Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[OH:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[CH3:20][O:19][C:17]1[C:16]([O:21][CH3:22])=[CH:15][C:14]2[N:10]([C:8]3[S:9][C:5]([C:3]([OH:2])=[O:4])=[C:6]([C:29]4[CH:28]=[CH:27][CH:26]=[C:25]([OH:24])[CH:30]=4)[N:7]=3)[CH:11]=[N:12][C:13]=2[CH:18]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Product: COc1cc2ncn(-c3nc(-c4cccc(O)c4)c(C(=O)O)s3)c2cc1OC
Yield: 6 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 3-hydroxyphenylboronic acid (20.7 mg, 0.15 mmol) gave 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-(3-hydroxy-phenyl)-thiazole-5-carboxylic acid (2.4 mg, 6%) as a white solid. MS m/z 398 (M+1).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11][C:12]1[CH:13]=[C:14]([C@H:19]2[NH:24][C:23](=O)[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20]2)[CH:15]=[C:16]([F:18])[CH:17]=1.C([Al]CC(C)C)C(C)C>C1(C)C=CC=CC=1.C1COCC1>[F:18][C:16]1[CH:15]=[C:14]([C@@H:19]2[CH2:20][CH2:21][C:22]([CH3:27])([CH3:26])[CH2:23][NH:24]2)[CH:13]=[C:12]([F:11])[CH:17]=1
Reactant: CC1(C)CC[C@@H](c2cc(F)cc(F)c2)NC1=O
Agent: CC(C)C[Al+]CC(C)C
Agent: CC(C)C[Al]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1(C)CC[C@@H](c2cc(F)cc(F)c2)NC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
7.0 mL (7.0 mmol) of a 1 molar diisobutyl-aluminium hydride solution in toluene were added to 0.48 g (2.0 mmol) (S)-6-(3,5-difluorophenyl)-3,3-dimethylpiperidin-2-one in 10 mL THF while cooling with ice and the mixture was stirred for 20 h at RT. Then the reaction mixture was refluxed for 8 h. A 1 M diisobutylaluminium hdyride solution in toluene was added twice more and the mixture was refluxed for 8 h and 24 h, respectively. After hydrolysis of the reaction mixture the precipitate formed was suction filtered and washed with THF. The filtrate was evaporated down and the residue was purified by flash chromatography (aluminium oxide).
Reaction SMILES: F[C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[OH-:18].[Na+]>S([O-])([O-])(=O)=O.[Cu+2]>[OH:18][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CCCCCCOc1cccc(C(N)=O)c1F
Reactant: [OH-]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: CCCCCCOc1cccc(C(N)=O)c1O
Temperature: 100 °C
Reaction time: 14 h

Procedure:
A mixture of 2-fluoro-3-Hexoxy-benzamide (0.30 g, 1.2 mmol), copper sulfate (0.10 g, 0.4 mol) copper (0.015 g, 0.2 mmol) and NaOH (2.5 ml) was stirred at 100° C. for 14 hrs. After completion of reaction the reaction mixture was acidified and extracted with EtOAc. The obtained crude compound was purified by column chromatography on silica (230-4000 using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as yellow (0.15 g, 50%). 1H NMR (DMSO-d6, 400 MHz with D2O): δ 3.9 (s, 3H), 7.11-7.18 (m, 2H), 7.53-7.58 (m, 1H). MS ES+ (229.0 M+2H adduct). HPLC (Method 7) Rt=11.16 min.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[N+:12]([O-])=O.CO.[ClH:21]>C(OCC)(=O)C>[NH2:12][C:7]1[C:8]([Cl:21])=[N:9][CH:10]=[CH:11][C:6]=1[NH:5][CH2:4][C:3]1[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1cnccc1NCc1ccccc1F
Reactant: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1c(NCc2ccccc2F)ccnc1Cl
Reaction time: 0.5 h

Procedure:
A mechanically stirred solution of 4-[(2-fluorobenzyl)amino]-3-nitropyridine (12.31 g, 49.8 mmol) in concentrated hydrochloric acid (118 ml) was heated to 90° under a nitrogen atm. Stannous chloride dihydrate (55.56 g, 246 mmol) was added in small portions over a 5 min period (the oil bath was removed until the reaction subsided). After an additional 30 min at 90°, the reaction mixture was cooled, diluted with water (200 ml) and spin evaporated in vacuo. The residue was diluted with water (200 ml) and cooled in an ice-bath, while concentrated ammonium hydroxide was added to adjust the pH to 7-8. The solids were collected and allowed to air dry overnight. The solid was treated with ethyl acetate and filtered (12×200 ml), the combined extracts were washed with water, dried (sodium sulphate) and spin evaporated in vacuo. The residue was combined with the product from a separate reaction (12 g, 48.5 mmoles) and dissolved in ethyl acetate. This solution was added to Silica Gel 60 and spin evaporated in vacuo. The residual solids were introduced to a column (5 cm×30 cm) of Silica Gel 60 wetted with ethyl acetate. The column was eluted with ethyl acetate using flash chromatography. The appropriate fractions were combined and spin evaporated in vacuo to give 20.8 g (84%) of 3-amino-2-chloro-4-[2-fluorobenzyl)amino]pyridine as a white solid, mp.=185°-187°; UV (0.1M hydrochloric acid+5% methanol), λmax 233 nm (ξ17900), 302 nm (ξ14900); (pH 7.0 buffer+5% methanol), λmax 262 nm (ξ11200), (0.1N sodium hydroxide+5% methanol), λmax 262 nm (ξ10700), 1H nmr (DMSO-d6): δ7.36-7.15 (complex m, 5H,Ar+pyridine H-6), 6.35-6.30 (d,1H,pyridine H-5), 6.27-6.33 (overlapping,1H,NH). 4.84 (2,2H,NH2), 4.41 (d,2H,J=5 Hz, CH2Ar).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:19](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH3:19])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)cc(NC2CCCC2)c1C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1cc(Cl)cc(N(C)C2CCCC2)c1C
Temperature: 80 °C
Yield: 95.4 %

Procedure:
To a stirred solution of methyl 5-chloro-3-(cyclopentylamino)-2-methylbenzoate (0.5 g, 1.86 mmol) in acetonitrile (5 mL) was added cesium carbonate (1.22 g, 3.7 mmol) and methyl iodide (1.32 g, 9.33 mmol). The resulting mixture was heated at 80° C. for 12 h. On completion, the mixture was cooled to room temperature and filtered, the residue was washed with ethyl acetate and the filtrate was concentrated and then purified by column chromatography to afford methyl 5-chloro-3-(cyclopentyl(methyl)amino)-2-methylbenzoate (0.5 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[F:21][C:22]([F:32])([F:31])[C:23](N1CCOCC1)=[O:24].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[C:5]([C:23](=[O:24])[C:22]([F:32])([F:31])[F:21])=[CH:4][CH:3]=1
Reactant: O=C(N1CCOCC1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cl)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nc(Cl)ccc1C(=O)C(F)(F)F
Temperature: -50 °C
Reaction time: 2 h

Procedure:
8 g (35 mmol) of tert-butyl (6-chloropyridin-2-yl)carbamate (Example 1A) were initially charged in 100 ml of THF and cooled to −50° C. 55 ml (87 mmol) of butyllithium (1.6 N) were added dropwise. After the dropwise addition had ended, the reaction was warmed gradually to −10° C. and stirred at 0° C. for 2 h. Subsequently, the mixture was cooled again to −40° C., and 12.8 g (70 mmol) of 4-(trifluoroacetyl)morpholine (Example 6A), dissolved in 4 ml of THF, were added. The reaction solution was stirred at −40° C. for 1 h, then poured at −40° C. onto 1 l of ethyl acetate and 350 ml of ammonium chloride solution, and extracted. The organic phase was removed, dried over magnesium sulphate and concentrated on a rotary evaporator. The reaction mixture was chromatographed on silica gel (eluent: cyclohexane/ethyl acetate 10:1). 9 g (79% of theory) of the product were obtained as an oil.
Reaction SMILES: Cl.[C:2](=[NH:7])(OCC)[CH3:3].[F:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([NH:15][NH2:16])=[O:14])=[CH:11][CH:10]=1>>[NH:7]=[C:2]([N:15]([C:13](=[O:14])[C:12]1[CH:17]=[CH:18][C:9]([F:8])=[CH:10][CH:11]=1)[NH2:16])[CH3:3]
Reactant: CCOC(C)=N
Reactant: NNC(=O)c1ccc(F)cc1
Agent: Cl
Product: CC(=N)N(N)C(=O)c1ccc(F)cc1

Procedure:
Prepared from 7.2 g (58 mmol) ethyl acetimidate hydrochloride and 5.00 g (32 mmol) 4-fluoro-benzoic acid hydrazide analogously to the method described for intermediate product la). Yield: 5.78 g (91%); mass spectroscopy [M+H]+=196.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:16]2[O:20][N:19]=[C:18]([C:21]([NH:23][CH:24]3[CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]3)=[O:22])[N:17]=2)[CH2:11][C:12]([NH:14][OH:15])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[NH:26]1[CH2:25][CH:24]([NH:23][C:21]([C:18]2[N:17]=[C:16]([C@@H:10]([CH2:11][C:12]([NH:14][OH:15])=[O:13])[CH2:9][CH2:8][CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[O:20][N:19]=2)=[O:22])[CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)NO)n2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(C[C@@H](CCCC1CCCCC1)c1nc(C(=O)NC2CNC2)no1)NO
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 98.2 %

Procedure:
A solution of tert-butyl 3-{[(5-{(1R)-4-cyclohexyl-1-[2-(hydroxyamino)-2-oxoethyl]butyl}-1,2,4-oxadiazol-3-yl)carbonyl]amino}-1-azetidinecarboxylate (Example 43) (160 mg, 0.33 mmol) in dichloromethane (10 ml) was cooled to 0° C. and treated with trifluoroacetic acid (7 ml) and the resulting mixture was stirred at 0° C. under a nitrogen atmosphere for 45 minutes. The solvent was removed under reduced pressure and the residue azeotroped from dichloromethane (×2). The residue was triturated with diethylether, filtered and dried to afford the title compound as a white solid (123 mg).
Reaction SMILES: N#N.[Cl:3][CH2:4][C:5]1[N:6]=[C:7]([C:10](=[O:12])[CH3:11])[S:8][CH:9]=1.[CH2:13](O)[CH2:14][OH:15].COC(OC)OC>C([O-])(O)=O.[Na+]>[Cl:3][CH2:4][C:5]1[N:6]=[C:7]([C:10]2([CH3:11])[O:15][CH2:14][CH2:13][O:12]2)[S:8][CH:9]=1
Reactant: CC(=O)c1nc(CCl)cs1
Reactant: OCCO
Agent: N#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(OC)OC
Product: CC1(c2nc(CCl)cs2)OCCO1
Temperature: 95 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and a condenser under inert atmosphere (N2), a solution of 1-(4-chloromethyl-thiazol-2-yl)-ethanone (992 mg, 5.65 mmol) in ethylene glycol (6.30 mL, 112.96 mmol) was treated with trimethylorthoformate (1.24 mL, 11.30 mmol) followed by LiBF4 (106 mg, 1.13 mmol). The reaction mixture was heated at 95° C. for 2 h. Sat. aq. NaHCO3 (50 mL) was added and the mixture was extracted with EA (50 mL). The org. extracts were washed with brine (2×50 mL), dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (4:1 hept-EA) gave the title compound as a yellow oil. TLC: rf (4:1 hept-EA)=0.30. LC-MS-conditions 02: tR=0.84 min, [M+H]+=220.36.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=1>CN(C=O)C>[F:35][C:34]([F:36])([F:37])[C:32]1[CH:33]=[C:28]([CH:29]=[C:30]([C:38]([F:41])([F:39])[F:40])[CH:31]=1)[CH2:27][O:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.1 %

Procedure:
Ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (61 mg, 0.235 mmol), was dissolved in DMF (1.0 mL) and cesium carbonate (77 mg, 0.235 mmol) and 1-(bromomethyl)-3,5-bis(trifluoromethyl)benzene (72 mg, 0.235 mmol) were added. The reaction mixture was stirred at room temperature for 16 h and then filtered through a pad of Celite®. The filtrate was diluted with water and extracted three times with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (28.6 mg). LCMS m/z=486.4 [M+H]+.
Reaction SMILES: FC(F)(F)S(O[C:7]12[CH2:13][CH:10]([CH2:11][CH2:12]1)[CH2:9][C:8]2=[O:14])(=O)=O.C([OH:19])C.O>>[C:7]12([C:8]([OH:14])=[O:19])[CH2:9][CH:10]([CH2:13]1)[CH2:11][CH2:12]2
Reactant: O=C1CC2CCC1(OS(=O)(=O)C(F)(F)F)C2
Reactant: CCO
Solvent: O
Product: O=C(O)C12CCC(C1)C2
Temperature: 130 °C
Yield: 45 %

Procedure:
A mixture of 2-oxobicyclo[2.2.1]heptan-1-yl trifluoromethanesulfonate (4.6 g, 18.1 mmol) in 600 mL ethanol/water (60% w/w) and TEA (3.7 g, 36.2 mmol) was heated at 130° C. for 100 h. The mixture was concentrated under reduced pressure and the residue was poured into aqueous hydrochloric acid solution (1 mol/L, 150 mL) and extracted with diethyl ether (3×100 mL). The combined extracts were washed with brine (100 mL) and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure to give the crude product which was purified by silica gel column chromatography (10% ethyl acetate in petroleum ether) to give the desired product (1.00 g, 8.09 mmol, yield: 45%). 1H NMR (400 MHz, CDCl3) δ ppm 2.47-2.45 (m, 1H), 1.94-1.90 (m, 4H), 1.79-1.74 (m, 2H), 1.37-1.35 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:19]2[C:16]3=[C:17]4[C:18]5[C:9]([C:10](=[O:46])[N:11]([C:34]6[C:39]([CH:40]([CH3:42])[CH3:41])=[CH:38][CH:37]=[CH:36][C:35]=6[CH:43]([CH3:45])[CH3:44])[C:12](=[O:33])[C:13]=5[CH:14]=[C:15]3[O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=3)=[CH:8][C:7]([O:47][C:48]3[CH:53]=[CH:52][C:51]([C:54]([CH3:57])([CH3:56])[CH3:55])=[CH:50][CH:49]=3)=[C:6]4[C:5]3=[CH:58][CH:59]=[CH:60][C:3]=1[C:4]=23.[NH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=1[SH:68].C(=O)([O-])[O-].[K+].[K+].Cl>CN1CCCC1=O>[NH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=1[S:68][C:2]1[CH:21]=[CH:20][C:19]2[C:16]3=[C:17]4[C:18]5[C:9]([C:10](=[O:46])[N:11]([C:34]6[C:39]([CH:40]([CH3:42])[CH3:41])=[CH:38][CH:37]=[CH:36][C:35]=6[CH:43]([CH3:45])[CH3:44])[C:12](=[O:33])[C:13]=5[CH:14]=[C:15]3[O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=3)=[CH:8][C:7]([O:47][C:48]3[CH:53]=[CH:52][C:51]([C:54]([CH3:57])([CH3:56])[CH3:55])=[CH:50][CH:49]=3)=[C:6]4[C:5]3=[CH:58][CH:59]=[CH:60][C:3]=1[C:4]=23
Reactant: CC(C)c1cccc(C(C)C)c1N1C(=O)c2cc(Oc3ccc(C(C)(C)C)cc3)c3c4cccc5c(Br)ccc(c6c(Oc7ccc(C(C)(C)C)cc7)cc(c2c36)C1=O)c54
Reactant: Nc1ccccc1S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(C)c1cccc(C(C)C)c1N1C(=O)c2cc(Oc3ccc(C(C)(C)C)cc3)c3c4cccc5c(Sc6ccccc6N)ccc(c6c(Oc7ccc(C(C)(C)C)cc7)cc(c2c36)C1=O)c54
Reaction time: 8 h
Yield: 65.3 %

Procedure:
Compound 8-bromo-5,12-bis(4-(tert-butyl)phenoxy)-2-(2,6-diisopropylphenyl)-1H-benzo[5,10]anthra[2,1,9-def]isoquinoline-1,3(2H)-dione (3.0 g), 2-aminobenzenthiol (0.48 g, 10% excess) and anhydrous potassium carbonate (0.24 g) were added to 30 mL of N-methyl-2-pyrrolidinone (NMP). The solution was heated rapidly and refluxed for 30 min. After a minute the liquor was added to 2% aqueous hydrochloride acid (250 ml) and after standing overnight, filtered and dried at 105° C. to give a red-blue solid of 8-((2-aminophenyl)thio)-5,12-bis(4-(tert-butyl)phenoxy)-2-(2,6-diisopropylphenyl)-1H-benzo[5,10]anthra[2,1,9-def]isoquinoline-1,3(2H)-dione (2.06 g) with a nominal yield of 60.0%. 8-((2-aminophenyl)thio)-5,12-bis(4-(tert-butyl)phenoxy)-2-(2,6-diisopropylphenyl)-1H-benzo[5,10]anthra[2,1,9-def]isoquinoline-1,3(2H)-dione (2.06 g) was dissolved in warm glacial acetic (12 mL) and concentration hydrochloride acid (1.3 mL) giving a fine suspension. The suspension was cooled to 0° C. and a solution of sodium nitrite (0.16 g) in water (3.6 mL) added and stirred continuously till clear. The prepared solution was added to a boiling solution of hydrated cupric sulphate (2.6 g) in water (60 mL) with good stirring within 1 hour. After boiling a further 1 hour, the solution was cooled, filtered and a blue-red solid was given. The solid was washed with a warm solution of sodium hydroxide (20 mL, 3%) three times and purified on Chromatography Column to eliminate by-products. The blue solid of 5,15-bis(4-(tert-butyl)phenoxy)-2-(2,6-diisopropylphenyl)-1H-thioxantheno[2′,1′,9′:10,5,6]anthra[2,1,9-def]isoquinoline-1,3(2H)-dione (0.69 g) was given with a nominal yield of 34.2%. MS: base peak 884.
Reaction SMILES: [CH3:1][P:2](=[O:9])([O:6][CH2:7][CH3:8])[O:3][CH2:4][CH3:5].C([Li])CCC.[CH3:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([N:22]2[CH2:27][CH2:26][CH:25]([C:28](OCC)=[O:29])[CH2:24][CH2:23]2)[CH:17]=1.C(O)(=O)C>C1COCC1>[CH2:4]([O:3][P:2]([CH2:1][C:28]([CH:25]1[CH2:26][CH2:27][N:22]([C:18]2[CH:17]=[C:16]([CH3:15])[CH:21]=[CH:20][N:19]=2)[CH2:23][CH2:24]1)=[O:29])([O:6][CH2:7][CH3:8])=[O:9])[CH3:5]
Reactant: CCOC(=O)C1CCN(c2cc(C)ccn2)CC1
Reactant: CCOP(C)(=O)OCC
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOP(=O)(CC(=O)C1CCN(c2cc(C)ccn2)CC1)OCC
Reaction time: 0.33 h

Procedure:
Diethyl methylphosphonate (1.27 g, 8.36 mmol) was dissolved in anhydrous THF (7 ml), the solution was purged with argon and cooled to −78° C. n-Butyllithium (2M in hexane, 2.67 ml, 5.34 mmol) was added at such a rate that the temperature remained below −65° C. After addition was complete, stirring was continued for 20 minutes, then a solution of ethyl 1-(4-methyl-2-pyridyl)piperidine-4-carboxylate (626 mg, 2.52 mmol) in anhydrous THF (1 ml) was added dropwise so that the temperature remained below −70° C. Stirring was continued overnight while the temperature was allowed to reach room temperature. The mixture was neutralized with glacial acetic acid, concentrated under reduced pressure, water was added and the mixture was extracted with DCM (3×). The combined organic phases were dried (sodium sulfate), and concentrated under reduced pressure to give a brown oil that was used directly in the next step MS (multi-mode) m/z=355.1 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12](C)[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][N:27]=1>CN(C=O)C.C([O-])([O-])=O.[K+].[K+].CO.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>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:29]5[CH:28]=[N:27][C:26]([O:25][CH3:24])=[CH:31][CH:30]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[NH:12][C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: COc1ccc(B(O)O)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc(-c2ccc3ncc4[nH]c(=O)n(-c5cn(C)nc5C)c4c3c2)cn1
Temperature: 105 °C
Reaction time: 1.5 h

Procedure:
A mixture of 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Stage A.1, 49 mg, 0.137 mmol), 2-methoxypyridine-5-boronic acid (Sigma-Aldrich, Buchs, Switzerland, 26 mg, 0.170 mmol), and PdCl2(PPh3)2 (6 mg, 0.0085 mmol) in DMF (1.2 ml) and 1 M aqueous K2CO3 (0.343 ml) was stirred under argon at 105° C. for 1.5 h. The RM was cooled toll. The mixture was diluted with MeOH+3 drops TFA and purified directly by Prep.HPLC (H2O (0.1% TFA)/CH3CN 95:5 to 60:40). The fractions containing products were collected together and basified with NaHCO3 (0.3 g), before being concentrated. The resulting suspension was filtered and the cake was washed with water, before being dried under high vacuum to give the title compound as a white solid. (HPLC: tR 2.46 min (Method A); M+H=387 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 11.66 (s, br, 1H), 8.72 (s, 1H), 8.33-8.26 (m, 1H), 8.16-8.10 (m, 1H), 8.09-8.01 (m, 1H), 7.91-7.84 (m, 1H), 7.81-7.74 (m, 1H), 7.51-7.43 (m, 1H), 6.98-6.91 (m, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 1.95 (s, 3H))
Reaction SMILES: Cl.[F:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].[F:14][C:15]([F:23])([F:22])[C:16]1([C:19](O)=[O:20])[CH2:18][CH2:17]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:19]([C:16]2([C:15]([F:23])([F:22])[F:14])[CH2:18][CH2:17]2)=[O:20])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)C1(C(F)(F)F)CC1
Reactant: NCc1ccc(F)c([N+](=O)[O-])c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(F)c([N+](=O)[O-])c1)C1(C(F)(F)F)CC1

Procedure:
The sub-title compound was prepared in analogy to the procedure in Example 94, step (c) using 4-fluoro-3-nitro-benzylamine hydrochloride (3.0 g; 14.5 mmol), 1-(trifluoromethyl)-cyclopropanecarboxylic acid (2.5 g; 16.0 mmol), HBTU (6.07 g; 16.0 mmol), TEA (5.88 g; 58.1 mmol) and DMF (50 mL).
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]([O:12]CC)=[O:11])[CH2:6][CH2:5]1)=[CH:2][CH3:3].[OH-].[Na+].O>C(O)C>[CH:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]1)=[CH:2][CH3:3]
Reactant: CC=CC1CCC(C(=O)OCC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC=CC1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
170 g of ethyl 4-propenylcyclohexanecarboxylate from Example 2, 38 g of sodium hydroxide, 215 ml of water and 1075 ml of ethanol were combined and stirred overnight at RT. Conventional work-up gave 4-propenylcyclohexanecarboxylic acid as an E/Z isomer mixture.
Reaction SMILES: [CH3:1][N:2]([S:16]([CH3:19])(=[O:18])=[O:17])[C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:13]([O-])=O)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].CO>[Pd].C(OCC)(=O)C>[NH2:13][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([N:2]([CH3:1])[S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(N(C)S(C)(=O)=O)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cc(N)cc(N(C)S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
A mixture of methyl 3-[methyl(methylsulfonyl)amino]-5-nitrobenzoate obtained in Reference Example 95.76 g (20 mmol), 10% Pd/C (50% wet) (1.50 g), methanol (80 mL) and ethyl acetate (80 mL) was stirred at room temperature under hydrogen atmosphere for 1.5 hours. The reaction solution was filtered on Celite and the solvent was evaporated to give 5.11 g (19.8 mmol) of the title compound (yield: 99%).