Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([SH:19])[CH:13]=[CH:12]2.I[C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[C:23]#[N:24].C(=O)([O-])[O-].[K+].[K+].C(O)CO>C(O)(C)C.[Cu]I.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([S:19][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[C:23]#[N:24])[CH:13]=[CH:12]2
Reactant: Fc1ccc(-c2ccc3cc(S)ccc3c2)c(F)c1
Reactant: N#Cc1ccccc1I
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: OCCO
Solvent: CC(C)O
Product: N#Cc1ccccc1Sc1ccc2cc(-c3ccc(F)cc3F)ccc2c1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 20.2 %

Procedure:
6-(2,4-Difluorophenyl)-2-naphthyl hydrosulfide (Step 2, 0.78 g) was dissolved in isopropyl alcohol (15 mL). 2-Iodobenzonitrile (0.66 g, 2.88 mmol), copper(I) iodide (29 mg, 0.15 mmol), potassium carbonate (0.8 g, 5.79 mmol) and ethylene glycol (320 μL) were added and the reaction heated to 80° C. under nitrogen overnight. Ethyl acetate was added to the cooled reaction mixture and stirred for 15 minutes. The mixture was filtered and the filtrate evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 10-20% ethyl acetate/isohexane, followed by recrystallisation from ethyl acetate/isohexane, to give 2-{[6-(2,4-difluorophenyl)-2-naphthyl]thio}benzonitrile (216 mg, 20%). 1H NMR (500 MHz, CDCl3) δ 8.04 (1H, s), 7.97 (1H, s), 7.88 (2H, t, J=7.8 Hz), 7.68 (2H, d, J=8.0 Hz), 7.54-7.48 (2H, m), 7.43-7.39 (1H, m), 7.28 (1H, t, J=7.6 Hz), 7.19 (1H, d, J=7.9 Hz), 7.03-6.95 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26]Cl)[CH2:21][CH2:20]3)[C:4]=2[CH:3]=1.[ClH:28].[CH3:29][N:30]([CH3:42])[CH2:31][CH2:32][CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1.[OH-].[Na+]>CS(C)=O.O>[ClH:1].[ClH:28].[ClH:1].[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][O:41][C:38]4[CH:37]=[CH:36][C:35]([O:34][CH2:33][CH2:32][CH2:31][N:30]([CH3:29])[CH3:42])=[CH:40][CH:39]=4)[CH2:23][CH2:24]3)[C:4]=2[CH:3]=1
Reactant: ClCCN1CCN(CCCN2c3ccccc3Sc3ccc(Cl)cc32)CC1
Reactant: CN(C)CCCOc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CN(C)CCCOc1ccc(OCCN2CCN(CCCN3c4ccccc4Sc4ccc(Cl)cc43)CC2)cc1
Temperature: 55 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
A solution of 1-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-4-(2-chloroethyl)piperazine (4.22 g) and 4-(3-dimethylaminopropoxy)phenol hydrochloride, (2.3 g) in dimethylsulfoxide (100 ml) was stirred under nitrogen and warmed to 55° C. Then a solution of sodium hydroxide (0.8 g) in water (3 ml) was added and the reaction was stirred at 55°-65° for 2 hours. The usual work-up furnished the crude salt, which was crystallized from methanol-ethyl acetate to give 1.5 g of 3-[[4-[2-[4-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-1-piperazinyl]ethoxy]phenyl]oxy] -N,N-dimethylpropanamine trihydrochloride, mp 228°-230°.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[S:23])=[CH:17][CH:16]=1>CN(C)P(=O)(N(C)C)N(C)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[S:23])[NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(=O)c1csc(NC(=S)Nc2ccc(Cl)cc2)n1

Procedure:
Following a procedure similar to that described in Preparation 1, the desired compound was prepared from 5 g of ethyl 2-aminothiazol-4-ylglyoxylate, 6.35 g of p-chlorophenyl isothiocyanate and 30 ml of hexamethylphosphoric triamide. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9](N)[S:10][C:6]=2[CH:5]=1)[CH2:2][CH3:3].C([CH2:16][O:17][C:18]1[C:19]([F:28])=[C:20]([C:25]([NH2:27])=[O:26])[C:21]([F:24])=[CH:22][CH:23]=1)#N>>[F:28][C:19]1[C:18]([O:17][CH2:16][C:9]2[S:10][C:6]3[CH:5]=[C:4]([CH2:1][CH2:2][CH3:3])[CH:13]=[CH:12][C:7]=3[N:8]=2)=[CH:23][CH:22]=[C:21]([F:24])[C:20]=1[C:25]([NH2:27])=[O:26]
Reactant: CCCc1ccc2nc(N)sc2c1
Reactant: N#CCOc1ccc(F)c(C(N)=O)c1F
Product: CCCc1ccc2nc(COc3ccc(F)c(C(N)=O)c3F)sc2c1
Yield: 18 %

Procedure:
Synthesised from 6-propyl-1,3-benzothiazol-2-amine and 3-(cyanomethoxy)-2,6-difluorobenzenecarboxamide, according to Method K, scheme 26. Yield 18% (second step), mp 173-175° C. HPLC-MS (method 1): m/z 363 [M+H]+, Rt=4.35 min.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:6]=2[N:7]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)C>CN(C=O)C.O>[N+:12]([C:10]1[CH:9]=[CH:8][C:6]2[N:7]=[C:3]([CH2:2][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[O:4][C:5]=2[CH:11]=1)([O-:14])=[O:13]
Reactant: C1CCNC1
Reactant: O=[N+]([O-])c1ccc2nc(CCl)oc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: O=[N+]([O-])c1ccc2nc(CN3CCCC3)oc2c1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A reaction mixture of 3.00 g (14.1 mmol) of 2-chloromethyl-6-nitrobenzoxazole (VIII.1.a), 1.50 mL (18.0 mmol) of pyrrolidine, and 3.90 g (28.2 mmol) of potassium carbonate in 30 mL of DMF is stirred for 12 hours at 50° C. After this time, the mixture is diluted with water and covered with diethyl ether. The precipitate formed is filtered off and dried at 80° C. Yield: 1.80 g (52% of theory); C12H13N3O3; EII mass spectrum: m/z=248 [M+H]+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([C:11]23[CH2:20][CH:15]([CH2:16][CH:17]([NH2:19])[CH2:18]2)[N:14]([CH3:21])[CH2:13][CH:12]3[CH3:22])[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[C:23]1(=O)[O:28][C:26](=[O:27])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([C:11]23[CH2:20][CH:15]([CH2:16][CH:17]([N:19]4[C:26](=[O:27])[C:25]5[C:24](=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:23]4=[O:28])[CH2:18]2)[N:14]([CH3:21])[CH2:13][CH:12]3[CH3:22])[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)Oc1cccc(C23CC(N)CC(C2)N(C)CC3C)c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)Oc1cccc(C23CC(CC(N4C(=O)c5ccccc5C4=O)C2)N(C)CC3C)c1
Yield: 61.9 %

Procedure:
5-(3-Isopropoxy-phenyl)-2,4-dimethyl-2-aza-bicyclo[3.3.1 ]non-7-ylamine (2.4) (1.69 g, 5.6 mmol) was dissolved in toluene followed by the addition of phthalic anhydride (2.5 g, 16.8 mmol) and the reaction mixture was refluxed with a Dean-Stark trap overnight. The solution was then cooled, diluted with ethyl acetate, and filtered into a separatory funnel. The organic layer was washed with 1 N NaOH (3×30 ml) and water. The organic layer was collected, dried (Na2SO4) and the solvent removed under reduced pressure yielding crude product. The crude product was purified by filtering through a short column of neutral alumina (Brockman activity II-III) eluting with ethyl acetate to afford the title compound (1.50 g, 62%) as an off white solid. 1H NMR (CDCl3) δ: 7.76 (m, 2H), 7.65 (m, 2H), 7.23 (t, 1H, J=7.8), 7.00-6.72 (m, 3H), 5.08 (m, 1H), 4.52 (sept., 1H, J=6.1 Hz), 3.15 (m, 1H), 2.96 (m, 1H), 2.62 (m, 1H), 2.45-2.32 (m, 4H), 2.23 (s, 1H), 2.11 (m, 1H), 1.67 (m, 2H), 1.31 (d, 6H, J=6.0 Hz), 1.15 (m, 1H), 0.94 (m, 1H), 0.73 (d, 3H, J=6.9 Hz).
Reaction SMILES: [ClH:1].Cl.[N:3]1([C:9]2[N:14]=[CH:13][N:12]=[C:11]3[NH:15][N:16]=[CH:17][C:10]=23)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(OC([NH:46][CH2:47][CH2:48][CH:49]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[Cl:59])[C:50](O)=[O:51])=O)(C)(C)C.C(N(CC)CC)C>CN(C=O)C>[ClH:59].[ClH:1].[NH2:46][CH2:47][CH2:48][CH:49]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[Cl:59])[C:50]([N:6]1[CH2:5][CH2:4][N:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]3[NH:15][N:16]=[CH:17][C:10]=23)[CH2:8][CH2:7]1)=[O:51]
Reactant: CC(C)(C)OC(=O)NCCC(C(=O)O)c1ccccc1Cl
Reactant: c1nc(N2CCNCC2)c2cn[nH]c2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NCCC(C(=O)N1CCN(c2ncnc3[nH]ncc23)CC1)c1ccccc1Cl
Reaction time: 4 h
Yield: 133.1 %

Procedure:
The 4-piperazin-1-yl-1H-pyrazolo[3,4-d]pyrimidine bis-hydrochloride salt (60 mg, 0.22 mmol), HOBt (29 mg, 0.22 mmol), EDCI (46 mg, 0.24 mmol), and 4-tert-butoxycarbonylamino-2-(2-chlorophenyl)-butyric acid [prepared by procedures described in Example 61 (68 mg. 0.22 mmol)] were suspended/dissolved in 1.5 mL of DMF then treated with triethylamine (121 μL, 0.87 mmol). The mixture was allowed to stir for four hours to completion then partitioned between ethyl acetate and diluted NaHCO3 solution. The aqueous was extracted with ethyl acetate, and the organics were combined. The organic was washed with water, brine, separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was dissolved in 1 mL of 1,4-dioxane and treated with 1 mL of 4M HCl in 1,4-dioxane. The solution stirred overnight to completion at room temperature and diluted with diethyl ether to afford a precipitate. This material was broken up to afford a suspended granular solid which was stirred for 30 minutes. The suspension was filtered, washed with diethyl ether, and dried over a stream of nitrogen to afford the 4-amino-2-(2-chlorophenyl)-1-[4-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-piperazin-1-yl]-butan-1-one bis-hydrochloride salt as a tan solid (69.2 mg, 67%). 1H NMR (D6O, 400 MHz) δ 8.52 (brs, 1H), 8.31 (s, 1H), 7.40 (d, J=7.2 Hz, 1H), 7.12 (m, 3H), 4.42 (t, J=6.8 Hz, 1H), 4.11 (m, 1H), 3.98 (m, 3H), 3.70 (m, 2H), 3.61 (m, 1H), 3.41 (m, 1H), 2.96 (m, 1H), 2.80 (m, 1H), 2.21 (m, 1H), 1.94 (m, 1H). LCMS (APCI+) m/z 400 [M+H]+; Rt=1.52 min.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:25]3[CH2:26][O:27][CH2:28][CH2:29][CH:30]=3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]>CCOC(C)=O.[Pd].[O-2].[O-2].[Mn+4]>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([CH:25]3[CH2:30][CH2:29][CH2:28][O:27][CH2:26]3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(c1ccc(Oc2nccnc2C2=CCCOC2)cc1)c1nc2ccccc2[nH]1
Agent: [Mn+4]
Agent: [Pd]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Oc2nccnc2C2CCCOC2)cc1)c1nc2ccccc2[nH]1
Reaction time: 24 h

Procedure:
1H-Benzimidazol-2-yl(4-((3-(5,6-dihydro-2H-pyran-3-yl)-2-pyrazinyl)oxy)phenyl)methanone (0.20 g, 0.50 mmol) was suspended in 15 mL of EtOAc in a pressure tube. Palladium on carbon, 10% (0.20 g) was added. The mixture was hydrogenated at 50 psi. After 24 hours, the mixture was filtered through celite and eluted with 50 mL of 9:1 chloroform:isopropanol. The product was taken up in 10 mL of dichloromethane. Manganese dioxide (0.58 g, 6.7 mmol) was added. After 1 h, the mixture was filtered through celite and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (0 to 2% MeOH/dichloromethane) affording 1H-benzimidazol-2-yl(4-((3-(tetrahydro-2H-pyran-3-yl)-2-pyrazinyl)oxy)phenyl)methanone. MS (ESI, pos. ion) m/z: 401 (M+1). IC50 (uM) +++++.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[CH:16][C:17]=4[CH2:18][CH2:19][C:8]=3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:22])[CH3:2].[BH4-].[Na+].C(O)(=O)C>CO>[CH2:1]([C@:3]12[CH2:11][CH2:10][C:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[CH:16][C:17]=4[CH2:18][CH2:19][C:8]=3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:22])[CH3:2]
Reactant: CC[C@]12CCC3=C(CCc4cc(OC)ccc43)[C@@H]1CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC[C@]12CCC3=C(CCc4cc(OC)ccc43)[C@@H]1CC[C@@H]2O

Procedure:
Add 13β-ethyl-3-methoxygona-1,3,5(10),8-tetraen-17-one (16.8 g.) to a solution of sodium borohydride (6 g.) in methanol (500 cc.), swirl the mixture which boils spontaneously. When all the material has been added and the reaction has subsided, add acetic acid (15 cc.). Reduce the mixture in volume by evaporation of most of the solvent, add water and extract the product with ether. Evapoate the washed and dried extracts to obtain crude crystalline product (16.8 g.), m.p. 102°-5° on recrystallization from acetonitrile.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[CH:20]=[CH:21][CH:22]=1.[Br:31]N1C(=O)CCC1=O>C(#N)C.C(OCC)(=O)C>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:31])[N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([P:23](=[O:30])([O:24][CH2:25][CH3:26])[O:27][CH2:28][CH3:29])[CH:20]=[CH:21][CH:22]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOP(=O)(OCC)c1cccc(Cn2cnc3c(N)nc(OCCOC)nc32)c1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOP(=O)(OCC)c1cccc(Cn2c(Br)nc3c(N)nc(OCCOC)nc32)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Diethyl 3-((6-amino-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)phenylphosphonate (30) (400 mg, 0.92 mmol) was dissolved in acetonitrile and N-bromosuccinimide (500 mg, 2.8 mmol) was added in one portion. After stirring at room temperature for 2 h, the reaction mixture was diluted with ethyl acetate (150 mL) and washed with water, 0.2 M sodium thiosulfate solution and brine. The organic phase was dried with sodium sulfate and the solvent was removed under vacuum. The crude diethyl 3-((6-amino-8-bromo-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)phenylphosphonate (450 mg, 95%) was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[C:3]2[N:18]=[C:17]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:26])[S:16][C:4]=2[C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11][N:10]=2)=[N:6][CH:7]=1.[CH3:27][N:28](CCN(C)C)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].CN(C=O)C>[Cl:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:19]=1[C:17]1[S:16][C:4]2[C:5]([NH:8][C:9]3[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11][N:10]=3)=[N:6][CH:7]=[C:2]([C:27]#[N:28])[C:3]=2[N:18]=1
Reactant: CN(C)CCN(C)C
Reactant: Cc1cc(Nc2ncc(Br)c3nc(-c4c(F)cccc4Cl)sc23)ncn1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: Cc1cc(Nc2ncc(C#N)c3nc(-c4c(F)cccc4Cl)sc23)ncn1
Temperature: 140 °C
Yield: 47.9 %

Procedure:
A mixture of 7-bromo-2-(2-chloro-6-fluoro-phenyl)-N-(6-methylpyrimidin-4-yl)thiazolo[5,4-c]pyridin-4-amine (0.15 mmol, 69 mg), Zn(CN)2 (0.30 mmol, 36 mg), Pd2(dba)3 (0.015 mmol, 13.8 mg), and dppf (0.030 mmol, 16.5 mg) in a 10 mL microwave vial was purged with nitrogen for 5 min. DMF (3 mL) and TMEDA (0.03 mmol; 3.6 mg) were added. The vial was sealed and heated at 140° C. in a microwave reactor for 20 min. The reaction mixture was filtered through celite, washed with EtOAc. Filtrate was concentrated to give a crude product which was purified by reverse phase HPLC to give the title compound as an off-white solid (5.7 mg, 9.6% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 8.89 (s, 1H), 8.74 (s, 1H), 7.75 (td, J=8.3, 6.2 Hz, 1H), 7.68 (s, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.54 (t, J=8.9 Hz, 1H), 2.43 (s, 3H). LCMS (Method B): RT=4.33 min, m/z 397.1 [M+H+].
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:13]=[C:12]([F:14])[C:9]([CH2:10][OH:11])=[C:8]([F:15])[CH:7]=2)[CH2:3][CH2:2]1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29](Cl)=[O:30])[C@H:25]([CH2:32][CH3:33])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].[H-].[Na+]>CN(C)C=O>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([F:15])[C:9]([CH2:10][O:11][C:29]([N:26]3[CH2:27][CH2:28][N:23]([C:21]([O:20][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:22])[CH2:24][C@H:25]3[CH2:32][CH3:33])=[O:30])=[C:12]([F:14])[CH:13]=2)[CH2:3][CH2:2]1
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)Cl
Reactant: OCc1c(F)cc(OCC2CC2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1c(F)cc(OCC2CC2)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 70.9 %

Procedure:
A mixture of 4-cyclopropylmethoxy-2,6-difluoro-benzylalcohol (270 mg, 1.26 mM) and (R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butyl ester (349 mg, 1.26 mM) in dimethylformamide (2 mL) was added slowly to a suspension of sodium hydride (83 mg, 55%, 1.89 mM) in dimethylformamide (2 mL). The mixture was stirred at room temperature for 5 h and partitioned between water and diethylether. Organic phases were pooled, washed with brine and dried with MgSO4 to yield after evaporation a yellow oil (585 mg). This residue was purified by column chromatography (silica gel; n-hexane/ethylacetate gradient) to yield 406 mg (71%) of the product as a yellowish oil. MS (ISP): 477.3 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=CC=CC=2)[CH:3]=[CH:2]1.C([N:17]1[C:29]2[C:28]([OH:30])=[C:27]3[N:31](C(OC(C)(C)C)=O)[C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([Cl:46])[CH:22]=2)(OC(C)(C)C)=O.O[C@H]1CCN(C(OC(C)(C)C)=O)C1>>[Cl:38][C:35]1[CH:36]=[C:37]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:27]1[C:28]([O:30][C@H:3]3[CH2:4][CH2:9][NH:1][CH2:2]3)=[C:29]3[NH:17][C:18]4[CH:19]=[CH:20][C:21]([Cl:46])=[CH:22][C:23]=4[C:24]3=[CH:25][C:26]2=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)n1c2ccc(Cl)cc2c2cc3c4cc(Cl)ccc4n(C(=O)OC(C)(C)C)c3c(O)c21
Agent: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Product: Clc1ccc2[nH]c3c(O[C@H]4CCNC4)c4[nH]c5ccc(Cl)cc5c4cc3c2c1

Procedure:
The title compound was prepared in a manner analogous to Example 28 except the starting indole is 5,7-diBOC-2,10-dichloro-6-hydroxyindolo[2,3-b]carbazole and the reagent is (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate. 1H-NMR (400 MHz, CDCl3) δ ppm 9.27 (br s, 2H), 8.35 (s, 1H), 8.07 (s, 2H), 7.38-7.30 (m, 4H), 5.09 (t, J=4.0 Hz, 1H), 3.55-3.46 (m, 2H), 3.29 (d, J=12.0 Hz, 1H), 3.15 (td, J=10.0, 4.8 Hz, 1H), 2.83 (dd, J=11.6, 3.6 Hz, 1H), 2.38-2.28 (m, 1H), 2.21-2.10 (m, 1H); MS (ESI) m/z 408.2 (M−H)−; MS (ESI) m/z 410.1 (M+H)+
Reaction SMILES: C([N:4]1[C:28](=O)[C:7]2=[N:8][N:9]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[CH:26][CH:25]=[N:24]4)=[CH:19][CH:18]=3)C3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]2=[N:5]1)C=C.C[N+]1([O-])CCOCC1.I([O-])(=O)(=O)=O.[Na+].[C:44](=[O:47])(O)[O-].[Na+]>O1CCOCC1.[Os](=O)(=O)(=O)=O.O>[N:23]1([C:20]2[CH:19]=[CH:18][C:17]([CH2:16][N:9]3[C:44](=[O:47])[C:28]4=[N:4][NH:5][C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=5[C:7]4=[N:8]3)=[CH:22][CH:21]=2)[CH:27]=[CH:26][CH:25]=[N:24]1
Reactant: C=CCn1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)nc-2c1=O
Reactant: O=C([O-])O
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=c1c2n[nH]c3ccccc3c-2nn1Cc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Prop-2-en-1-yl-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-one [(Example 10), 209 mg, 0.547 mmol], N-methylmorpholine oxide (192 mg, 1.64 mmol, 3.0 equiv), osmium(VIII)tetraoxide (69.5 mg, 0.273 mmol, 0.5 equiv) and sodium periodate (292 mg, 1.37 mmol, 2.5 equiv) were combined in dioxane (10 mL) and water (1 mL) and placed into an oil bath preheated to 60° C. for 18 hours. The mixture was cooled to ambient temperature, poured into sodium bicarbonate (20 mL, aqueous saturated) and extracted with ethyl acetate (3×25 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 90:10; dichloromethane:methanol), providing the titled compound.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=[O:7].[CH3:17]CCCC.C(OCC)C>>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[C:5]([CH:6]2[O:7][CH2:17]2)[CH:8]=[C:9]([C:11]([F:14])([F:12])[F:13])[CH:10]=1
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCCCC
Solvent: CCOCC
Product: FC(F)(F)c1cc(C2CO2)cc(C(F)(F)F)c1

Procedure:
Following General Procedure EC and using 3,5-bis-(trifluoromethyl)-benzaldehyde (Lancaster), the title compound was isolated after flash chromatography with 10:1 pentane/diethylether.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:22])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][N:17]=[CH:16]4)[CH:7]=2)[CH2:3][CH2:2]1.[H-].[Na+].[CH:25]1([CH2:28]Br)[CH2:27][CH2:26]1>CN(C=O)C.CO>[CH:1]1([NH:4][C:5](=[O:22])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:28][CH:25]3[CH2:27][CH2:26]3)[N:17]=[CH:16]4)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2[nH]ncc2c1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(cnn2CC2CC2)c1
Reaction time: 18 h

Procedure:
A solution of N-cyclopropyl-3-(1H-indazol-5-yl)-4-methylbenzamide (Example 17) (0.10 g) in dry DMF (3 ml) was treated with sodium hydride (60% oil dispersion, 0.017 g) under nitrogen. After 5 min cyclopropylmethyl bromide (0.04 ml) was added and the yellow solution was stirred at room temp. for 18 h. Methanol (2 drops) was added and the solvent was evaporated. The residue was purified by column chromatography on silica eluting with cyclohexane:ethyl acetate (2:1 to 1:1) to give the title compound (0.05 g).
Reaction SMILES: [NH2:1][N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]1=[NH2+:9].CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[Cl:23][CH2:24][C:25](OC)=O.C(=O)([O-])[O-].[K+].[K+]>CCO>[Cl:23][CH2:24][C:25]1[N:9]=[C:3]2[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][N:2]2[N:1]=1
Reactant: Cc1cccn(N)c1=[NH2+]
Reactant: COC(=O)CCl
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1cccn2nc(CCl)nc12
Temperature: 80 °C
Reaction time: 4 h
Yield: 27 %

Procedure:
A suspension of 1-amino-3-methylpyridin-2(1H)-iminium-2,4,6-trimethylbenzenesulfonate (630 mg, crude product from the previous step, 1.95 mmol), methyl 2-chloroacetate (423 mg, 3.90 mmol) and potassium carbonate (540 mg, 3.9 mmol) in EtOH (10 mL) was stirred at 80° C. for 4 h. After cooled to room temperature, the reaction mixture was concentrated and the residue was purified by silica gel column chromatography (eluting with 25% v/v EtOAc in PE) to give the title compound (95 mg, yield 27%). ESI MS: m/z 182, 184 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]2[CH:22]=1.[CH:23]1([CH2:26][C:27](O)=[O:28])[CH2:25][CH2:24]1.C(N(CC)C(C)C)(C)C.[Cl-].[Na+].O.O>CN(C=O)C>[CH:23]1([CH2:26][C:27]([NH:21][C:18]2[CH:19]=[CH:20][C:15]3[N:16]([CH:22]=[C:13]([C:3]4[C:4]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=5)=[N:5][O:6][C:2]=4[CH3:1])[N:14]=3)[CH:17]=2)=[O:28])[CH2:25][CH2:24]1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2cc(N)ccc2n1
Reactant: O=C(O)CC1CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccccc2)c1-c1cn2cc(NC(=O)CC3CC3)ccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.7 %

Procedure:
A solution of 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridin-6-ylamine (63.9 mg, 0.22 mmol) in DMF (0.2 mL) was added to a solution containing of cyclopropylacetic acid (20 μL, 0.22 mmol), N,N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)uranium tetrafluoroborate (70.6 mg, 0.22 mmol), N,N-diisopropyl ethyl amine (129 μL, 1.0 mmol) in DMF (0.3 mL) and the resulting mixture stirred at room temperature for 2 h. The resulting mixture was then poured into a mixture of brine:water (1:1) and extracted with ethyl acetate. The combined organic layers were then washed with brine, dried over sodium sulphate and evaporated to leave a brown solid. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 50:50) afforded the title compound (44 mg, 59%) which was obtained as a light green solid. MS: m/e=373.3 [M+H]+.