Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([N:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:23](=[O:34])[C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:25]=1I)[CH3:21]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(=O)([O-])[O-].[Ag+2]>[CH2:20]([N:22]1[C:23](=[O:34])[C:24]2[C:29](=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]1=2)[CH3:21]
Reactant: CCN(C(=O)c1ccc([N+](=O)[O-])cc1I)c1ccccc1
Agent: [Ag+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: CCn1c(=O)c2ccc([N+](=O)[O-])cc2c2ccccc21
Temperature: 23 °C

Procedure:
Palladium acetate (826 mg, 3.68 mol) was added to a suspension of silver carbonate (10.1 g, 36.8 mmol), triphenylphosphine (1.93 g, 7.36 mmol), and N-ethyl-2-iodo-4-nitro-N-phenyl-benzamide (7.29 g, 18.4 mmol) in acetonitrile (92 ml). The reaction mixture was heated to reflux for 30 minutes and cooled to 23° C. The mixture was filtered through a plug of celite, and the filter cake was washed with ethyl acetate (100 ml) and diethyl ether (100 ml). The combined filtrates were washed with saturated sodium chloride (100 ml), dried over anhydrous sodium sulfate, and were concentrated. The residue was purified by flash column chromatography (150 ml diethyl ether followed by 150 ml of ethyl acetate) afforded 5-ethyl-9-nitro-5H-phenanthridin-6-one I-1d (2.87 g, 58%) as a yellow solid.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:23])[C:16]3[N:21]=[CH:20][C:19](Br)=[CH:18][N:17]=3)[CH2:11]2)=[N:3][CH:2]=1.[C:24]([Zn]C#N)#[N:25]>CN(C=O)C.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>[N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:23])[C:16]3[N:21]=[CH:20][C:19]([C:24]#[N:25])=[CH:18][N:17]=3)[CH2:11]2)=[N:3][CH:2]=1
Reactant: CN(c1ncc(Br)cn1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Reactant: N#C[Zn]C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CN(c1ncc(C#N)cn1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Temperature: 120 °C
Reaction time: 0.67 h

Procedure:
A mixture of (R)—N-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-5-bromo-N-methylpyrimidin-2-amine (50.0 mg, 0.134 mmol), dicyanozinc (15.7 mg, 0.134 mmol) and tetrakis(triphenylphosphine)palladium (15.4 mg, 0.0134 mmol) in 5 mL of DMF was stirred at 120° C. for 40 min in an Initator™ Biotage microwave reactor. The reaction mixture was partitioned between 15 mL of water and 20 mL of ethyl acetate. The organic layer was washed by brine, dried, concentrated and the residue was purified by preparative TLC to afford the title compound. MS (m/z): 321 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([NH:8][C:9]2[C:10]([CH3:31])=[C:11]([C:18](=[O:30])[C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[C:21]([O:28][CH3:29])[CH:20]=3)[N:12]3[C:17]=2[CH:16]=[CH:15][CH:14]=[CH:13]3)=[O:7])=[CH:4][CH:3]=1.[H][H]>CN(C)C=O.[Pt]=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[C:10]([CH3:31])=[C:11]([C:18](=[O:30])[C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([O:28][CH3:29])[CH:20]=3)[N:12]3[C:17]=2[CH:16]=[CH:15][CH:14]=[CH:13]3)=[O:7])=[CH:32][CH:33]=1
Reactant: COc1cc(C(=O)c2c(C)c(NC(=O)c3ccc(Cl)cc3)c3ccccn23)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)c2c(C)c(NC(=O)c3ccc(Cl)cc3)c3ccccn23)ccc1N

Procedure:
A mixture of 384 mg (0.83 mmol) of 4-chloro-N-[3-(3-methoxy-4-nitrobenzoyl)-2-methylindolizin-1-yl]benzamide and 115 mg of platinum oxide in 9 ml of dimethylformamide is stirred, under 5 bar of hydrogen, at room temperature for 24 hours, and then filtered on talc. The filtrate is concentrated under reduced pressure.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[C:14]1([CH3:23])[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[I:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:22]([CH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([CH3:23])=[CH:15][CH:16]=1)[CH2:11]2
Reactant: Cc1ccc(CCN)cc1
Reactant: COC(=O)c1c(I)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(CCN2Cc3cccc(I)c3C2=O)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
A mixture of 2-bromomethyl-6-iodo-benzoic acid methyl ester (0.107 g, 0.3 mmol), 2-p-tolyl-ethylamine (0.072 mL, 0.5 mmol), and K2CO3 (0.083 g, 0.6 mmol) in toluene (4 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-iodo-2-(2-p-tolyl-ethyl)-2,3-dihydro-isoindol-1-one (0.060 g, 53%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.28 (s, 3H), 2.94 (t, 2H), 3.81 (t, 2H), 4.76 (s, 2H), 7.12-7.36 (m, 6H), 7.86 (d, 1H). GC-MS: m/z 377 (M)+, 272(M−105)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:23][CH:22]=[N:21][CH:20]=2)=[CH:15][CH:14]=1)=O>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[O:23][CH:22]=[N:21][CH:20]=4)=[CH:15][CH:14]=3)[N:1]=2)[CH:4]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C(CBr)c1ccc(-c2cnco2)cc1
Product: Clc1ccc2nc(-c3ccc(-c4cnco4)cc3)cn2c1
Yield: 27 %

Procedure:
The procedure of Referential Example 1 was repeated, except that 2-amino-5-chloropyridine (49 mg) and 2-bromo-1-[4-(1,3-oxazol-5-yl)phenyl]-1-ethanone (100 mg), which had been produced in Referential Example 10 were used, to thereby yield the title compound (30 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[C:6]2[N:7]([C:16](=[O:19])[NH:17][N:18]=2)[C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[C:10]([F:15])[CH:9]=2.Cl[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[F:15][C:10]1[CH:9]=[C:8]2[C:13]([N:14]=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=3)[C:6]3[N:7]2[C:16](=[O:19])[NH:17][N:18]=3)=[CH:12][CH:11]=1
Reactant: NCCNc1nc2ccc(F)cc2n2c(=O)[nH]nc12
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: O=c1[nH]nc2c(NCCNc3ccc(C(F)(F)F)cn3)nc3ccc(F)cc3n12
Temperature: 25 °C

Procedure:
A solution of 259 mg of 4-(2-amino-ethylamino)-8-fluoro-2H-[1,2,4]triazolo[4,3-a]quinoxalin-1-one, 422 mg of 2-chloro-5-trifluoromethylpyridine and 411 mg of sodium carbonate in n-butanol (1 mL) was heated to reflux for 48 hrs. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and the filtrate concentrated to give a solid residue. This was separated by silica gel chromatography to provide the title compound. MS (M+H)+=407.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([CH3:20])[CH:3]=1.[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(=[O:24])=[O:23].C(=O)([O-])O.[Na+]>O1CCOCC1.O.C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Rh].[Rh]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]2[CH:29]=[CH:30][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:26][CH:27]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([CH3:20])[CH:3]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1cc(Cl)ccc1/C=C/C(=O)c1ccc(=O)n(C)c1
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: C1=CCCC=CCC1
Solvent: O
Product: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(S(C)(=O)=O)cc1

Procedure:
In analogy to example 203, step 1, 5-[(E)-3-(4-chloro-2-methyl-phenyl)-acryloyl]-1-methyl-1H-pyridin-2-one (example 323, step 3) was reacted with 4-(methylsulfonyl)phenyl-boronic acid in the presence of chloro(1,5-cyclooctadiene)rhodium(I) dimer and sodium hydrogencarbonate in 1,4-dioxane and water at 60° C. to give the title compound as a colourless solid, MS (ESI+): m/z=444.2 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].O1CCCC1.B.ClCCl>O1CCCC1.O=[Mn]=O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[CH:7]=[O:8]
Reactant: Cc1ccc(I)cc1C(=O)O
Agent: O=[Mn]=O
Agent: B
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(I)cc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.6 %

Procedure:
To a solution of 5-iodo-2-methyl benzoic acid (24 g, 91 mmol) (AKSCI) in anhydrous tetrahydrofuran (100 mL) at 0° C. was added borane tetrahydrofuran (1 M, 250 mL, 250 mmol) dropwise. The reaction mixture was then stirred at room temperature for 2 h. The mixture was concentrated and residue was partitioned between ethyl acetate and water. Organic layer was separated, washed with brine, dried over MgSO4, and concentrated to give an off-white solid. The solid was dissolved into dichloromethane (300 mL), and activated MnO2 (20 g) was added. The mixture was then heated at reflux for 4 h, cooled to room temperature, and filtered through a short pad of celite. The filtrated was concentrated and purified by chromatography (EtOAc:hexanes=1;8) to give 5-Iodo-2-methyl-benzaldehyde as an off-white solid (Yield 5.5 g, 25%).
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[C:3](=[O:21])[CH2:4][O:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[N:9]=[C:8]([C:18]([OH:20])=[O:19])[CH:7]=1.[CH3:24][Mg]Br.C(OCC)C.C(Cl)Cl>C1COCC1.O.CC(=O)OCC>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:10]1[C:6]([O:5][CH2:4][C:3]([OH:21])([CH3:24])[C:2]([CH3:23])([CH3:22])[CH3:1])=[CH:7][C:8]([C:18]([OH:20])=[O:19])=[N:9]1
Reactant: C[Mg]Br
Reactant: CC(C)(C)C(=O)COc1cc(C(=O)O)nn1-c1ccccc1F
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)(C)C(C)(O)COc1cc(C(=O)O)nn1-c1ccccc1F
Temperature: 0 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
610 mg (1.9 mmol) of 5-(3,3-dimethyl-2-oxo-butoxy)-1-(2-fluoro-phenyl)-1H-pyrazole-3-carboxylic acid were dissolved in 20 ml of dry THF under argon and cooled to 0° C. 1.4 ml of a 3 M solution of methylmagnesium bromide in diethyl ether (4.2 mmol) were added over 10 min. The mixture was allowed to reach room temperature overnight and then diluted with 50 ml of water and 30 ml of EA. After phase separation, the aqueous phase was adjusted to pH=3 by addition of 1 M hydrochloric acid. The precipitate which formed was dissolved by addition of 40 ml of DCM, the organic phase was separated, dried over sodium sulfate and evaporated. 390 mg (61%) of the title compound were obtained.
Reaction SMILES: CO[C:3](=[NH:35])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([S:20](=[O:34])(=[O:33])[NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)=[CH:16][CH:15]=2)=[O:12])[CH:5]=1.[CH2:36](N)[CH2:37][NH2:38]>C(O)C>[NH:38]1[CH2:37][CH2:36][N:35]=[C:3]1[C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:12])[NH:13][C:14]2[CH:15]=[CH:16][C:17]([S:20]([NH:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([S:29](=[O:31])(=[O:32])[NH2:30])=[CH:27][CH:28]=3)(=[O:33])=[O:34])=[CH:18][CH:19]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=N)c1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Reactant: NCCN
Solvent: CCO
Product: NS(=O)(=O)c1ccc(CNS(=O)(=O)c2ccc(NC(=O)Nc3cccc(C4=NCCN4)c3)cc2)cc1

Procedure:
3-{3-[4-(4-Sulfamoylbenzylsulfamoyl)-phenyl]-ureido}-benzimidic acid methyl ester (130 mg, 1 eq.) was suspended in anhydrous ethanol (10 ml), ethylenediamine (0.1 ml, 5.7 eq.) was added and the mixture was refluxed for 16 h. The precipitate was filtered off, washed with diethylether and dried in vacuo. Yield: 60 mg (45%) of 4-{3-[4-(4,5-dihydro-1H-imidazol-2-yl)-phenyl]-ureido}-N-(4-sulfamoylbenzyl)-benzenesulfonamide.
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:11]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O>[Cl:8][C:7]1[C:2]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([N+:16]([O-:18])=[O:17])[C:10]=2[F:9])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1cccnc1Br
Reactant: CC1(C)OB(c2cccc([N+](=O)[O-])c2F)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc(-c2ncccc2Cl)c1F
Temperature: 120 °C

Procedure:
To a solution of 2-bromo-3-chloropyridine [96424-68-9] (144 mg, 0.75 mmol) and 2-fluoro-3-nitrophenylboronic acid pinacol ester [1189042-70-3] (200 mg, 0.75 mmol) in dioxane (4 mL) and water (1 mL) was added potassium carbonate (259 mg, 1.87 mmol) and Pd(dppf)Cl2CH2Cl2 adduct (61.2 mg, 0.075 mmol). The solution was heated for 60 min at 120° C. under microwave irradiation. The reaction mixture was diluted with EtOAc and the resulting solution was washed successively with saturated aqueous NaHCO3 solution and brine, then dried (Phase separator) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (c-hexane/EtOAc 4:1) to give the title compound. MS (LC-MS): 253 [M+H]+; tR (HPLC conditions k): 3.45 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C@H:13]([C@@H:29]2[O:33]C(C)(C)O[C:30]2=[O:36])[C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)[CH2:18][CH2:17]2)=[O:15])=[CH:6][CH:5]=1)[CH3:2].[NH2:37][OH:38].O>CC(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][C@@H:13]([C:14]([N:16]2[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)[CH2:20][CH2:21]2)=[O:15])[C@H:29]([OH:33])[C:30]([NH:37][OH:38])=[O:36])=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(CCC[C@@H](C(=O)N2CCN(CCc3cccs3)CC2)[C@@H]2OC(C)(C)OC2=O)cc1
Reactant: NO
Solvent: O
Solvent: CC(C)O
Product: CCOc1ccc(CCC[C@@H](C(=O)N2CCN(CCc3cccs3)CC2)[C@H](O)C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
To a solution of (5S)-5-[(1R)-4-(4-ethoxyphenyl)-1-({4-[2-(2-thienyl)ethyl]-1-piperazinyl}carbonyl)butyl]-2,2-dimethyl-1,3-dioxolan-4-one (101 mg, 0.20 mmol) in iPrOH (3 mL) was added a 50% aqueous solution of hydroxylamine (60 μL) and the resulting mixture was stirred at RT for 1 hour. Then water (12 mL) was added and the resulting mixture was purified by reverse-phase chromatography (using a mixture of water and iPrOH with a ratio from 4:1 to 1:1 as eluent) to give 40 mg (42%) of the title compound as a white powder. M−(ESI): 488.4; M+(ESI): 490.4. HPLC, Rt: 2.5 min (purity: 97.0%).
Reaction SMILES: [H-].[Na+].[CH:3]1([NH:6][C:7](=[O:25])[C:8]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][N:18]=[CH:17]4)[C:11]([CH3:23])=[C:10]([F:24])[CH:9]=2)[CH2:5][CH2:4]1.Br[CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1>CN(C=O)C.C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH:3]1([NH:6][C:7](=[O:25])[C:8]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)[N:18]=[CH:17]4)[C:11]([CH3:23])=[C:10]([F:24])[CH:9]=2)[CH2:4][CH2:5]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2[nH]ncc2c1
Reactant: BrCC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(cnn2CC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60% in mineral oil, 12 mg) was added to N-cyclopropyl-3-fluoro-5-(1H-indazol-5-yl)-4-methylbenzamide (Intermediate 3, 45 mg) in DMF (5 ml) and the mixture was stirred at room temperature for 1 h. 2-(Bromomethyl)tetrahydro-2H-pyran (20.5 μl) was added and stirring continued for 18 h. The mixture was diluted with chloroform/ethyl acetate (1:1, 5 ml) and washed with water (2×5 ml). The organic phase was concentrated under vacuum and the residue was purified by preparative HPLC to give the title compound as a colourless glass (23 mg).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]2[N:9]([CH:13]([C:15]3[O:16][C:17](=[O:31])[C:18]4[C:23]([C:24]=3[C:25]3[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH3:14])[N:10]=[C:11]([I:12])[C:4]=12.[CH:32]([N:35]1[CH2:40][CH2:39][C:38](=O)[CH2:37][CH2:36]1)([CH3:34])[CH3:33].CCN(C(C)C)C(C)C.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)=O.O.CC#N>[CH:17]([OH:31])=[O:16].[NH2:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]2[N:9]([CH:13]([C:15]3[O:16][C:17](=[O:31])[C:18]4[C:23]([C:24]=3[C:25]3[CH2:26][CH2:27][N:28]([CH:38]5[CH2:39][CH2:40][N:35]([CH:32]([CH3:34])[CH3:33])[CH2:36][CH2:37]5)[CH2:29][CH:30]=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH3:14])[N:10]=[C:11]([I:12])[C:4]=12
Reactant: CC(C)N1CCC(=O)CC1
Reactant: CC(c1oc(=O)c2ccccc2c1C1=CCNCC1)n1nc(I)c2c(N)ncnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCC(N2CC=C(c3c(C(C)n4nc(I)c5c(N)ncnc54)oc(=O)c4ccccc34)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 160.4 %

Procedure:
A mixture of 3-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-isochromen-1-one hydrochloride (Intermediate D23, 0.1 g, 0.182 mmol), 1-isopropylpiperidin-4-one (0.064 ml, 0.438 mmol), DIPEA (0.032 ml, 0.182 mmol) and a spatula of sodium sulfate in DCM (3 ml) was stirred at rt for 10 min. Acetic acid (0.061 mL, 1.09 mmol) was then added followed by sodium triacetoxyborohydride (154 mg, 0.726 mmol). The resulting suspension was stirred for 3 hrs at rt, then the reaction was quenched by the addition of 2 N HCl. The heterogeneous mixture was concentrated under reduced pressure. Purification by RP-flash chromatography (Biotage 30 g C18 column, gradient elution from 100:0 to 60:40 A/B in 15 CV; A: water/MeCN 95/5+0.01% HCOOH, B: water/MeCN 5/95+0.01% HCOOH) yielded title compound (99.8 mg, 0.146 mmol, 80% yield) as a light yellow powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.[NH2:8][C:9]1[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=1[CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[N:8][C:9]1[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=1[CH2:11][N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: O=C1CCCCN1
Reactant: Nc1ccccc1CN1CCOCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: c1ccc(N=C2CCCCN2)c(CN2CCOCC2)c1

Procedure:
A mixture of 2-piperidone (3.6 g) in benzene (30 ml), 4-(2-aminobenzyl)morpholine (5.7 g) in benzene (20 ml) and phosphorus oxychloride (3.6 ml) was heated at 65°-70° C. for 48 hours to yield 4-[2-(2-piperidinylideneamino)benzyl]morpholine (m.p. 108°-110° C.) which was recrystallised from hexane.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[C:12]([C:18]([OH:20])=O)[NH:13]3)[CH:5]=[CH:4][CH:3]=1.Cl.Cl.Cl.[N:24]1([CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:24]1([CH2:31][CH2:32][N:33]2[CH2:34][CH2:35][CH:36]([NH:39][C:18]([C:12]3[NH:13][C:14]4[C:10]([CH:11]=3)=[C:9]([O:8][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=3)[CH:17]=[CH:16][CH:15]=4)=[O:20])[CH2:37][CH2:38]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Reactant: O=C(O)c1cc2c(Oc3cccc(Cl)n3)cccc2[nH]1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(Oc3cccc(Cl)n3)cccc2[nH]1

Procedure:
This compound is synthesized analogously to Example 1 from 4-(6-Chloro-pyridin-2-yloxy)-1H-indole-2-carboxylic acid 157 (preparation see below) and amine 5.
Reaction SMILES: C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.Cl[C:21]1[N:26]=[CH:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]([OH:38])([CH3:37])[CH3:36])=[C:29]([O:39][CH3:40])[CH:28]=2)[C:23](=[O:41])[CH:22]=1.[C:42]1([CH:48]2[CH2:50][CH:49]2B(O)O)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[OH:38][C:35]([CH3:37])([CH3:36])[CH2:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([N:24]2[C:23](=[O:41])[CH:22]=[C:21]([CH:49]3[CH2:50][CH:48]3[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[N:26]=[CH:25]2)=[CH:28][C:29]=1[O:39][CH3:40]
Reactant: OB(O)C1CC1c1ccccc1
Reactant: COc1cc(-n2cnc(Cl)cc2=O)ccc1OCC(C)(C)O
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(-n2cnc(C3CC3c3ccccc3)cc2=O)ccc1OCC(C)(C)O
Temperature: 100 °C
Reaction time: 2 h
Yield: 23.49 %

Procedure:
Tricyclohexyl phosphine (10 μL, 9.24 μmol) was added under nitrogen to a mixture of 6-chloro-3-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)-pyrimidin-4(3H)-one Part A of Procedure 11 (10 mg, 0.031 mmol), 2-phenylcyclopropylboronic acid (5.5 mg, 0.034 mmol), palladium (II) acetate (2 mg, 6.16 μmol), and potassium phosphate, tribasic (20 mg, 0.09 mmol) in toluene (0.16 mL), and water (0.07 mL). The reaction stirred at 100° C. for 2 hours. The reaction mixture was filtered and concentrated to afford the crude product. The crude was purified using HPLC (C18 column/10:90:0.1 to 90:10:0.1 MeOH—H2O-TFA) to afford the desired product 3-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)-6-(2-phenylcyclopropyl)pyrimidin-4(3H)-one K-1 (3 mg, 7.23 μmol, 23.49% yield) as a light yellow solid. LC/MS 407 (M+H)+, tR 0.92 min (method 5); 1H NMR (400 MHz, CHLOROFORM-d) δ 8.11 (1H, s), 7.28-7.41 (2H, m), 7.20-7.26 (1H, m), 7.13-7.19 (2H, m), 7.00 (1H, d), 6.85-6.90 (2H, m), 6.48 (1H, s), 3.88 (5H, br. s.), 2.60-2.66 (1H, m), 2.08-2.14 (1H, m), 1.75-1.81 (1H, m), 1.51-1.57 (1H, m), 1.37 (6H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@:15]23[CH2:24][C:23]4[N:25]=[C:26]5[C:31](=[CH:32][C:22]=4[CH2:21][C@H:20]2[CH2:19][NH:18][CH2:17][CH2:16]3)[CH:30]=[CH:29][CH:28]=[CH:27]5)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:33]1([CH:36]=O)[CH2:35][CH2:34]1.C(O)(=O)C.C(=O)(O)[O-].[Na+]>C1COCC1.O>[CH:33]1([CH2:36][N:18]2[CH2:17][CH2:16][C@:15]3([C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[CH:10]=4)[C@@H:20]([CH2:21][C:22]4[CH:32]=[C:31]5[C:26]([CH:27]=[CH:28][CH:29]=[CH:30]5)=[N:25][C:23]=4[CH2:24]3)[CH2:19]2)[CH2:35][CH2:34]1
Reactant: c1ccc(COc2cccc([C@@]34CCNC[C@@H]3Cc3cc5ccccc5nc3C4)c2)cc1
Reactant: O=CC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: c1ccc(COc2cccc([C@@]34CCN(CC5CC5)C[C@@H]3Cc3cc5ccccc5nc3C4)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
(4aR, 12aR)-4a-(3-benzyloxyphenyl)-1,2,3,4,4a,5,12,12a-octahydroquinolino[2, 3-g]isoquinoline (84 mg), and cyclopropanecarboaldehyde (0.0305 ml, 0.40 mmol) were dissolved in dry THF (4 ml), and triacetoxysodium borohydride (84. 8 mg, 0.40 mmol) and acetic acid (0.0126 ml, 0.22 mmol) were added to the resultant solution, followed by stirring at room temperature for 2 hours. A saturated aqueous sodium bicarbonate solution (30 ml) and water (30 ml) were then added to the solution, and the resultant mixture was extracted with chloroform (100 ml, twice). The organic layers were dried over sodium sulfate, and then concentrated. The residue was purified by using a silica gel column to obtain (4aR, 12aR)-2-cyclopropylmethyl-4a-(3-benzyloxyphenyl)-1,2,3,4,4a,5,12,12a-octahydroquinolino[2, 3-g]isoquinoline (78 mg, 82% in two steps).