Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:10]1([CH2:16][CH:17]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:29][CH3:30])[CH:25]=3)[CH:20]=2)[CH3:18])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(N1CCOCC1)C>C(Cl)Cl.CCOCC>[C:1]([N:13]1[CH2:12][CH2:11][N:10]([CH2:16][CH:17]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:29][CH3:30])[CH:25]=3)[CH:20]=2)[CH3:18])[CH2:15][CH2:14]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2cc(C(C)CN3CCNCC3)ccc2c1
Reactant: O=C(Cl)c1ccccc1
Agent: CCN1CCOCC1
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc2cc(C(C)CN3CCN(C(=O)c4ccccc4)CC3)ccc2c1
Reaction time: 3 h

Procedure:
Benzoyl chloride (0.58 ml, 5 mmols) is added, at 0° C., to a solution of 2-(2-piperazino-1-methylethyl)-6-methoxynaphthalene (1.42 g, 5 mmols) and N-ethylmorpholine (0.65 ml, 5 mmols) in 15 ml of methylene chloride. The mixture is allowed to return to ambient temperature and stirred for 3 hours. The reaction medium is washed with water and dried over sodium sulphate. Concentration of the mixture yields an oily residue which dissolves in ether and crystallises. The compound is recrystallised from ethyl acetate (15 ml).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22](F)=[C:23]([O:26][CH2:27][CH3:28])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:30]#[N:31])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[CH3:32][N:33]1[CH2:37][CH2:36][CH2:35][C:34]1=O>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([N:15]4[CH2:16][CH2:17][CH:32]([N:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)[CH2:3][CH2:4]4)=[C:23]([O:26][CH2:27][CH3:28])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:30]#[N:31])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1
Reactant: CCOc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1F
Reactant: CN1CCCC1=O
Product: CCOc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1N1CCC(N2CCCC2)CC1
Temperature: 105 °C

Procedure:
Following the procedure of Example 11, a mixture of 150 mg (0.33 mmol) of 4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)sulfanyl]phenyl}amino)-6-ethoxy-7-fluoro-3-quinolinecarbonitrile and 306 mg (1.98 mmol) of 4-(1-pyrrolidinylpiperidine) in 1 mL of 1-methyl 2-pyrrolidinone is heated at 105° C. for 17 hours to yield the crude product. Purification by silica gel chromatography (gradient 98:2 methylene chloride/methanol to 4:1 methylene chloride/methanol) gives 122 mg of 4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)thio]phenyl}amino)-6-ethoxy-7-(4-pyrrolidin-1-ylpiperidin-1-yl)quinoline-3-carbonitrile as a yellow solid, mp 203-207° C.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8](I)=[CH:9][CH:10]=3)[C:5]3([CH2:20][O:19][C:18]([NH2:21])=[N:17]3)[C:4]=2[CH:3]=1.[N:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[N:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([C:26]4[CH:27]=[N:22][CH:23]=[N:24][CH:25]=4)=[CH:9][CH:10]=3)[C:5]3([CH2:20][O:19][C:18]([NH2:21])=[N:17]3)[C:4]=2[CH:3]=1
Reactant: OB(O)c1cncnc1
Reactant: NC1=NC2(CO1)c1cc(Br)ccc1Oc1ccc(I)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: NC1=NC2(CO1)c1cc(Br)ccc1Oc1ccc(-c3cncnc3)cc12
Temperature: 65 °C
Reaction time: 16 h

Procedure:
50 ml Flask was charged with 2′-bromo-7′-iodo-5H-spiro[oxazole-4,9′-xanthen]-2-amine (1.000 g, 2.188 mmol), pyrimidin-5-ylboronic acid (0.380 g, 3.06 mmol), tetrakis(triphenylphosphine)palladium (0.126 g, 0.109 mmol) and DME (10 mL). Sodium carbonate (3.28 mL, 6.56 mmol) was added and the reaction mixture was stirred at 65° C. for 16 hrs. The brown mixture with precipitate was filtered and the solids were washed with DME (3 ml), water (5 ml) and methanol (5 ml), dried on air. The material was treated with 10 ml of DCM and filtered, filtrate was evaporated to afford to afford 2′-bromo-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine as white solid
Reaction SMILES: [OH:1][C:2]1[C:3]([Cl:13])=[C:4]([C:8]([Cl:12])=[CH:9][C:10]=1[Cl:11])[C:5]([NH2:7])=[O:6].[Na].C([O:17][C:18](=[O:21])[CH2:19]Br)C>CO>[C:5]([C:4]1[C:3]([Cl:13])=[C:2]([C:10]([Cl:11])=[CH:9][C:8]=1[Cl:12])[O:1][CH2:19][C:18]([OH:21])=[O:17])(=[O:6])[NH2:7]
Reactant: CCOC(=O)CBr
Reactant: NC(=O)c1c(Cl)cc(Cl)c(O)c1Cl
Agent: [Na]
Solvent: CO
Product: NC(=O)c1c(Cl)cc(Cl)c(OCC(=O)O)c1Cl
Temperature: 60 °C
Yield: 84.1 %

Procedure:
16 g (66.9 mmol) of 3-hydroxy-2,4,6-trichlorobenzamide is suspended in 100 ml of methanol and dissolved by adding 1.54 g (66.9 mmol) of sodium. After the addition of 16.8 g (66.9 mmol) of bromoacetic acid ethyl ester, the mixture is maintained under reflux until the reaction is complete (TLC control). The product is then concentrated to dryness under vacuum and the resultant 3-carbamoyl-2,4,6-trichlorophenoxyacetic acid methyl ester is suspended in 100 ml of water. The mixture is combined with 20 ml of concentrated sodium hydroxide solution and maintained for 3 hours at 60° C. for saponifying. The solution is filtered over active carbon, brought to pH 2 by adding concentrated hydrochloric acid, and the precipitate is vacuum-filtered after several hours of stirring in an ice bath. After washing with water and drying, 16.8 g (84% of theory) of 3-carbamoyl-2,4,6-trichlorophenoxyacetic acid is obtained as a white powder, mp 261°-262° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.C([Li])CCC.[O:16]1[CH2:20][CH2:19]OS1(=O)=O.C(=O)=O.Cl.CC1CCCO1>C1COCC1>[Cl:1][C:2]1[C:7]([CH2:19][CH2:20][OH:16])=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: O=S1(=O)OCCO1
Agent: Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC1CCCO1
Product: CSc1nc(Cl)c(CCO)c(Cl)n1
Reaction time: 0.5 h
Yield: 758.5 %

Procedure:
To a vial containing 4,6-dichloro-2-(methylsulfanyl)pyrimidine (200 mg, 0.102 mmol) in THF (10 mL) was added n-butyllithium (0.554 mL, 1.38 mmol, 2.5 M in hexane) at −78° C. and the resulting mixture was stirred for 30 min. 1,3,2-dioxathiolane 2,2-dioxide (172 mg, 1.39 mmol) was added at −78° C. and stirring was continued for 2 h. The reaction vial was removed from the dry ice bath, 6 N HCl (3.5 mL, 21 mmol) was added, and the mixture was stirred at room temperature for 18 h. 2-Methyltetrahydrofuran (20 mL) was added and the solution was washed with a 1:1 mixture of brine/water and then with saturated aqueous NaHCO3. The organic layer was dried over Na2SO4, filtered, concentrated and purified via silica gel chromatography using a gradient of EtOAC/heptane (30-50%) to give the title compound (185 mg, 76% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 4.84 (t, J=5.4 Hz, 1 H), 3.61 (q, J=6.3 Hz, 2 H), 2.93 (t, J=6.8 Hz, 2 H), 2.52 (s, 3 H). m/z (APCI+) for C7H8Cl2N2OS 239.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:15])[CH2:13][CH3:14])[CH2:7][C:6](=[CH:16][N:17](C)C)[C:5]2=[O:20].[C:21]([O:25][C:26]([N:28]([CH3:30])N)=[O:27])([CH3:24])([CH3:23])[CH3:22].C(O)(=O)C>CO.O1CCCC1>[C:21]([O:25][C:26]([N:28]([CH3:30])[NH:17][CH:16]=[C:6]1[C:5](=[O:20])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]([C:12](=[O:15])[CH2:13][CH3:14])[CH2:7]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: CCC(=O)N1CC(=CN(C)C)C(=O)c2cc(Cl)ccc21
Reactant: CN(N)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: CCC(=O)N1CC(=CNN(C)C(=O)OC(C)(C)C)C(=O)c2cc(Cl)ccc21
Reaction time: 8 h
Yield: 78 %

Procedure:
A solution of 6-chloro-3-dimethylaminomethylene-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (2.00 g), 1-tert-butoxycarbonyl-1-methylhydrazine (1.50 g) and acetic acid (1.20 ml) in methanol (100 ml) and tetrahydrofuran (100 ml) was refluxed for 9 hours with stirring. 1-tert-Butoxycarbonyl-1-methylhydrazine (1.50 g) was added to the mixture and the stirring was continued for 8 hours at reflux conditions. After the solvent was evaporated in vacuo, saturated aqueous sodium hydrogen carbonate (15 ml) was added to the mixture and extracted with ethyl acetate (30 ml). The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue (3.90 g) was chromatographed on silica gel by eluting with chloroform to give 3-(2-tert-butoxycarbonyl-2-methylhydrazino)methylene-6-chloro-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (2.10 g) as yellow amorphous.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=O)[CH3:2].C([O-])(=O)C.[Na+].Cl.[NH2:16][OH:17]>O.C(O)C>[CH2:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[N:16][OH:17])[CH3:2]
Reactant: NO
Reactant: CCC1CCCCC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCC1CCCCC1=NO
Temperature: 70 °C
Yield: 52 %

Procedure:
To a solution of 2-ethylcyclohexanone (104.3 mmol) in water and ethanol, and sodium acetate (125.1 mmol) were added hydroxylamine hydrochloride (156.4 mmol), the reaction was heated at 70° C. overnight. The ethanol was removed under reduced pressure, and the reaction mixture was dissolved in water. The aqueous layer was extracted with ether, and the combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated to give 2-ethyl-1-(hydroxyimino)cyclohexane (52%) as a thick oil.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[OH:12].[CH2:14]1[CH2:24][CH2:23]N2C(=NCCC2)C[CH2:15]1.C1(CBr)CC1.O>O1CCCC1>[CH:14]1([CH2:15][O:12][C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=2[O:3][CH:2]([F:13])[F:1])[CH:8]=[O:9])[CH2:23][CH2:24]1
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Reactant: C1CCC2=NCCCN2CC1
Agent: BrCC1CC1
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 77.5 °C

Procedure:
4-Difluoromethoxy 3-hydroxy benzaldehyde in tetrahydrofuran (5 vol with respect to 4-Difluoromethoxy 3-hydroxy benzaldehyde) was taken in a vessel and DBU (1.5 eq respect to 4-Difluoromethoxy 3-hydroxy benzaldehyde) was added. To this first lot of cyclopropylmethylbromide (1.5 eq respect to 4-Difluoromethoxy 3-hydroxy benzaldehyde) was added and heated to 75-80° C. After 2 hours second lot of cyclopropylmethyl bromide (0.5 eq with respect to 4-Difluoromethoxy 3-hydroxy benzaldehyde) was added and maintained at 75-80° C. for 2 hours. To this third lot of cyclopropylmethyl bromide (0.5 eq with respect to 4-Difluoromethoxy 3-hydroxy benzaldehyde) was added and maintained for 2 hours. The reaction mass was cooled to 20-25° C. and water was added. The reaction mixture was extracted with EtOAc and EtOAc extracts were washed with water. EtOAc was distilled out under reduced pressure at 40° C. to get 3-cyclopropylmethoxy 4-Difluoromethoxy benzaldehyde as brown oil.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[NH:12][C:11]2[C:10](=[O:13])[N:9]([CH2:14][CH:15]3[CH2:17][CH2:16]3)[C:8](=[O:18])[N:7]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:6]=2[N:5]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.Cl>O1CCCC1.O>[CH:15]1([CH2:14][N:9]2[C:10](=[O:13])[C:11]3[NH:12][C:4]([NH:3][S:31]([C:28]4[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=4)(=[O:33])=[O:32])=[N:5][C:6]=3[N:7]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:8]2=[O:18])[CH2:16][CH2:17]1
Reactant: Nc1nc2c([nH]1)c(=O)n(CC1CC1)c(=O)n2CC1CC1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(S(=O)(=O)Nc2nc3c([nH]2)c(=O)n(CC2CC2)c(=O)n3CC2CC2)cc1
Reaction time: 0.5 h
Yield: 30.8 %

Procedure:
Sodium hydride (0.31 g of a 60% suspension in oil, 2.1 eq) was added to a suspension of 8-amino-1,3-di(cyclopropylmethyl)xanthine (1 g, 3.64 mmol) in tetrahydrofuran (25 ml). After 30 minutes, 4-methoxybenzenesulphonyl chloride (0.82 g, 1.1 eq) was added and stirring continued for 48 hours. The reaction mixture was poured into water, acidified with dilute hydrochloric acid and extracted into ethyl acetate. The combined organic solutions were dried (MgSO4), filtered and concentrated. The crude residue was purified by column chromatography over silica in 2-5% methanol/dichloromethane to afford 1,3-di(cyclopropylmethyl)-8-(4-methoxybenzenesulphonylamino )xanthine (0.50 g, 31%) as a white solid m.pt>200° C. (decomp.)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([S:25]([NH:28][C@H:29]([C:33]([OH:35])=[O:34])[CH:30]([CH3:32])[CH3:31])(=[O:27])=[O:26])=[CH:21][CH:20]=4)=[CH:15][CH:14]=3)=[O:11])=[CH:7][C:6]=2[CH:36]=1.C(N(CC)C(C)C)(C)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>C(Cl)Cl>[CH3:46][S:47]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:20]=[CH:21][C:22]([S:25]([NH:28][C@H:29]([C:33]([OH:35])=[O:34])[CH:30]([CH3:32])[CH3:31])(=[O:26])=[O:27])=[CH:23][CH:24]=4)=[CH:15][CH:14]=3)=[O:11])=[CH:7][C:6]=2[CH:36]=1)(=[O:49])=[O:48]
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3cc4cc(N)ccc4o3)cc2)cc1)C(=O)O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3cc4cc(NS(C)(=O)=O)ccc4o3)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-[(4′-{[(5-amino-1-benzofuran-2-yl)carbonyl]amino}-1,1′-biphenyl-4-yl)sulfonyl]-L-valine-Wang resin (0.3 g), from Example 7, was suspended in methylene chloride (6 mL). To the suspension was added with N,N-diisopropylethylamine (6.0 equiv.) and methanesulfonyl chloride (3.0 equiv.). The reaction was allowed to proceed at room temperature for 1 h and the reagent was removed by filtration. The resin was washed with methylene chloride (2×), methanol and methylene chloride (2×) before being treated with a 95% solution of TFA in methylene chloride (5 mL) and agitated at room temperature for 2 h. The solution was collected by filtration and the solvent was removed via vacuum. The crude product was then purified by flash chromatography to give N-({4′-[({5-[(methylsulfonyl)amino]-1-benzofuran-2-yl}carbonyl)amino]-1,1′-biphenyl-4-yl}sulfonyl)-L-valine LCMS MH+ (m/z) 586. 1H NMR (300 MHz, DMSO-d6): δ 10.53 ppm (s, 1H), 9.59 ppm (s, 1H), 7.78-7.16 ppm (m, 12H), 3.30 ppm (m, 1H), 1.87 ppm (m, 1H), 0.63 ppm (m, 6H).
Reaction SMILES: ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O.[CH:13]([O:16][CH2:17][CH2:18]O)([CH3:15])[CH3:14].Cl.[NH2:21][C:22]1[N:23]=[CH:24][NH:25][C:26]=1[C:27]([NH2:29])=[O:28]>C(Cl)Cl.CO.CC1(C)N([O])C(C)(C)CCC1>[CH:13]([O:16][CH2:17][CH2:18][NH:21][C:22]1[N:23]=[CH:24][NH:25][C:26]=1[C:27]([NH2:29])=[O:28])([CH3:14])[CH3:15]
Reactant: NC(=O)c1[nH]cnc1N
Reactant: CC(C)OCCO
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: Cl
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: CO
Solvent: ClCCl
Product: CC(C)OCCNc1nc[nH]c1C(N)=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 38.3 %

Procedure:
Trichlorocyanuric acid (1.23 g, 5.29 mmol) was added to a solution of 2-isopropoxyethanol (0.50 g, 4.80 mmol) in CH2Cl2 (3 mL). The reaction mixture was cooled to 0° C. and TEMPO (0.015 g, 0.09 mmol) was carefully added in small portions. The mixture was stirred at r.t. for 20 minutes and then filtrated through Celite and washed with CH2Cl2. The filtrate was kept cold, 0° C., during the filtration. The obtained aldehyde solution was added to a stirred mixture of 4-amino-1H-imidazole-5-carboxamide hydrochloride (0.78 g, 4.80 mmol), which was obtained from Example 3(b), at 0° C. in MeOH (5 mL). The mixture was stirred for 20 minutes, then NaCNBH4 (0.30 g, 4.80 mmol) was added. After stirring at r.t for 5 h the mixture was concentrated and purified by flash chromatography (CH2Cl2/methanol gradient; 0 to 5% methanol), to yield the title compound (0.39 g, 38%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([CH3:15])[CH:3]=1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:27][CH2:28][CH:29]=[C:30]1[C:36]2=[CH:37][CH:38]=[CH:39][NH:40][C:35]2=[CH:34][O:33][C:32]2[CH:41]=[CH:42][C:43]([C:45]([OH:48])([CH3:47])[CH3:46])=[CH:44][C:31]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:9][CH2:10][N:11]([CH2:27][CH2:28][CH:29]=[C:30]3[C:36]4[CH:37]=[CH:38][CH:39]=[N:40][C:35]=4[CH2:34][O:33][C:32]4[CH:41]=[CH:42][C:43]([C:45]([OH:48])([CH3:47])[CH3:46])=[CH:44][C:31]3=4)[CH2:12][CH2:13]2)=[C:4]([CH3:15])[CH:3]=1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)C1=CC=CNC1=CO2
Reactant: Cc1cc(Cl)ccc1C1(O)CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: Cc1cccc(C)n1
Solvent: CC(C)O
Product: Cc1cc(Cl)ccc1C1(O)CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CC1
Temperature: 80 °C
Reaction time: 14 h
Yield: 42.4 %

Procedure:
To a solution of the 4-(4-chloro-2-methyl-phenyl)-piperidin-4-ol (0.160 g, 0.71 mmol) in isopropanol was added 2,6-lutidine (0.24 mL, 2.1 mmol) and catalytic potassium iodide. This mixture was heated to 80° C., and treated with 2-[5-(3-Bromo-propylidene)-5,1-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.221 g, 0.59 mmol), added in portions over 1 h. The solution was then stirred at 80° C. for an additional 14 h. The reaction was concentrated in vacuo, then purified by Isco flash chromatography (15% methanol/85% methylene chloride) to yield the title compound (0.130 g, 36%). 1H-NMR (CDCl3): δ 1.57 (s, 6H), 1.92 (d, 2H), 2.30 (t, 2H), 2.49 (s, 3H), 2.48-2.63 (m, 2H), 2.74-3.11 (m, 6H), 3.40 (s, 1H), 5.21 (bs, 2H), 6.09 (t, 1H), 6.75 (d, 1H), 7.06 (d, 1H), 7.08 (s, 1H), 7.20 (d, 2H), 7.22-7.36 (m, 1H), 7.57 (d, 1H), 8.36 (dd, 1H). ESI-MS m/z: 519 (M+1), retention time 1.61.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[OH-:9].[Na+].[CH:11](Cl)(Cl)Cl>O>[CH3:8][C:3]1[CH:4]=[C:5]([CH:11]=[O:9])[C:6]([OH:7])=[CH:1][CH:2]=1
Reactant: ClC(Cl)Cl
Reactant: Cc1ccc(O)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(O)c(C=O)c1
Temperature: 62.5 °C
Reaction time: 2 h

Procedure:
28.8 g of p-cresol (0.26 mol) are dissolved in 100 ml of water in a round-bottomed flask containing 80 g of NaOH. The mixture is heated to 60-65° C. and 40.5 ml of CHCl3 (0.51 mol) are added in several portions over a period of 30 to 40 min. The mixture is refluxed for 1 h and then cooled. The excess chloroform is removed by distillation under reduced pressure. The medium is acidified with dilute H2SO4 and then subjected to vapor entrainment. The distillate collected (±500 ml) is extracted with ether. The solvent is removed by distillation under reduced pressure. The residue is taken up in 100 ml of saturated sodium bisulfite solution. After vigorous stirring for 2 h, followed by leaving to stand for 1 h, the bisulfite adduct precipitated is collected by filtration and washed with ether. The bisulfite combination is decomposed by heating on a water bath in dilute H2SO4 for 30 min. The aldehyde is extracted with ether. The ether solution is dried over MgSO4. The solvent is removed under reduced pressure. The residue is recrystallized from ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.[Cl:12][CH2:13][C:14](Cl)=[O:15]>C(Cl)Cl>[Cl:12][CH2:13][C:14]([NH:11][CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:15]
Reactant: O=C(Cl)CCl
Reactant: COc1cccc(CCN)c1
Solvent: ClCCl
Product: COc1cccc(CCNC(=O)CCl)c1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
The amine, 2-(3-Methoxy-phenyl)-ethylamine, was taken up as a 0.6 M solution in DCM, followed by addition of TEA (2 equiv.). The mixture was then cooled in an IPA/dry ice bath. When the reaction temperature reached −60° C., a solution of chloroacetylchloride in DCM (2.6 M) was added dropwise so as to keep the temperature below −60° C. After complete addition, the reaction was stirred at −60° C. for 1 h. The reaction was then warmed to −20° C. and filtered over GF filter paper to remove some of the TEA —HCl salt. The filtrate was warmed the rest of the way to rt and transferred to a separatory funnel where it was washed with 1 N HCl (2×) and brine. The organic layer was dried over MgSO4 and concentrated to give a dark purple solid. This crude product was directly used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[OH:10]N1C2C=CC=CC=2N=N1>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:1]=[O:10])=[CH:3][CH:4]=1
Reactant: On1nnc2ccccc21
Reactant: COc1ccc(C)cc1
Product: COc1ccc(C=O)cc1
Yield: 48 %

Procedure:
195 mg (1.60 mmol) of 4-methylanisole were reacted analogously to Example 1 in the presence of 24.3 mg (0.180 mmol) of 1-hydroxy-1H-benzotriazole. After a reaction time of 22 hours, the reaction solution was extracted with chloroform and examined by NMR spectroscopy. Yield 48% of 4-methoxybenzaldehyde (approx. 90%, based on conversion).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11].[CH:32](O)=[O:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:27][CH2:28][N:29]([CH:32]=[O:33])[CH2:30][CH2:31]4)[CH:25]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11]
Reactant: O=CO
Reactant: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C4CCNCC4)c3)cc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C4CCN(C=O)CC4)c3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-[1-(2,6-dichloro-3-fluorophenyl)ethyl]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine (8.0 mg, 0.0174 mmol), formic acid (1.3 μL, 0.0349 mmol), TBTU (11.2 mg, 0.0349 mmol), DIPEA (20 μL, 0.09 mmol) and DCM (1 mL) was stirred at rt for 30 min. The solution was concentrated in vacuo, redissolved in MeOH (0.5 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.88 (d, J=7.1 Hz, 3 H), 1.90-2.07 (m, 2 H), 2.10-2.23 (m, 2 H), 2.90 (td, J=12.9, 2.9 Hz, 1 H), 3.32-3.37 (m, 1 H), 3.89 (ddd, J=13.5, 2.2, 2.0 Hz, 1 H), 4.41-4.56 (m, 2 H), 5.28 (q, J=7.2 Hz, 1 H), 7.18 (t, J=8.6 Hz, 1 H), 7.30-7.53 (m, 3 H), 7.58 (s, 1 H), 7.90 (s, 1 H), 8.07 (s, 1 H), 8.31 (d, J=1.8 Hz, 1H). MS (ES+): m/z 486.00 (100) [MH+]. HPLC: tR=3.30 min (ZQ3, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([N+:16]([O-:18])=[O:17])[C:14]=1F)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[S-:19][CH2:20][CH3:21].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([N+:16]([O-:18])=[O:17])[C:14]=1[S:19][CH2:20][CH3:21])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CC[S-]
Reactant: O=[N+]([O-])c1c(F)c(Cl)cc2c1[nH]c1cnccc12
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1c(Cl)cc2c([nH]c3cnccc32)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 81.2 %

Procedure:
A 25 ml round-bottom flask with a magnetic stirrer was charged with 6-chloro-7-fluoro-8-nitro-9H-β-carboline (102 mg, 0.38 mmol) in 5 ml of anhydrous DMF. To the resulting orange mixture at RT was slowly added sodium thioethoxide (80% pure, 69.7 mg, 0.66 mmol) in powder form. The reaction mixture was stirred at RT for 45 minutes, then added drop-wise to a 5:1 mixture of H2O/saturated sodium bicarbonate (30 ml). The resulting precipitated solid was collected by suction filtration, washed with 1:1 hexanes/diethyl ether (2×20 ml), and air-dried to afford 95.0 mg of 6-chloro-7-ethylsulfanyl-8-nitro-9H-β-carboline as an orange solid (79%). 1H-NMR (300 MHz, CD3OD, ppm) δ 8.91 (1H, s) 8.63 (1H, s) 8.42 (1H, d) 8.18 (1H, d) 3.04 (2H, q) 1.20 (3H, t). Retention Time (LC, formic acid standard method): 1.71 min. MS (M+H+): 308.