was heated at reflux overnight, then cooled to room temperature and poured into water. The mixture was extracted twice with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered, and concentrated under reduced pressure to give a dark-brown oil. Flash chromatography of this oil on silica gel eluting with 1:25 ethyl acetate/hexane afforded the title compound of Step G, a compound of the invention, as light-yellow solid melting at 154°-155° C. (525 mg, 25%). 1H NMR (CDCl3): δ2.64 (s,3H), 7.15-7.25 (m,3H), 7.39 (t, 1H), 7.7 (s, 1H), 7.97 (s, 1H), 8.62 (s, 1H).
Reaction SMILES: C([O:8][C:9](=[O:23])[CH:10]([CH3:22])[CH2:11][CH:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:14][CH2:15][CH3:16])C1C=CC=CC=1>C(O)C.[Pd]>[CH2:20]([O:19][C:17]([CH:12]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:11][CH:10]([CH3:22])[C:9]([OH:23])=[O:8])=[O:18])[CH3:21]
Reactant: CCCCC(CC(C)C(=O)OCc1ccccc1)C(=O)OCC
Agent: [Pd]
Solvent: CCO
Product: CCCCC(CC(C)C(=O)O)C(=O)OCC

Procedure:
4-ethoxycarbonyl-2-methyloctanoic acid benzyl ester (10 g) is dissolved in ethanol (100 ml), 10% palladium on charcoal (2 g) is added, and the mixture is hydrogenated until complete removal of the benzyl ester is achieved to yield 4-ethoxycarbonyl-2-methyloctanoic acid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=O>CCOCC>[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH2:12][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C(c1cccs1)N1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: c1csc(CN2CCCC2)c1

Procedure:
Lithium aluminium hydride (9.6 g) was added to N-(2-thienylcarbonyl)pyrrolidine (35.4 g) in ether. After 41/2 hr the reaction was quenched with water and extracted with chloroform. Evaporation of the organic extracts gave an oil which was distilled under reduced pressure (21.5 g) b.p. 60°-70° (10-16 mm). TLC silica/ethyl acetate, methanol, Rf 0.7.
Reaction SMILES: [C:1]([N:8]1[C:20]2[C:19]([O:21][CH2:22][CH2:23]Br)=[C:18]3[N:25]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:26]4[CH:27]=[CH:28][C:29]([F:32])=[CH:30][C:31]=4[C:17]3=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([F:40])[CH:13]=2)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].OCC[N:44]1[CH2:50][CH2:49][CH2:48][N:47](C(OC(C)(C)C)=O)[CH2:46][CH2:45]1.C([O-])([O-])=O.[K+].[K+].C([O-])([O-])=O.[Cs+].[Cs+].[I-].[K+]>CS(C)=O.CC#N.CN(C=O)C>[N:44]1([CH2:23][CH2:22][O:21][C:19]2[C:20]3[N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[C:9]4[C:14](=[CH:13][C:12]([F:40])=[CH:11][CH:10]=4)[C:15]=3[CH:16]=[C:17]3[C:31]4[CH:30]=[C:29]([F:32])[CH:28]=[CH:27][C:26]=4[N:25]([C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[C:18]=23)[CH2:50][CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1
Reactant: CC(C)(C)OC(=O)N1CCCN(CCO)CC1
Reactant: CC(C)(C)OC(=O)n1c2ccc(F)cc2c2cc3c4cc(F)ccc4n(C(=O)OC(C)(C)C)c3c(OCCBr)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c2ccc(F)cc2c2cc3c4cc(F)ccc4n(C(=O)OC(C)(C)C)c3c(OCCN3CCCNCC3)c21
Temperature: 25 °C

Procedure:
A mixture of 5,7-diBOC-2,10-difluoro-6-(2-bromoethoxy)indolo[2,3-b]carbazole (150.0 mg, 0.24 mmol), tert-butyl 4-(2-hydroxyethyl)-1,4-diazepane-1-carboxylate (97.6 mg, 0.49 mmol), a base (K2CO3 or Cs2CO3; 2-10 equiv) and potassium iodide (0.1 equivalent) in a anhydrous solvent (DMF, MeCN or DMSO; 30 mL per mmol) was heated to 80-90° C. for 1-2 hours. The reaction was cooled to room temperature and filtered. The solution was concentrated and dried under vacuum pump. The residue was purified by flash chromatography to provide the 6-(2-(1,4-diazepan-1-yl)ethoxy)-2,10-difluoro-5,7-diBOC-indolo[2,3-b]carbazole.
Reaction SMILES: [OH:1][C:2]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:5]2[O:6][CH:7]=[C:8]([C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[O:10])[C:4]=2[CH:3]=1.[N+]([O-])(O)=[O:26].O.C(Cl)Cl.CO>C(O)(=O)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]([C:8]2[C:4]3[C:3](=[O:26])[C:2](=[O:1])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:5]=3[O:6][CH:7]=2)=[O:10])=[CH:12][CH:13]=1
Reactant: COc1ccc(C(=O)c2coc3c2cc(O)c2ccccc23)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)c2coc3c2C(=O)C(=O)c2ccccc2-3)cc1
Temperature: 45 °C

Procedure:
To a suspension of compound 23 (100 mg, 0.31 mmol) in glacial acetic acid (1.5 mL) at room temperature was added nitric acid (0.2 mL, d 1.35) dropwise with vigorous stirring. The mixture was then heated at 45° C. for 30 min, left to cool for 30 min, and poured into cold water. The resulting precipitate was filtered and recrystallized to obtain compound SKC-NF-01 (45 mg, 43%) as an orange solid. TLC Rf=0.4 (CH2Cl2-MeOH, 9:1); 1H NMR (CDCl3) δ 8.13 (d, J=7.0 Hz, 1H), 7.90 (app d, 2H), 7.86-7.82 (m, 2H), 7.72 (app t, 1H), 7.54 (app t, 1H), 6.94 (m, 2H), 3.88 (s, 3H); MS (ES) m/z 333 (M+H)+.
Reaction SMILES: Br.[CH3:2][C@H:3]1[CH2:12][CH2:11][C:10]2[C:9]([OH:13])=[CH:8][CH:7]=[CH:6][C:5]=2[NH:4]1.N1C=CC=CC=1.[CH:20]1([C:23](Cl)=[O:24])[CH2:22][CH2:21]1.Cl>CN(C=O)C>[CH:20]1([C:23]([N:4]2[C:5]3[CH:6]=[CH:7][CH:8]=[C:9]([OH:13])[C:10]=3[CH2:11][CH2:12][C@@H:3]2[CH3:2])=[O:24])[CH2:22][CH2:21]1
Reactant: C[C@H]1CCc2c(O)cccc2N1
Reactant: O=C(Cl)C1CC1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: C[C@H]1CCc2c(O)cccc2N1C(=O)C1CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.5 %

Procedure:
A 1000-mL round bottomed flask fitted with a nitrogen inlet, overhead stirrer, addition funnel, and thermocouple, was charged with (S)-2-methyl-1,2,3,4-tetrahydroquinolin-5-ol hydrobromide (20 g, 82 mmol), followed by anhydrous DMF (109 mL), and pyridine (19.8 mL, 246 mmol). Cyclopropanecarbonyl chloride (7.43 mL, 82 mmol) was added dropwise over 30 minutes while holding temperature below 20° C. with a cool water bath. Following completion of the addition, the reaction mixture was stirred for 1.5 h at ambient temperature. The pot was cooled to 0° C. in an ice bath and 0.29 M aqueous HCl solution (315 mL) was added dropwise over 15 minutes. The slurry was stirred for 90 minutes in the ice bath before being filtered. The pot and filter cake were washed with 25 mL of ice water. The filter cake was dried under nitrogen on a Buchner funnel to afford (2S)-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinolin-5-ol (17.16 g, 91%) as an off-white powder. MS (ES, m/z): 232 [M+H]+
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:19][CH3:20])[C:10]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:6]2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:24][CH:25]1[CH2:27][CH2:26]1.C(OCC)(=O)C>CN(C)C=O>[Br:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:19][CH3:20])[C:10]([N:11]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: CCc1nn2c(Br)cccc2c1NC(=O)OC(C)(C)C
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1nn2c(Br)cccc2c1N(CC1CC1)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl N-(7-bromo-2-ethylpyrazolo[1,5-a]pyridin-3-yl)carbamate (658 mg) in N,N-dimethylformamide (15 mL) was added sodium hydride (60% in oil; 116 mg) at room temperature under a nitrogen stream, and the reaction mixture was stirred for 30 minutes. (Bromomethyl)cyclopropane (0.286 mL) was added thereto at the same temperature, and the reaction mixture was stirred for 1 hour at 60° C. After completion of the reaction, the reaction mixture was gradually added to ice, ethyl acetate was added and the organic extract was washed with water and brine, after which it was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to afford a crude product of tert-butyl N-(7-bromo-2-ethylpyrazolo[1,5-a]pyridin-3-yl) -N-cyclopropylmethylcarbamate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4]([Cl:11])[CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[F:19]>C1(C)C=CC=CC=1.C(O)C.O>[Cl:11][C:4]1[CH:3]=[C:2]([C:15]2[CH:16]=[CH:17][C:18]([F:19])=[C:13]([Cl:12])[CH:14]=2)[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]=12
Reactant: Clc1cc(Cl)c2c(n1)CCC2
Reactant: OB(O)c1ccc(F)c(Cl)c1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Fc1ccc(-c2cc(Cl)c3c(n2)CCC3)cc1Cl
Yield: 64 %

Procedure:
Following General Procedure F, 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.300 g, 1.60 mmol) in toluene/ethanol/water (6 mL:3 mL:1 mL) was reacted with (3-chloro-4-fluorophenyl)boronic acid (0.362 g, 2.07 mmol) to afford the title compound (0.289 g, 96%) as a white solid. MW=282.14. 1H NMR (CD3OD, 300 MHz) δ 8.15-8.07 (m, 1H), 7.94-7.86 (m, 1H), 7.66 (s, 1H), 7.33 (t, J=8.8 Hz, 1H), 3.12 (t, J=7.6 Hz, 2H), 3.04 (t, J=7.6 Hz, 2H), 2.21 (quin, J=7.6 Hz, 2H); APCI MS m/z 282 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C(Cl)Cl>[O:21]1[CH2:22][CH2:23][N:18]([CH2:2][C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=2)[CH2:19][CH2:20]1
Reactant: C1COCCN1
Reactant: N#Cc1ccc(CBr)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a stirred suspension of 4-(bromomethyl)benzonitrile (4.00 g, 20 mmol) in DCM (50 ml), at room temperature, triethylamine (4.12 g, 41 mmol) and morpholine (2.67 g, 31 mmol) were added. The reaction mixture was stirred overnight at room temperature. The solution was then diluted with DCM (100 ml) and washed with NaHCO3 saturated aqueous solution (50 ml), the organic phase was separated, dried over magnesium sulphate and solvents evaporated under reduced pressure. The product was purified by column chromatography using a 80 g silica gel cartridge and the following gradient: Solvent A: DCM, Solvent B: MeOH, 1 min hold at 100% A followed by 12 min ramp to 2.5% B and then 5 min hold at 2.5% B. The desired fractions were combined and concentrated to dryness under reduced pressure to obtain the desired product as a white solid (3 g, 14.8 mmol, Yield 72%).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:29]3[N:30]=[C:31]4[C:36](=[C:37]5[C:42]=3[CH:41]=[CH:40][CH:39]=[CH:38]5)[CH:35]=[CH:34][C:33]([F:43])=[CH:32]4)[CH2:27][C@H:21]2[C:20](=[O:44])[NH:19][C@:18]2([C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:45][C@H:17]2[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:51]>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[ClH:51].[NH2:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:29]3[N:30]=[C:31]4[C:36](=[C:37]5[C:42]=3[CH:41]=[CH:40][CH:39]=[CH:38]5)[CH:35]=[CH:34][C:33]([F:43])=[CH:32]4)[CH2:27][C@H:21]2[C:20](=[O:44])[NH:19][C@:18]2([C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:45][C@H:17]2[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3nc4cc(F)ccc4c4ccccc34)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](N)C(=O)N1C[C@H](Oc3nc4cc(F)ccc4c4ccccc34)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3nc4cc(F)ccc4c4ccccc34)C[C@H]1C(=O)N2
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](N)C(=O)N1C[C@H](Oc3nc4cc(F)ccc4c4ccccc34)C[C@H]1C(=O)N2

Procedure:
A solution of (2R,6S,13aS,14aR,16aS,Z)-ethyl 6-(tert-butoxycarbonylamino)-2-(3-fluorophenanthridin-6-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (Example 1c, 1.3 g, 1.9 mmol) in 1 N HCl (4.7 ml, 19 mmol) was stirred at room temperature for 2 h. The reaction mixture was diluted with chloroform and toluene and evaporated to provide the title compound (1.11 g, quantitative yield) as a colorless solid. This material was used without further purification.