Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6](=[O:10])[CH:7]([F:9])[F:8])[CH3:2].S([N:22]=[N+:23]=[N-])(C1C=CC(C)=CC=1)(=O)=O>>[N+:22](=[C:5]([C:6](=[O:10])[CH:7]([F:9])[F:8])[C:4]([O:3][CH2:1][CH3:2])=[O:11])=[N-:23]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CCOC(=O)CC(=O)C(F)F
Product: CCOC(=O)C(=[N+]=[N-])C(=O)C(F)F

Procedure:
This compound was synthesised from 4,4-difluoro-3-oxo-butyric acid ethyl ester (CAS 352-24-9) and polymer-bound tosylazide using similar conditions as described in Intermediate 1-7. The crude was used directly in next step.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([C:13]#[N:14])=[CH:9][CH:10]=2)[NH:5]1.Cl[C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][N+:17]=1[O-].P(Cl)(Cl)Cl>C(=O)([O-])O.[Na+].CN(C)C=O>[C:13]([C:8]1[CH:7]=[C:6]2[C:11]([C:12]([C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][N:17]=3)=[C:4]([OH:3])[NH:5]2)=[CH:10][CH:9]=1)#[N:14]
Reactant: CCOC(=O)c1ccc(Cl)[n+]([O-])c1
Reactant: N#Cc1ccc2c(c1)NC(=O)C2
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: ClP(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2c(O)[nH]c3cc(C#N)ccc23)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.7 %

Procedure:
To a N,N-dimethylformamide (6 mL) suspension of sodium hydride (97%, 0.144 g, 6.0 mmol) was added 2-oxoindoline-6-carbonitrile (0.712 g, 4.5 mmol). The formed mixture was stirred for 10 min at room temperature followed by the addition of ethyl 6-chloronicotinate 1-oxide (0.605 g, 3.0 mmol). The resulting reaction mixture was set under N2 atmosphere and stirred for 2 h at room temperature. The N,N-dimethylformamide reaction solution was diluted with a saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform and ethyl acetate. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The remaining N,N-dimethylformamide was removed by co-evaporation with toluene. The residue was dissolved in chloroform (10 mL) and phosphorus trichloride (1.65 g, 12.0 mmol) was added. The reaction mixture was stirred for 30 min at 60° C. and then cooled to room temperature. The mixture was poured into a saturated aqueous sodium hydrogen carbonate solution. The resulting brown precipitate was filtered off and the mother liquor was extracted with chloroform (4×). The organic layers were concentrated in vacuo and the residue was combined with the filtrate and was washed with ethyl acetate and diethyl ether to afford 0.55 g (60% yield) of the title compound as a yellow-brown solid: 1H NMR (DMSO-d6, 400 MHz) δ 8.85 (s, 1H), 8.06 (s, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.45 (s, 1H), 7.29 (d, J=8.8 Hz, 1H), 4.33 (m, 2H), 1.35 (t, J=7.2 Hz, 3H); MS (EI) m/z 308 (M++1).
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][N:11]=[C:12]=[S:13].[N:14]#[C:15][NH2:16].C1CCN2C(=NCCC2)CC1>C(Cl)(Cl)Cl>[C:15]([NH:16][C:12]([NH:11][CH2:10][CH2:9][S:8][CH2:7][C:3]1[N:4]=[CH:5][NH:6][C:2]=1[CH3:1])=[S:13])#[N:14]
Reactant: Cc1[nH]cnc1CSCCN=C=S
Reactant: N#CN
Solvent: ClC(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1[nH]cnc1CSCCNC(=S)NC#N
Reaction time: 8 h
Yield: 71.5 %

Procedure:
A solution of 2-(5-methylimidazol-4-ylmethylthio)ethylisothiocyanate [obtained from its hydrochloride (4.17 g)] in CHCl3 (20 ml) was added to a solution of cyanamide (1.05 g) and DBU (3.80 g) in CHCl3 (50 ml) and stirred overnight. After concentration, the residue was dissolved in water (30 ml) and washed with ether, decolorized with charcoal and acidified to pH 5 with 10% HCl under ice-cooling. The precipitate was filtered, washed with water and dried to give N-cyano-N'-[2-(5-methylimidazol-4-ylmethylthio)ethyl]thiourea(mono-hydrate, 3.57 g). Yield 78.1%, m.p. 158°-161° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[S:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)=[O:6].C([C:28]1[C:29]([N:34]=[CH:35][N:36]([CH3:38])C)=[N:30][CH:31]=[CH:32][CH:33]=1)#N>>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:15]=[CH:16][C:17]([S:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)=[C:2]([NH:1][C:38]3[C:28]4[CH:33]=[CH:32][CH:31]=[N:30][C:29]=4[N:34]=[CH:35][N:36]=3)[CH:3]=2)=[CH:9][CH:10]=1
Reactant: CN(C)C=Nc1ncccc1C#N
Reactant: Nc1cc(C(=O)Nc2ccc(Br)cc2)ccc1Sc1ccc(O)cc1
Product: O=C(Nc1ccc(Br)cc1)c1ccc(Sc2ccc(O)cc2)c(Nc2ncnc3ncccc23)c1
Yield: 24 %

Procedure:
The product of Example 28A was reacted with the product of Example 29A using the procedure of Example 22C substituting the product of Example 28A for the product of Example 22B and substituting the product of Example 29A for the product of Example 8E to provide the crude title compound which was purified by column chromatography on silica gel using methanol/dichloromethane as eluent to provide the title product (11 mg, 24%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 6.85 (d, J=8.82 Hz, 2 H) 6.88-7.01 (br m, 1 H) 7.31 (d, J=8.46 Hz, 2 H) 7.52 (d, J=8.82 Hz, 2 H) 7.61-7.87 (br m, 2 H) 7.73 (d, J=9.19 Hz, 2 H) 7.92-8.09 (br m, 1 H) 8.54-8.72 (br m, 1 H) 8.87-9.04 (br m, 1 H) 9.03-9.19 (br m, 1 H) 9.96 (br s, 1 H) 10.31 (br d, J=9.56 Hz, 2 H); MS (ESI+) m/z 544/546 (M+H)+.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[NH:14][CH:13]=[CH:12]2.[CH2:20](I)[CH3:21]>O>[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH3:21])[CH:13]=[CH:12]2
Reactant: O=c1[nH]ccc2cc(Br)ccc12
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1ccc2cc(Br)ccc2c1=O
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere, 22 mg of 60% sodium hydride was added at 0° C. to 3 ml solution of dimethylformamide with 100 mg of 6-bromo-2H-isoquinoline-1-one, and the mixture was stirred for 30 min. 0.04 ml of ethyl iodide was added at 0° C., and the mixture was stirred at room temperature for 3 hours. Cold water was added to the reaction solution, extracted with chloroform. Chloroform layer was washed with saturated saline solution, and dried with anhydrous sodium sulfate. After distilling out the solvents under reduced pressure, the residues were separated and purified by thin-layer chromatography (hexane/ethyl acetate=3/1) to obtain 30 mg of the above compound as a white solid.
Reaction SMILES: [NH2:1][C@:2]1([C:16]2[S:20][N:19]=[CH:18][CH:17]=2)[C@H:6]([CH2:7]O)[CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.[C:21]([N:29]=[C:30]=[S:31])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1>[C:21]([NH:29][C:30]1[S:31][CH2:7][C@@H:6]2[CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][C@:2]2([C:16]2[S:20][N:19]=[CH:18][CH:17]=2)[N:1]=1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CO)[C@](N)(c2ccns2)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2ccns2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl (3R,4R)-3-amino-4-(hydroxymethyl)-3-isothiazol-5-yl-pyrrolidine-1-carboxylate (148.10 g, 494.67 mmol) and tetrahydrofuran (1.48 L) are added together and the solution is cooled to 0° C. Benzoyl isothiocyanate (82.34 g, 504.56 mmol) is added over 5 minutes and the reaction mixture is stirred for 30 minutes at 0° C. and then warmed to room temperature over 1 hour. 1,1′-Carbonyldiimidazole (92.24 g, 568.87 mmol) is added and the reaction mixture is stirred at room temperature for 2 h. The mixture is heated to 65° C. and stirred for a further 12 hours. The reaction mixture is concentrated under reduced pressure and the oily residue is partitioned between water (1.5 L) and ethyl acetate (1.5 L). The pH is adjusted with citric acid 50% w/w aq. solution to 4.0 and the organic layer is separated. The aqueous layer is extracted with MTBE (2×500 mL), the organics are combined, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude product is slurried in MTBE (740.50 mL) at 60° C. then at room temperature for 45 minutes. The solid is collected, washed with MTBE (4×150 mL), and dried under vacuum overnight to give the title compound as an off white solid (162.68 g, 74.0%). ES/MS (m/e): 445 (M+H), ee=99.5%.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][O:12][C@H:13]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:15]([C:25]([N:27]([CH3:29])[CH3:28])=[O:26])[CH2:14]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[CH3:29][N:27]([CH3:28])[C:25]([C@@H:15]1[CH2:14][C@@H:13]([O:12][CH2:11][CH2:10][CH2:9][OH:8])[CH2:17][N:16]1[C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])=[O:26]
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](OCCCO[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)[C@@H]1C[C@@H](OCCCO)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 116 %

Procedure:
To a solution of 2.10 g of the compound obtained in Step 139-1 in THF (100 ml) was added a solution 1 mol/L TBAF in THF (10 ml) under ice cooling and the reaction mixture was stirred at room temperature for two hours. Water was poured, the solution was extracted twice with CHCl3; the combined organic layer was washed with saturated brine and dried over MgSO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60N; mobile phase: CHCl3/MeOH=20/1 to 10/1; v/v) to obtain 1.79 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:16]([C@@H:23]1[CH2:28][C@@H:27]([N:29]([CH2:36][C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]=[CH:39][CH:38]=2)[C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])[CH2:26][CH2:25][NH:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N>C(Cl)Cl>[CH2:16]([C@@H:23]1[CH2:28][C@@H:27]([N:29]([CH2:36][C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]=[CH:39][CH:38]=2)[C:30](=[O:35])[C:31]([F:33])([F:34])[F:32])[CH2:26][CH2:25][N:24]1[C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: N
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cc1ccc(Cl)cc1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1

Procedure:
96 mg (0.56 mmol) of 4-chlorophenylacetic acid are reacted in analogy to Example 2j first with 58 μl (0.795 mmol) of thionyl chloride and subsequently with 200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine to give the product. TLC: methylene chloride/methanot/conc. ammonia (700:50: 1) Rf =0.39, FD-MS: M+ =580.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[NH:24]1[CH:28]=[CH:27][CH:26]=[N:25]1.[I-].[Na+]>C1COCC1>[N:24]1([CH2:21][C:17]2[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=2)[C:14]([NH:13][CH2:12][CH2:11][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][CH:6]=2)=[O:23])[CH:28]=[CH:27][CH:26]=[N:25]1
Reactant: c1cn[nH]c1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(Cn2cccn2)c1
Yield: 99 %

Procedure:
3-((1H-Pyrazol-1-yl)methyl)-N-(2-(5-Chloro-1H-indol-3-yl)ethyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.050 g; 0.144 mmol), pyrazole (0.034 g; 0.5 mmol) and sodium iodide (0.090 g; 0.6 mmol) in THF (3 mL), under a microwave irradiation at 150° C. for 20 minutes. Flash chromatography on silica gel (eluent 0 to 10% methanol in dichloromethane) furnished 0.054 g (99%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=O)[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4].[Cl:25][C:26]1[CH:27]=[C:28]([CH2:33]/[C:34](=[N:37]/[H])/[NH:35]O)[CH:29]=[CH:30][C:31]=1[Cl:32].[O-]CC.[Na+]>CCO>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][C:19]2[O:21][N:35]=[C:34]([CH2:33][C:28]3[CH:29]=[CH:30][C:31]([Cl:32])=[C:26]([Cl:25])[CH:27]=3)[N:37]=2)[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: [H]/N=C(/Cc1ccc(Cl)c(Cl)c1)NO
Reactant: CCCCn1c(=O)n(CCCC(=O)OCC)c(=O)c2[nH]c(Cl)nc21
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCn1c(=O)n(CCCc2nc(Cc3ccc(Cl)c(Cl)c3)no2)c(=O)c2[nH]c(Cl)nc21
Yield: 47.7 %

Procedure:
Ethyl 4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate (71 mg, 0.2 mmol), (1Z)-2-(3,4-dichlorophenyl)-N-hydroxyethanimidamide (48 mg, 0.22 mmol) and 21% by wt. ethanolic sodium ethoxide (0.111 ml, 0.3 mmol) were heated together in EtOH (1 ml) in the microwave reactor at 140° C. for 10 min. The mixture was then partitioned between EtOAc and 2M HCl, the organic phase separated and evaporated, and the crude product was purified by MDAP to give the title compound as a solid (48.8 mg).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:15]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26]Cl)=[CH:20][CH:19]=3)=[O:17])=[C:14]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[S:13][C:12]=2[CH:33]=1>>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:15]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:20][CH:19]=3)=[O:17])=[C:14]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[S:13][C:12]=2[CH:33]=1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCCl)cc3)c(C3CCCC3)sc2c1
Reactant: C1CCNC1
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCC4)cc3)c(C3CCCC3)sc2c1

Procedure:
1 mL of pyrrolidine is added to 30 mg of (6-methoxy-2cyclopentylbenzo[b]thien-3-yl)[4-(2chloroethoxy)phenyl]methanone, and this mixture is heated and refluxed for one hour. The mixture is condensed under reduced pressure to distill off the pyrrolidine, and then is refined by TLC (developing solvent was chloroform:methanol=19:1) which gives 28 mg of (6-methoxy-2-cyclopentylbenzo[b]thien-3-yl)[4-[2-(1-pyrrolidinyl)ethoxy)phenyl]methanone.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[C:9]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])#[N:10]>ClCCl>[C:19]([O:18][C:17](=[O:23])[NH:16][C:12]1[S:13][C:14]([I:1])=[CH:15][C:11]=1[C:9]#[N:10])([CH3:20])([CH3:22])[CH3:21]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)OC(=O)Nc1sccc1C#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1sc(I)cc1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-Iodosuccinimide (9.28 g, 41.2 mmol, 1.0 eq) was added to a stirred mixture of tert-butyl (3-cyano-2-thienyl)carbamate (9.25 g, 4.1.2 mmol, 1.0 eq) in dichloromethane (82 ml, 0.5 M) and the mixture was stirred at room temperature for 2 h. The mixture was diluted with dichloromethane and washed with 1N sodium hydroxide (300 mL), sodium thiosulfate (2×300 mL), water (2×300 mL), and brine. The organic layers was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford the title compound as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]1=2.[N:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.O.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>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[C:26]3[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: OB(O)c1ccncc1
Reactant: Cc1ccc2c(c1)c1c(n2-c2ccccc2Br)CCN(C)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2ccccc2-c2ccncc2)CCN(C)C1
Temperature: 95 °C
Yield: 7.8 %

Procedure:
To a de-aerated solution of 5-(2-bromo-phenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (180 mg, 0.508 mmol), 4-pyridinylboronic acid (93.8 mg, 0.762 mmol) and K3PO4 (270 mg, 1.27 mmol) in DMF-water (9:1 mL) was added PdCl2(PPh3)2 (18 mg, 5 mol %). The reaction mixture was heated at 95° C. for 30 min under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(2-pyridin-4-yl-phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as semisolid (14 mg). 1H NMR (Freebase, CDCl3) d (ppm): 8.38 (d, 2H), 7.58 (m, 3H), 7.40 (d, 1H), 7.20 (s, 1H), 6.90 (m, 4H), 3.75 (m, 2H), 2.76 (m, 1H), 2.60 (m, 1H), 2.50 (m, 1H), 2.48 (s, 3H), 2.42 (s, 3H), 2.20 (m, 1H).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Br[C:27]1[C:32]([F:33])=[CH:31][C:30]([C:34]([F:37])([F:36])[F:35])=[CH:29][N:28]=1>>[F:33][C:32]1[C:27]([N:23]2[CH2:24][CH2:25][CH:20]([C@@H:18]3[O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][CH:7]=5)[CH:12]=[C:13]4[CH2:19]3)[CH2:21][CH2:22]2)=[N:28][CH:29]=[C:30]([C:34]([F:36])([F:35])[F:37])[CH:31]=1
Reactant: Fc1cc(C(F)(F)F)cnc1Br
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCNCC2)C3)CC1
Product: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCN(c4ncc(C(F)(F)F)cc4F)CC2)C3)CC1

Procedure:
The title compound is prepared from (R)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 39, the configuration of the stereocenter is arbitrarily assigned) and 2-bromo-3-fluoro-5-trifluoromethyl-pyridine following a procedure analogous to that described for Example 79. LC (method 7): tR=1.75 min; Mass spectrum (ESI+): m/z=527 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C=O)C.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Cl)(=[O:30])=[O:29]>>[CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:14])[CH3:15])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH3:21])(=[O:30])=[O:29])[CH:7]=[CH:6]2
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Reactant: Cc1ccccc1S(=O)(=O)Cl
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2S(=O)(=O)c2ccccc2C)c1CN(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 27.9 %

Procedure:
To a solution of 1-(5-methoxy-11H-indol-4-yl)-N,N-dimethylmethanamine (15 mg, 0.07 mmol; Intermediate 97) in DMF (1 mL) NaH (4 mg, 0.15 mmol) was added at rt. The reaction mixture was stirred at rt for 15 min and 2-methylbenzene-1-sulfonyl chloride (21 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at rt over night. The reaction was quenched by addition of water. Purification by preparative HPLC/UV (System B) afforded the title product (7 mg, 28%) as a white solid. MS (ESI+) for C19H22N2O3S m/z 359 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH2:16][C:17]([NH2:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:16][C:17]([NH2:19])=[O:18])[CH:10]=2)[O:3]1
Reactant: NC(=O)CBr
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)OB(c2cnn(CC(N)=O)c2)OC1(C)C
Temperature: 50 °C

Procedure:
A suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.00 g, 10.3 mmol), 2-bromoacetamide (2.14 g, 15.5 mmol), and potassium carbonate (2.14 g, 15.5 mmol) in acetone (60 mL) was heated at about 50° C. for about 3.5 days. The reaction mixture was then cooled to ambient temperature, filtered through diatomaceous earth, while washing with additional acetone, and then concentrated under reduced pressure. The crude material was then dissolved in a minimal amount of dichloromethane and purified via silica gel chromatography eluting with a gradient of 80-100% ethyl acetate in heptane to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.88 (s, 1H), 7.57 (s, 1H), 7.46 (s, 1H), 7.24 (s, 1H), 4.77 (s, 2H), 1.26 (s, 12H). MS (ESI+) m/z 252.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1)[CH3:2].F[C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=[O:18].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[CH:17]=[O:18])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(O)c1
Reactant: O=Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)Cc1cccc(Oc2ccccc2C=O)c1
Temperature: 120 °C
Yield: 67.6 %

Procedure:
(3-Hydroxy-phenyl)-acetic acid ethyl ester (1.0 g, 5.2 mmol), 2-fluorobenzaldehyde (0.66 g, 5.2 mmol), and potassium carbonate (1.44 g, 10.4 mmol) were combined in 1,4-dioxane (30 mL) and heated to 120° C. for 3 days. After work-up, the crude material was purified by silica gel chromatography (0-20% EtOAc in hexanes) to give the desired product (1 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[CH:12]=[CH:13][C:14]([CH:16]([OH:18])[CH3:17])=[CH:15][C:4]=2[N:3]=1>C(Cl)Cl.O=[Mn]=O>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[CH:12]=[CH:13][C:14]([C:16](=[O:18])[CH3:17])=[CH:15][C:4]=2[N:3]=1
Reactant: CC(O)c1ccc2c(c1)nc(N)c1ncccc12
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)nc(N)c1ncccc12

Procedure:
A solution 1-(5-aminobenzo[f][1,7]naphthyridin-8-yl)ethanol (from Example 88) (1.0 eq.) and activated MnO2 (20 eq.) in DCM (0.1 M) was stirred at ambient temperature over night. The reaction mixture was diluted with DCM. The MnO2 was filtered off, and the filtrate was concentrated en vacuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-5% MeOH/DCM to give 1-(5-aminobenzo[f][1,7]naphthyridin-8-yl)ethanone as a yellow solid: 1H NMR (acetone-d6): δ 9.11 (dd, 1H), 8.99 (dd, 1H), 8.56 (d, 1H), 8.20 (d, 1H), 7.94-7.88 (m, 2H), 6.90 (br s, 2H), 2.70 (s, 3H). LRMS [M+H]=238.1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:10].Cl[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[CH:23][CH:22]=1>CS(C)=O.C(OCC)(=O)C>[CH3:7][O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=[CH:23][CH:22]=2)[CH:12]=1)=[O:10]
Reactant: Clc1ccnc2ccccc12
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cn(-c2ccnc3ccccc23)c2ccccc12
Temperature: 20 °C
Reaction time: 1 h
Yield: 152.2 %

Procedure:
1.73 g (12.5 mmol) of potassium carbonate are added at 20° C. under an argon atmosphere to 0.876 g (5 mmol) of 3-methoxycarbonyl-1H-indole in 10 cm3 of dimethyl sulphoxide. After stirring at 20° C. for 1 hour, 0.654 cm3 (5 mmol) of 4-chloroquinoline is added. After stirring at 100° C. for 43 hours, the reaction mixture is cooled and diluted with 20 cm3 of ethyl acetate and then washed with 3 times 10 cm3 of water and 10 cm3 of saturated aqueous sodium chloride solution. After separating the phases by settling, the organic phase is dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 2.30 g of a residue which is purified by flash chromatography [eluent: cyclohexane/ethyl acetate (7/3 by volume)]. After concentrating the fractions under reduced pressure, 1.07 g of 3-methoxycarbonyl-1-(quinol-4-yl)-1H-indole are obtained in the form of a white solid melting at 142° C.