Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][CH:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:9]=[CH:10][CH:11]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CI.[CH2:35]1COC[CH2:36]1>>[CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][CH:13]([CH3:17])[C:14]([O:16][CH2:35][CH3:36])=[O:15])[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cccc(C)c1COc1cccc(CC(C)C(=O)O)c1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Product: CCOC(=O)C(C)Cc1cccc(OCc2c(C)cccc2C)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirred solution of Ethyl 3-(2,6-dimethylbenzyloxy)phenylacetate (Step B, 4.53 g, 14.5 mmol) in dry THF (30 ml) at −68° C. under a dry argon atmosphere was added LiHMDS drop wise (1 M solution in THF, 21.77 ml, 21.77 mmol), and the resulting orange solution was stirred at low temperature for 30 minutes before CH3I (20.60 g, 145.2 mmol) was added. The reaction mixture was slowly warmed to room temperature and stirred for 15 hours. The reaction was quenched with ice, and the product was extracted with EtOAc (2×), the organic phase was washed with brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (hex:ether 5:1) to give the title compound.
Reaction SMILES: Cl[S:2]([C:5]1[C:9]2[C:10]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[N:11][CH:12]=[CH:13][C:8]=2[S:7][CH:6]=1)(=[O:4])=[O:3].[CH:27]([C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)([CH3:29])[CH3:28]>>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][N:14]([C:10]2[C:9]3[C:5]([S:2]([NH:34][C:33]4[CH:35]=[CH:36][C:30]([CH:27]([CH3:29])[CH3:28])=[CH:31][CH:32]=4)(=[O:4])=[O:3])=[CH:6][S:7][C:8]=3[CH:13]=[CH:12][N:11]=2)[CH2:15][CH2:16]1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)c1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc3scc(S(=O)(=O)Cl)c23)CC1
Product: CC(C)c1ccc(NS(=O)(=O)c2csc3ccnc(N4CCN(C(=O)OC(C)(C)C)CC4)c23)cc1
Yield: 52.5 %

Procedure:
Prepared from tert-butyl 4-[3-(chlorosulfonyl)thieno[3,2-c]pyridin-4-yl]piperazine-1-carboxylate (90.0 mg, 0.215 mmol) and 4-isopropylaniline (37.9 mg, 0.28 mmol) to give the title compound as an off-white solid (58.3 mg, 52%). 1H NMR (400 MHz, CDCl3) δ 1.12 (d, J=7.0 Hz, 6H), 1.47 (s, 9H), 2.76 (sept., J=6.9 Hz, 2H), 3.01-3.53 (m, 6H), 4.04-4.41 (m, 2H), 6.79 (d, J=8.5 Hz, 2H), 6.66 (d, J=8.5 Hz, 2H), 7.69 (d, J=5.5 Hz, 1H), 8.23 (s, 1H), 8.40 (d, J=5.5 Hz, 1H), 9.90 (s, 1H). MS (ESI+) m/z 517.2 (M+H)+. HPLC 97%, RT: 4.01 min (5-99% MeCN over 3 min).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[O:10][C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:8][C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:19]CC1C=CC=CC=1.C1CCCCC=1>C(OCC)(=O)C.[Pd]>[OH:19][C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:18])[CH:8]=[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[O:10][C:11]=2[C:2]=1[CH3:1]
Reactant: Cc1c(OCc2ccccc2)ccc2c(=O)cc(N3CCOCC3)oc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1=CCCCC1
Product: Cc1c(O)ccc2c(=O)cc(N3CCOCC3)oc12
Yield: 73.9 %

Procedure:
Part A: 8-Methyl-2-(4-morpholinyl)-7-(phenylmethoxy)-4H-1-benzopyran-4-one (8.59 g, 24.4 mmol.) is suspended in 250 ml of ethyl acetate. 9.9 ml of cyclohexene is added followed by 0.85 g of 10% Palladium on carbon. The mixture is heated at reflux for 18 hours. The reaction is allowed to cool and filtered, the solid is taken up in methanol, decanted and filtered. The methanol is evaporated to give 4.71 g (74%) of the phenol (mp>250° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[Cl:10][C:11]1[CH:18]=[C:17](F)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[Cl:10][C:11]1[CH:18]=[C:17]([O:9][C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([Cl:1])[CH:3]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: Cc1ccc(O)cc1Cl
Reactant: N#Cc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1ccc(Oc2ccc(C#N)c(Cl)c2)cc1Cl
Temperature: 120 °C
Reaction time: 5 h
Yield: 99.1 %

Procedure:
To a solution of 3-chloro-4-methylphenol (7.5 g) and 2-chloro-4-fluorobenzonitrile (8.14 g) in N,N-dimethylacetamide (23 ml) was added potassium carbonate (8.55 g). The mixture was stirred for 5 hours at 120° C. The mixture was poured into ice water and extracted with ethyl acetate. The organic phase was washed with water, dried (MgSO4), filtered and concentrated to dryness to give the title compound (14.42 g) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=2)=[N:6][N:5]2[CH:17]=[N:18][N:19]=[C:4]2[CH:3]=1>[Pt]=O.C(O)C>[NH2:14][C:10]1[CH:9]=[C:8]([C:7]2[C:2]([CH3:1])=[CH:3][C:4]3[N:5]([CH:17]=[N:18][N:19]=3)[N:6]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cc2nncn2nc1-c1cccc([N+](=O)[O-])c1
Agent: O=[Pt]
Solvent: CCO
Product: Cc1cc2nncn2nc1-c1cccc(N)c1

Procedure:
A mixture comprising 2.28 g of 7-methyl-6-(m-nitrophenyl)-1,2,4-triazolo[4,3-b]pyridazine (prepared as described in Example 5), 100 ml. of ethyl alcohol and a catalytic amount of platinum oxide is shaken in a Parr shaker under 40 pounds of hydrogen pressure for 11/2 hours. The reaction mixture is filtered free of catalyst and the filtrate is concentrated to afford the product of the example as a yellow solid, m.p. 182°-186° C.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[CH:10]=[C:11]([CH:16]([C:25]3([CH3:28])[CH2:27][CH2:26]3)[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:12]=[CH:13][C:14]=2[Cl:15])=CC=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(=O)(O)[O-].[Na+]>ClCCl.O>[NH2:8][C:9]1[CH:10]=[C:11]([CH:16]([C:25]2([CH3:28])[CH2:26][CH2:27]2)[CH2:17][C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(C(CC(=O)OC(C)(C)C)C3(C)CC3)ccc2Cl)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)CC(c1ccc(Cl)c(N)c1)C1(C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
159 mg (0.29 mmol) of tert-butyl 3-{3-[bis(4-methoxybenzyl)amino]-4-chlorophenyl}-3-(1-methylcyclopropyl)propanoate were taken up in 7 ml of dichloromethane and 1.2 ml of water. 145 mg (0.64 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) were then added, and the reaction solution was stirred at room temperature for 2 h. The reaction mixture was then added to 10 ml of saturated aqueous sodium bicarbonate solution. The phases were separated, and the aqueous phase was then extracted three more times with in each case about 10 ml of dichloromethane. The combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. The product was isolated from the residue by preparative RP-HPLC (mobile phase methanol/water). This gave 31 mg of the target product (34% of theory).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.CC(C)([O-])C.[Na+].[C:20](=[NH:33])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(OCC)C>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([N:33]=[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2ccccc2c1Cl
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1c(N=C(c2ccccc2)c2ccccc2)nc2ccccc2c1Cl
Temperature: 100 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
A solution of 2,4-dichloro-3-methylquinoline (1.08 g, 5.1 mmol), tris(dibenzylideneacetone)dipalladium (12 mg, 0.0025 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (32 mg, 0.01 mmol) and sodium-t-butoxide (735 mg, 7.6 mmol) in toluene (51 mL) was stirred at room temperature for 5 minutes. To the solution was added benzophenone imine (852 μL, 5.1 mmol), and the mixture was stirred at 100° C. for 4 hours. The reaction solution was cooled to room temperature, and then thereto was added diethyl ether (10 mL). The mixture was stirred for 10 minutes. The solution was filtered through diatomaceous earth, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane→hexane:ethyl acetate=10:1) to give a crude 4-chloro-N-(diphenylmethylene)-3-methylquinolin-2-amine (910 mg, 50%) as a yellow solid. (2) The above crude compound (910 mg, 2.6 mmol) was dissolved in tetrahydrofuran (10 mL), and then thereto was added 1 mol/L hydrochloric acid solution (2 mL), and the mixture was stirred at room temperature for 1 hour. Then, thereto was added additional 1 mol/L hydrochloric acid solution (1 mL), and then the mixture was stirred for 30 minutes. To the solution was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate twice. The organic layer was combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1→1:1) to give 4-chloro-3-methylquinolin-2-amine (261 mg, 53%) as a white solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]([C:14]#[N:15])=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:23])[CH:10]=3)[C:5]2=[O:24])[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[CH2:31]([O:38][CH2:39][CH2:40]Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[CH2:31]([O:38][CH2:39][CH2:40][O:23][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5](=[O:24])[N:4]([CH:1]1[CH2:2][CH2:3]1)[C:13]([C:14]#[N:15])=[C:12]2[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrCCOCc1ccccc1
Reactant: N#Cc1c(-c2cccc(F)c2)c2cc(O)ccc2c(=O)n1C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1c(-c2cccc(F)c2)c2cc(OCCOCc3ccccc3)ccc2c(=O)n1C1CC1
Temperature: 120 °C

Procedure:
A mixture of the phenol 62 (80 mg, 0.25 mmol), K2CO3 (104 mg, 0.75 mmol) and benzyloxyethyl bromide (64 mg, 0.3 mmol) in DMF (3 mL) was heated in a microwave reactor at 120° C. for 15 min. The mixture was filtered and directly purified using an automated high pressure chromatography unit.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=C(C2C=CC=CC=2)C(C2C=CC=CC=2)=[N:22]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]([C:50]([C:52]2[CH:57]=[CH:56][C:55]([Br:58])=[CH:54][CH:53]=2)=O)=O)=[CH:44][CH:43]=1>>[Br:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[C:50]([C:52]3[CH:57]=[CH:56][C:55]([Br:58])=[CH:54][CH:53]=3)=[N:22][C:21]3[C:26](=[CH:27][CH:28]=[C:19]([C:8]4[N:7]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)[C:11]5[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=5[N:9]=4)[CH:20]=3)[N:25]=2)=[CH:44][CH:43]=1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)c(-c4ccccc4)nc3c1)n2C1CCCCC1
Reactant: O=C(C(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccc(Br)cc4)c(-c4ccc(Br)cc4)nc3c1)n2C1CCCCC1

Procedure:
Prepared as described for Compound 406 using 4,4′-dibromobenzil in place of benzil.
Reaction SMILES: C=O.[NH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[C:9]([C:11]1[CH:20]=[CH:19][C:18]2[NH:17][C:16](=[O:21])[C:15]3[NH:22][CH:23]=[CH:24][C:14]=3[C:13]=2[CH:12]=1)#[CH:10].[CH2:25]([C:27]([O-:29])=[O:28])[CH3:26].C(O)(=O)C>O1CCOCC1.[Cu](I)I>[N:3]1([CH2:25][C:10]#[C:9][C:11]2[CH:20]=[CH:19][C:18]3[NH:17][C:16](=[O:21])[C:15]4[NH:22][CH:23]=[CH:24][C:14]=4[C:13]=3[CH:12]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[CH2:25]([C:27]([O-:29])=[O:28])[CH3:26]
Reactant: C#Cc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Reactant: C1COCCN1
Agent: I[Cu]I
Agent: C=O
Agent: CCC(=O)[O-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: O=c1[nH]c2ccc(C#CCN3CCOCC3)cc2c2cc[nH]c12
Temperature: 85 °C
Yield: 12.4 %

Procedure:
15 mg (0.17 mmol) of para-formaldehyde, 15 mg (0.17 mmol) of morpholine and 3 mg (0.02 mmol) of copper iodide are added to a suspension of 47 mg (0.17 mmol) of 8-ethynyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in 5 ml of anhydrous dioxan, then a drop of acetic acid is added and the mixture is heated at 85° C. for 48 hours. The raw reaction product is then filtered, the filtrate is evaporated and the residue is purified by preparative LCMS to give 4 mg (6%) of 8-(3-morpholin-4-yl-prop-1-ynyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a white solid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[C:5]([C:11](Cl)=[N:12][OH:13])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[C:20]([C:22]([C:24]([F:27])([F:26])[F:25])=[CH2:23])[CH:19]=[C:18]([Cl:28])[CH:17]=1.C(=O)([O-])O.[Na+]>CC(O)C>[Br:1][C:2]1[C:10]2=[N:9][S:8][N:7]=[C:6]2[C:5]([C:11]2[CH2:23][C:22]([C:20]3[CH:19]=[C:18]([Cl:28])[CH:17]=[C:16]([Cl:15])[CH:21]=3)([C:24]([F:25])([F:27])[F:26])[O:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: ON=C(Cl)c1ccc(Br)c2nsnc12
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(Br)c3nsnc23)=NO1
Temperature: 65 °C
Reaction time: 3 h
Yield: 52.2 %

Procedure:
To a solution of 7-bromo-N-hydroxybenzo[1,2,5]thiadiazole-4-carbimidoyl chloride (10.01 g) (Example I5) in 2-propanol (140 ml) was added 1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (6.87 g) (prepared according to WO 2005/085216) and sodium hydrogen carbonate (5.99 g). The reaction mixture was stirred at 65° C. for 3 hours. The reaction mixture was concentrated and the residue was purified by column chromatography (heptane/ethyl acetate 9:1) to give 4-bromo-7-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzo[1,2,5]thiadiazole (7.4 g). 1H-NMR (DMSO-d6, 400 MHz): 8.17-7.53 (m, 5H), 4.70 (d, 1H), 4.49 (d, 1H) ppm.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([OH:24])=O)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.[CH2:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][NH:26]1>>[F:1][C:2]1[C:3]([C:22]([N:26]2[CH2:27][C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:25]2)=[O:24])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)O)c3F)s2)c1
Reactant: c1ccc2c(c1)CNC2
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)N4Cc5ccccc5C4)c3F)s2)c1

Procedure:
Following the amide bond forming procedure given in example 37, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)picolinic acid (intermediate B in example 1) and isoindoline were reacted to give the title compound. LC/MS (M+H)+: 464. Ret. time: 1.66 min. (Condition M); analytical HPLC Ret. time: 17.03 min (Condition N).
Reaction SMILES: [C:1]1([N:7]2[CH:15]=[C:14]3[C:9]([CH:10]=[C:11]([C:16]4[CH:17]=[C:18]([CH:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)[N:19]5[C:24]=4[C:23]([NH2:25])=[N:22][CH:21]=[N:20]5)[CH:12]=[CH:13]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:32][S:33]([N:29]1[CH2:30][CH2:31][CH:26]([C:18]2[N:19]3[C:24]([C:23]([NH2:25])=[N:22][CH:21]=[N:20]3)=[C:16]([C:11]3[CH:12]=[CH:13][C:14]4[C:9]([CH:10]=3)=[N:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:15]=4)[CH:17]=2)[CH2:27][CH2:28]1)(=[O:35])=[O:34]
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(-c5ccccc5)nc4c3)c12
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCC(c2cc(-c3ccc4cn(-c5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 28.7 %

Procedure:
To a suspension of 5-(2-phenyl-2H-indazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (80 mg, 0.20 mmol) in DMF (1 mL) was added methanesulfonyl chloride (17 μL, 0.22 mmol) and N,N-diisopropylethylamine (68 μL, 0.39 mmol). The reaction was stirred at rt for 17 h. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 28 mg (29%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1 H), 8.10 (d, 2 H), 7.93 (s, 1 H), 7.85 (d, 1 H), 7.69 (s, 1 H), 7.55-7.63 (m, 2 H), 7.41-7.48 (m, 1 H), 7.22 (dd, 1 H), 6.68 (s, 1 H), 3.63-3.73 (m, 2 H), 3.21-3.32 (m, 1 H), 2.86-2.98 (m, 5 H), 2.10-2.21 (m, 2 H), 1.69-1.86 (m, 2 H); ES-MS m/z 488.23 [M+H]+, HPLC RT (min) 2.72.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.Cl.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][C:12]1=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:14]2[CH2:15][CH2:16][N:11]([CH3:10])[C:12](=[O:17])[CH2:13]2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CN1CCNCC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CN1CCN(c2ccc(Br)cc2)CC1=O
Temperature: 105 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
A mixture of 1,4-dibromobenzene (470 mg, 2.0 mmol), 1-methylpiperazin-2-one hydrochloride (150 mg, 1.0 mmol, from J&W PharmLab), palladium acetate (6.7 mg, 0.030 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.035 g, 0.060 mmol), and cesium carbonate (0.98 g, 3.0 mmol) in toluene (5.0 mL) was evacuated and refilled with nitrogen three times and then the reaction was stirred at 105° C. overnight. The mixture was diluted with ethyl acetate, washed with water, brine, then dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexane (0-60%) to afford the desired product (0.26 g, 49%). LCMS calculated for C11H14BrN2O (M+H)+: m/z=269.0. Found 269.0.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]3[CH:37]([NH:38][CH2:39][CH2:40][NH2:41])[CH2:36][C:35]([CH3:43])([CH3:42])[O:34][C:23]3=[N:24][C:25]=2[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[Cl:33])=[CH:16][CH:15]=1.CCN(CC)CC>C(Cl)(Cl)Cl.CCOC(C)=O>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[C:22]3[CH:37]([N:38]4[CH2:39][CH2:40][NH:41][C:1]4=[O:2])[CH2:36][C:35]([CH3:43])([CH3:42])[O:34][C:23]3=[N:24][C:25]=2[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[Cl:33])=[CH:18][CH:19]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC1(C)CC(NCCN)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC1(C)CC(N2CCNC2=O)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1,1′-carbonyldiimidazole (18.1 mg, 0.11 mmol) in 5.0 mL of CHCl3 was added the product of Step B (0.07 mmol) and NEt3 (51.8 μL, 0.37 mmol) in 5.0 mL of CHCl3. The mixture was allowed to stir at rt for 2 h and then refluxed for 16 h. After cooling to rt, the reaction mixture was diluted with EtOAc (50 mL) and washed with brine (2×50 mL). The organic layer was separated, dried over MgSO4, and concentrated. Chromatography on a Biotage 40+S cartridge using EtOAc as the eluant afforded the title compound: 1H NMR δ 1.48 (s, 3H), 1.58 (s, 3H), 2.00-2.09 (m, 2H), 3.18-3.50 (m, 4H), 4.70 (br. s, 1H), 5.44 (m, 1H), 7.00 (d, J=8.5, 2H), 7.18-7.27 (m, 4H), 7.50 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH2:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:19]1([N:25]2[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:28][C:27]([CH:36]=O)=[N:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([N:25]2[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:28][C:27]([CH2:36][NH:18][CH2:17][CH2:16][N:13]3[CH2:12][CH2:11][N:10]([C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=4)[CH2:15][CH2:14]3)=[N:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: O=Cc1cc(-c2ccccc2)n(-c2ccccc2)n1
Product: O=[N+]([O-])c1ccc(N2CCN(CCNCc3cc(-c4ccccc4)n(-c4ccccc4)n3)CC2)cc1
Yield: 68.5 %

Procedure:
Compound 55 was prepared using the same method as that of Example 1 except that 4-(4-nitrophenyl)piperazin-1-ylethylamine and 1,5-diphenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH2:20][OH:21])=[C:16]([Br:19])[CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][O:23][C:24]([CH3:26])=[CH2:25].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH2:20][O:21][C:24]([O:23][CH3:22])([CH3:26])[CH3:25])=[C:16]([Br:19])[CH:17]=3)[CH:12]=[CH:11]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(CO)c(Br)cc21
Reactant: C=C(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(C)(C)OCc1cc2ccn(S(=O)(=O)c3ccccc3)c2cc1Br
Yield: 98.7 %

Procedure:
Under a nitrogen stream, to a solution of (1-benzenesulfonyl-6-bromo-1H-indol-5-yl)methanol (234 mg, 0.64 mmol) and pyridinium p-toluenesulfonate (4 mg, 0.02 mmol) in THF (0.7 mL) was added 2-methoxypropene (92 μL, 0.96 mmol) under ice cooling, and the resultant mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added saturated aqueous potassium carbonate. The resultant mixture was then twice extracted with ethyl acetate. The organic layer was dried (anhydrous magnesium sulfate). Solvent was then removed by distillation under reduced pressure, to thereby obtain the titled compound (277 mg, 99%).
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[C:4]2[N:10]([CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:9]([OH:16])=[N:8][C:5]2=[N:6][CH:7]=1.[CH3:18][C:19]1(C)[C:23](C)(C)OB(C(C)=C)O1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>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.Cl[Pd]Cl.[Fe+2].O>[Cl:1][C:2]1[C:3]([C:19]([CH3:23])=[CH2:18])=[C:4]2[N:10]([CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:9]([OH:16])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: CCC(CC)n1c(O)nc2ncc(Cl)c(I)c21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: C=C(C)c1c(Cl)cnc2nc(O)n(C(CC)CC)c12
Temperature: 135 °C
Yield: 99.9 %

Procedure:
6-Chloro-7-iodo-1-(pentan-3-yl)-1H-imidazo[4,5-b]pyridin-2-ol (25 mg, 0.068 mmol) was added to a dried microwave tube, followed by 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (20 uL, 0.102 mmol), PdCl2(dppf) (5 mg, 0.0068 mmol), K2CO3 (33 mg, 0.238 mmol), dioxane (3 mL) and water (0.5 mL). The resulting mixture was heated in the microwave at 135° C. for 20 minutes. LCMS showed the starting material was consumed. To the reaction mixture was added saturated NaHCO3 (50 ml), and the product was extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with brine (50 mL) and concentrated. The crude product was flushed through silica gel plug and then purified by reverse phase HPLC to give 19 mg of the title compound as a white powder. m/z=280.20 [M+H]+