Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li][CH2:2]CCC.[CH2:6]([CH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[Se:21][CH:22]=[CH:23][CH:24]=3)=[C:16]([F:25])[C:15]=2[F:26])[CH2:10][CH2:9]1)[CH3:7].CI.[Cl-].[NH4+].N>C(OCC)C>[CH2:6]([CH:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[Se:21][C:22]([CH3:2])=[CH:23][CH:24]=3)=[C:16]([F:25])[C:15]=2[F:26])[CH2:12][CH2:13]1)[CH3:7]
Reactant: [Li]CCCC
Reactant: CCC1CCC(c2ccc(-c3ccc[se]3)c(F)c2F)CC1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CI
Product: CCC1CCC(c2ccc(-c3ccc(C)[se]3)c(F)c2F)CC1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
2.2 ml (13.0 mmol) of TMP are initially introduced at −15° C. in 15 ml of diethyl ether, and 8.2 ml (13.0 mmol, 15% soln. in hexane) of n-BuLi are metered in. After 25 min, a solution of 3.5 g (9.9 mmol) of 2-[4-(4-ethyl-cyclohexyl)-2,3-difluorophenyl]selenophene in 35 ml of diethyl ether is metered in at 0° C., and the mixture is stirred at RT for 2 h. The batch is cooled to −70° C., and 3.0 ml (48.2 mmol) of methyl iodide are added. The mixture is warmed to RT and stirred for 24 h. Sat. ammonium chloride soln. and conc. ammonia soln. are added successively, and the mixture is briefly stirred vigorously. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with 2 N hydrochloric acid and sat. sodium chloride soln. and dried using sodium sulfate. The solution is concentrated to dryness, and the residue is purified by column chromatography (SiO2, n-heptane). The further purification is carried out by recrystallisation from ethanol. 2-[4-(4-Ethylcyclohexyl)-2,3-difluorophenyl]-5-methylselenophene is obtained as a solid having an m.p. of 63° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=O)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[C:12]([CH2:14][C:15]([OH:17])=[O:16])#[N:13].C([O-])(=O)C.[NH4+]>N1C=CC=CC=1.C1C=CC=CC=1.Cl>[C:12]([C:14](=[CH:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1)[C:15]([OH:17])=[O:16])#[N:13]
Reactant: O=Cc1ccc2c(c1)CCO2
Reactant: N#CCC(=O)O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: N#CC(=Cc1ccc2c(c1)CCO2)C(=O)O

Procedure:
39.5 g of 2,3-dihydro-5-benzofurancarbaldehyde (prepared according to the process described in J. Org. Chem. (1984), 49, p. 409), 22.7 g of 2-cyanoacetic acid and 4.08 g of ammonium acetate are mixed in 37 ml of pyridine and 210 ml of benzene. The mixture is brought to reflux for 6 hours 30 minutes. The precipitate formed is isolated and then suspended in 600 ml of 6N hydrochloric acid. The solid isolated is filtered off and washed with water and dried in the air.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([Cl:16])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Cl:17]N1C(=O)CCC1=O.C(O)(C)C>O>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[C:13]([Cl:17])[C:12]([NH2:15])=[C:11]([Cl:16])[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1cc(Oc2ccc(N)c(Cl)c2)ccn1
Solvent: CC(C)O
Solvent: O
Product: Nc1cc(Oc2cc(Cl)c(N)c(Cl)c2)ccn1
Yield: 15 %

Procedure:
2-Amino-4-(4-amino-3-chlorophenoxy)pyridine (700 mg), N-chlorosuccinimide (0.44 g) and isopropanol (10 ml) were stirred at 80° C. for 1 hour. The mixture was returned to room temperature, water was added, and extraction was performed with ethyl acetate. Silica gel was added to the extract solution and the solvent was distilled off under reduced pressure. The silica gel was charged into a dry column packed with silica gel, and purification was performed by column chromatography (ethyl acetate), to obtain 120 mg of a brown oil.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12](O)=[O:13])(O)=[O:2].B.[H][H]>C1COCC1>[OH:2][CH2:1][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][OH:13]
Reactant: [H][H]
Reactant: O=C(O)Cc1ccccc1CC(=O)O
Agent: B
Solvent: C1CCOC1
Product: OCCc1ccccc1CCO
Temperature: 0 °C
Reaction time: 4 h
Yield: 79.4 %

Procedure:
(2-Carboxymethyl-phenyl)-acetic acid (5.0 g/25 mmol) was dissolved in THF (100 mL) and cooled to 0° C. Borane (1 M in THF, 100 mL/100 mmol) was then added dropwise while stirring (hydrogen evolution). The reaction was left to stir a 0° C. for four hours then carefully quenched by the addition of water (ca. 20 mL). The reaction was partitioned between diethyl ether (200 mL) and water (200 mL). The organic layer was extracted with an additional portion of ether (100 mL) and the combined organics washed with brine (100 mL), dried over magnesium sulfate, filtered and concentrated. To give 2-[2-(2-Hydroxy-ethyl)-phenyl]-ethanol (3.3 g/80%). 1H NMR (400 MHz, CDCl3) δ 7.2 (m, 4H), 3.9 (t, J=6.8 Hz, 4H), 2.95 (t, J=6.8 Hz, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.F[C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[C:13]#[N:14].CC(C)([O-])C.[K+].C(OCC)(=O)C>CS(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[C:13]#[N:14]
Reactant: Oc1cccc(F)c1
Reactant: N#Cc1cccc(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1cccc(Oc2cccc(F)c2)c1
Temperature: 140 °C
Reaction time: 3 h
Yield: 32.9 %

Procedure:
To a solution of 3-fluoro-phenol (500 mg, 4.46 mmol) and 3-fluoro-benzonitrile (540 mg, 4.46 mmol) in dimethylsulfoxide (1.0 mL) was added potassium tert-butoxide (500 mg, 4.46 mmol), and the solution was stirred at 140° C. for 3 hours. The reaction solution was allowed to room temperature, ethyl acetate and water were added for partitioning, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1), and 3-(3-fluoro-phenoxy)-benzonitrile (313 mg, 33%) was obtained as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]=1[C:19](=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1.[CH3:28][O:29][CH2:30][C:31](Cl)=[O:32]>>[CH2:17]([O:16][C:14]([N:4]1[C:5]2[C:10](=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)[C:2]([NH:1][C:31](=[O:32])[CH2:30][O:29][CH3:28])=[C:3]1[C:19](=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1)=[O:15])[CH3:18]
Reactant: CCOC(=O)n1c(C(=O)c2cccc(C)c2)c(N)c2cc([N+](=O)[O-])ccc21
Reactant: COCC(=O)Cl
Product: CCOC(=O)n1c(C(=O)c2cccc(C)c2)c(NC(=O)COC)c2cc([N+](=O)[O-])ccc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 2 (Method A) from 3-amino-2-(3-chlorobenzoyl)-1-(ethoxycarbonyl)-5-nitroindole (step 1) and methoxyacetyl chloride.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C@H:11]([C:22]([N:24]1[CH2:31][CH2:30][CH2:29][C@H:25]1[C:26]([OH:28])=[O:27])=[O:23])[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1.[NH:32]([C:54]([O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[O:55])[C@H:33]([C:44](ON1C(=O)CCC1=O)=[O:45])[CH2:34][C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[NH:37][CH:36]=1.CC(S[As](C)C)([C@@H](N)C(O)=O)C.OS([O-])(=O)=O.[K+]>C(OCC)(=O)C.CC(N(C)C)=O>[NH:32]([C:54]([O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[O:55])[C@H:33]([C:44]([NH:10][C@H:11]([C:22]([N:24]1[CH2:31][CH2:30][CH2:29][C@H:25]1[C:26]([OH:28])=[O:27])=[O:23])[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)=[O:45])[CH2:34][C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[NH:37][CH:36]=1
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)ON1C(=O)CCC1=O)OCc1ccccc1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC[C@H]1C(=O)O
Agent: C[As](C)SC(C)(C)[C@@H](N)C(=O)O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC[C@H]1C(=O)O)OCc1ccccc1
Temperature: 5 °C

Procedure:
DMA, 1.05 equivalents of DIPEA (Mw=129.2) and 1.05 equivalents of H-Trp-Pro-OH (Mw=301.3; purity=91.0%) were mixed at room temperature for at least 30 min until a solution had formed. The reaction mixture was then diluted with ethyl acetate and cooled to 5±5° C. Once this temperature was reached, 1.00 equivalent of Z-Trp-OSu (Mw=435.45; purity=98.0%) was added and stirring continued for at least 30 min before the solution was left to warm up to room temperature again. After the completion of the reaction was confirmed by HPLC, 0.2 eq of, DMAPA (N,N′-Dimethylaminopropylamine, Mw=102.2 g/mol) were added. The reaction mixture was diluted with ethyl acetate and washed with a 5% (weight) aqueous NaCl solution containing 2 equivalents of KHSO4. The organic phase was further washed first with a 5% (weight) aqueous NaCl solution and finally with water. The organic phase was partially concentrated in vacuo and the residue was suspended in ethyl acetate and further concentrated in order to eliminate the remaining water. The concentrated peptide solution was added in small portions to a cold (0±5° C.) mixture of MTBE/petroleum ether (45-55) (1/1) and the precipitate was kept at 0±5° C. for at least 30 min before filtration. After filtration, it was then washed with petroleum ether (45-55) and dried in vacuo at 45° C. A white solid was finally obtained.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[CH2:2]1.CCN(CC)CC.[CH:18]([N:21]1[C:25]([C:26]2[N:35]=[C:34]3[N:28]([CH2:29][CH2:30][O:31][C:32]4[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][C:33]=43)[CH:27]=2)=[N:24][CH:23]=[N:22]1)([CH3:20])[CH3:19]>C(Cl)Cl>[CH:18]([N:21]1[C:25]([C:26]2[N:35]=[C:34]3[C:33]4[CH:36]=[C:37]([S:40]([N:1]5[CH2:4][CH:3]([N:5]6[CH2:10][CH2:9][O:8][CH2:7][CH2:6]6)[CH2:2]5)(=[O:42])=[O:41])[CH:38]=[CH:39][C:32]=4[O:31][CH2:30][CH2:29][N:28]3[CH:27]=2)=[N:24][CH:23]=[N:22]1)([CH3:20])[CH3:19]
Reactant: C1CN(C2CNC2)CCO1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)Cl)ccc1OCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)N3CC(N4CCOCC4)C3)ccc1OCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-azetidin-3-ylmorpholine (52 mg, 0.36 mmol) and NEt3 (84 μL, 0.61 mmol) in DCM (5 mL) at 0° C. was added a suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-sulfonyl chloride from Example 121 (100 mg, 0.12 mmol) in DCM (5 mL) and the resulting mixture warmed to RT after 10 min then stirred for 16 h. The reaction mixture was diluted with DCM, washed with a saturated aqueous NaHCO3 solution then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-6% 2M NH3/MeOH in DCM then C18, gradient 20-50% MeOH in H2O). The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording 122 (40 mg, 65%). LCMS: RT 3.00 min [M+H]+ 500.3. 1H NMR (DMSO, 400 MHz): δ 8.87 (1H, d, J=2.40 Hz), 8.02 (1H, s), 7.94 (1H, d, J=0.62 Hz), 7.72 (1H, dd, J=8.62, 2.42 Hz), 7.32 (1H, d, J=8.62 Hz), 5.73-5.64 (1H, m), 4.64-4.63 (4H, m), 3.78 (2H, t, J=7.73 Hz), 3.58 (2H, dd, J=8.39, 5.80 Hz), 3.42 (4H, t, J=4.34 Hz), 3.03-3.01 (1H, m), 2.15-2.09 (4H, m), 1.49 (6H, d, J=6.62 Hz)
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH:12]2[CH2:15][O:14][CH2:13]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH3:16][C:17]([CH3:26])([CH3:25])[CH:18]([NH2:24])[C:19]1[S:20][CH:21]=[CH:22][N:23]=1>>[CH3:16][C:17]([CH3:26])([CH3:25])[CH:18]([NH:24][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH:12]2[CH2:15][O:14][CH2:13]2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])[C:19]1[S:20][CH:21]=[CH:22][N:23]=1
Reactant: CC(C)(C)C(N)c1nccs1
Reactant: O=C(O)c1cc(OC2COC2)c(Cl)cn1
Product: CC(C)(C)C(NC(=O)c1cc(OC2COC2)c(Cl)cn1)c1nccs1

Procedure:
The title compound was synthesized in analogy to Example 24d, using 5-Chloro-4-(oxetan-3-yloxy)-pyridine-2-carboxylic acid (Example 23a) and 2,2-Dimethyl-1-thiazol-2-yl-propylamine (CAN 1247122-26-4) as starting materials and isolated (21.6 mg, 37%) as white solid; MS (ESI, m/z): 382.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]2)=[C:4]([NH:18][C:19](=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[CH:3]=1.[OH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[Cl:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][C:15]([N:32]2[CH2:33][CH2:34][CH:29]([OH:28])[CH2:30][CH2:31]2)=[O:17])[CH2:12][CH2:13]1)=[O:27]
Reactant: O=C(O)CC1CCN(c2ccc(Cl)cc2NC(=O)c2cccc(Cl)c2)CC1
Reactant: OC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Cl)ccc1N1CCC(CC(=O)N2CCC(O)CC2)CC1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.2 %

Procedure:
A mixture of 0.100 g (0.246 mmol) of {1-[4-chloro-2-(3-chloro-benzoylamino)-phenyl]-piperidin-4-yl}-acetic acid, 0.124 g (1.23 mmol) of 4-hydroxypiperdine, 0.10 g (0.32 mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, and 0.10 mL (0.74 mmol) of triethylamine in N,N-dimethylformamide (3 mL) are stirred at room temperature for 3 hours. The mixture is concentrated under reduced pressure and the residue is purified by preparative reverse phase HPLC to provide 0.040 g (33%) of the title compound (278) as a colorless solid. [M+H]+=490.2.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([S:12][C:13]1[N:17]3[N:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]3=[N:15][N:14]=1)=[CH:7][CH:6]=2.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[N:33][N:34](COCC[Si](C)(C)C)[CH:35]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].C(O)(C(F)(F)F)=O>O1CCOCC1>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]2[N:17]([C:13]([S:12][C:8]3[CH:9]=[C:10]4[C:5](=[CH:6][CH:7]=3)[N:4]=[CH:3][C:2]([C:31]3[CH:32]=[N:33][NH:34][CH:35]=3)=[CH:11]4)=[N:14][N:15]=2)[N:18]=1
Reactant: Cc1ccc2nnc(Sc3ccc4ncc(Br)cc4c3)n2n1
Reactant: CC1(C)OB(c2cnn(COCC[Si](C)(C)C)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: Cc1ccc2nnc(Sc3ccc4ncc(-c5cn[nH]c5)cc4c3)n2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.5 %

Procedure:
A microwave vessel was charged with 3-bromo-6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinoline (970 mg, 2.606 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazole (930 mg, 2.866 mmol), and dichlorobis(triphenylphosphine) palladium(0) (92 mg, 0.13 mmol). 1,4-Dioxane (10 mL) and a 2 M aqueous solution of sodium carbonate (5 mL) were added. The vessel was capped and microwaved at 130° C. for 30 min. The reaction mixture was partitioned between water and 10% methanol/dichloromethane. The aqueous layer was extracted with 10% methanol/dichloromethane, and the combined organics were adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-8% methanol/dichloromethane afforded 1.073 g of the crude coupling product as a light brown oil. The oil was treated with TFA (10 mL). The reaction mixture was stirred at room temperature for 2 h, before concentrating in vacuo. The residue was treated with 1 N aqueous NaOH, and the precipitate was filtered, washed sequentially with water and ethyl acetate. The resulting yellow solid was dissolved in 10% methanol/dichloromethane and adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-10% methanol/dichloromethane afforded 417 mg of impure 6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-3-(1H-pyrazol-4-yl)-quinoline. Purification of 30 mg of material by mass-triggered HPLC (5-95% CH3CN/H2O, 0.1% HCOOH modifier) provided 12 mg of pure 6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-3-(1H-pyrazol-4-yl)-quinoline.
Reaction SMILES: [N:1]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7](=[O:22])[CH:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[N+:2]=[N-:3].[C:23](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O.C(OCC)C>[N:1]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7]([O:22][CH3:23])=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])=[N+:2]=[N-:3]
Reactant: O=C([O-])[O-]
Reactant: [N-]=[N+]=NC1C(=O)N2C(C(=O)OCc3ccccc3)C(=O)CC12
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: COS(=O)(=O)OC
Product: COC1=C(C(=O)OCc2ccccc2)N2C(=O)C(N=[N+]=[N-])C2C1
Temperature: 25 °C

Procedure:
Benzyl 6-azido-1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate (1 mmol) is dissolved in anhydrous acetone (5 ml) and treated with powdered, anhydrous potassium carbonate (2 mmol). The resulting suspension is treated with dimethyl sulfate (1.2 mmol) and stirred vigorously at room temperature for several hours. The mixture is diluted with ethylether and filtered. The filtrate is washed with water and brine, dried and evaporated under vacuum to give benzyl 6-azido-3-methoxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:8][C:7](=[O:9])[NH:6][C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[NH:3]1.[N+:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)([O-:17])=[O:16]>CN(C)C1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:14])[CH2:8][C:7](=[O:9])[NH:6][C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[N:3]1[C:22](=[O:23])[C:21]1[CH:20]=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[CH:26][CH:25]=1
Reactant: CC1(C)CC(=O)Nc2ccccc2N1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CN(C)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC1(C)CC(=O)Nc2ccccc2N1C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 150 °C
Reaction time: 9 h
Yield: 10.9 %

Procedure:
To a solution of 4,4-dimethyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (1.0 g) in N,N-dimethylaniline (20 ml) was added 4-nitrobenzoyl chloride (0.98 g) at ambient temperature. The mixture was stirred at 150° C. for 9 hours. The resulting mixture was diluted with chloroform and the organic layer was washed successively with 1N hydrochloric acid and saturated aqueous sodium bicarbonate. Drying, filtering and the removal of solvents afforded a crude product. The crude product was chromatographed on silica gel (1% methanol in chloroform) to give 4,4-dimethyl-5-(4-nitrobenzoyl)-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (195 mg) as a slightly yellow solid.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH3:67][N:68]([CH3:80])[CH2:69][CH2:70][O:71][C:72]1[CH:79]=[CH:78][C:75]([CH:76]=O)=[CH:74][CH:73]=1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:76]([C:75]3[CH:78]=[CH:79][C:72]([O:71][CH2:70][CH2:69][N:68]([CH3:67])[CH3:80])=[CH:73][CH:74]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: CN(C)CCOc1ccc(C=O)cc1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc(-c2nc3c(N4CCN(Cc5cccnc5)CC4)c(Br)cnc3[nH]2)cc1
Reaction time: 6 h
Yield: 24.5 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (30 mg, 0.076 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.23 mmol, 0.23 mL) and 4-(2-(dimethylamino)ethoxy)benzaldehyde (1.2 eq, 0.091 mmol, 18 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 85:15) gave the product (10 mg, 23%) as a colourless solid; δH (500 MHz, DMSO-d6) 2.23 (s, 6H, N(CH3)2), 2.62 (s, br, 4H, piperazine N(CH2)2), 2.65 (t, J=5.8 Hz, 2H, Me2NCH2), 3.61 (s, 2H, NCH2), 3.65 (t, J=4.4 Hz, 4H, piperazine N(CH2)2), 4.13 (t, J=5.8 Hz, 2H, OCH2), 7.09 (d, J=8.8 Hz, 2H, phenyl H-3 & H-5), 7.39 (dd, J=7.7, 4.8 Hz, 1H, pyridine H-5), 7.78 (dt, J=7.8, 1.7 Hz, 1H, pyridine H-4), 8.11 (d, J=8.8 Hz, 2H, phenyl H-2 & H-6), 8.20 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.49 (dd, J=4.8, 1.4 Hz, 1H, pyridine H-6), 8.56 (d, J=1.4 Hz, 1H, pyridine H-2), 13.34 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: C(OC([N:8]1[C:20]2[CH2:19][CH:18]([C:21]([S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:29])=[O:28])([F:26])[C:22](=[O:25])[NH:23][CH3:24])[CH2:17][CH2:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([Cl:36])[CH:13]=2)=O)(C)(C)C.[H-].[Na+].BrC[CH:41]=[C:42]([CH3:44])[CH3:43].[CH2:45]1COCC1>>[C:30]1([S:27]([C:21]([CH:18]2[CH2:17][CH2:16][C:15]3[C:14]4[C:9](=[CH:10][CH:11]=[C:12]([Cl:36])[CH:13]=4)[NH:8][C:20]=3[CH2:19]2)([F:26])[C:22]([N:23]([CH3:45])[CH2:24][CH:41]=[C:42]([CH3:44])[CH3:43])=[O:25])(=[O:29])=[O:28])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CNC(=O)C(F)(C1CCc2c(n(C(=O)OC(C)(C)C)c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Reactant: C1CCOC1
Reactant: CC(C)=CCBr
Agent: [H-]
Agent: [Na+]
Product: CC(C)=CCN(C)C(=O)C(F)(C1CCc2c([nH]c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Reaction time: 0.67 h
Yield: 19 %

Procedure:
To a stirred solution of 60 mg (0.11 mmol) of (RS,SR)-2-(benzenesulfonyl-fluoro-methylcarbamoyl-methyl)-6-chloro-1,2,3,4-tetrahydro-carbazole-9-carboxylic acid tert-butyl ester in 3 mL THF was added on 7 mg NaH (60% in oil, 0.165 mmol, 1.5 eq) at 0° C. The reaction mixture was stirred for 40 minutes and then, 52 μL (0.22 mmol, 2 eq) 1-bromo-3-methyl-but-2-ene (1 mL in THF) was added and the reaction mixture was stirred for 2 hours at 0° C. and then overnight at RT. The solvent was evaporated. Then, 1 mL CH2Cl2 was added and after dissolution, 1 mL TFA and 1 mL CH2Cl2 were added at RT. The reaction mixture was stirred overnight. The solvent was then evaporated and purification by prep. HPLC gave 9 mg (19%) of (RS,SR)-2-benzenesulfonyl-2-(-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-2-fluoro-N-methyl-N-(3-methyl-but-2-enyl)-acetamide as a white solid, MS: 503 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.[C:11]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:21]2[CH2:22][CH2:23][N:18]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:19][CH2:20]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(c1)NCC2
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CCc3ccc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-fluoroindoline (9.36 g, 68 mmol) in CH2Cl2 (100 mL) was added 1-Boc-4-piperidone (13.6 g, 68 mmol). The resulting mixture was stirred at room temperature for 1 h and NaBH(OAc)3 (18 g, 85 mmol, 1.25 equiv) was added. The resulting mixture was stirred at room temperature for 24 h and was then poured slowly to a vigorously stirred Na2CO3(aq). After 30 min stirring, the layers were separated. The aqueous layer was extracted with CH2Cl2 (100 mL). The combined organic layer was washed with brine (100 mL), dried (Na2SO4), and filtered. The solvent was removed by roto-evaporator, Et2O (10 mL) and then hexane (150 mL) were added to the resulting residue. The mixture was allowed to stand, resulting in the formation of a white solid, which was collected and washed with 5% Et2O/hexane and then dried. This was repeated to yield three crops of tert-butyl 4-(6-fluoroindolin-1-yl)piperidine-1-carboxylate as a white solid.