Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8](=[O:32])[N:9]([CH:16]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH2:30][CH3:31])[CH:22]=1)[CH2:17][C:18](=[O:20])[CH3:19])[C:10]2=[O:15])=[O:4].[CH3:33][NH:34][CH3:35].Cl>O1CCCC1.C(OCC)(=O)C.CCOCC>[ClH:1].[CH3:33][N:34]([CH3:35])[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8](=[O:32])[N:9]([CH:16]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH2:30][CH3:31])[CH:22]=1)[CH2:17][C:18](=[O:20])[CH3:19])[C:10]2=[O:15])=[O:4]
Reactant: CNC
Reactant: CCOc1cc(C(CC(C)=O)N2C(=O)c3cccc(NC(=O)CCl)c3C2=O)ccc1OC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOc1cc(C(CC(C)=O)N2C(=O)c3cccc(NC(=O)CN(C)C)c3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.1 %

Procedure:
A mixture of 2-chloro-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-3-oxobutyl]-1,3-dioxoisoindolin-4-yl}acetamide (1.07 g, 2.34 mmol) and N,N-dimethylamine (2.0 M in methanol, 3.5 mL, 7.0 mmol) in tetrahydrofuran (15 mL) was stirred at room temperature for 16 hours. The solvent was removed in vacuo to give an oil. The oil was purified by chromatography (silica gel, methylene chloride:ethyl acetate 7:3) to give a white solid. To a solution of the solid in ethyl acetate (10 mL) was added hydrogen chloride in ether (1N, 4 mL). The slurry was filtered and washed with ether to give 2-(dimethylamino)-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-3-oxobutyl]-1,3-dioxoisoindolin-4-yl}acetamide hydrochloride as a white solid (0.52 g, 44%); mp 100-102° C.; 1H NMR (DMSO-d6) δ 10.63 (s, 1H), 10.27 (s, 1H), 8.21 (d, J=8.2 Hz, 1H), 7.84 (t, J=7.7 Hz, 1H), 7.67 (d, J=7.3 Hz, 1H), 6.98 (s, 1H), 6.89 (s, 2H), 5.63-5.57 (dd, J=6.0 and 8.8 Hz, 1H), 4.19 (b, 2H), 3.99 (q, J=6.9 Hz, 2H), 3.77-3.67 (m, 1H), 3.74 (s, 3H), 3.52-3.42 (dd, J=6.1 and 18.1 Hz, 1H), 2.84 (s, 6H), 2.12 (s, 3H), 1.30 (t, J=6.9 Hz, 3H); 13C NMR (DMSO-d6) δ 205.81, 167.32, 167.14, 164.84, 148.49, 147.76, 135.85, 134.29, 131.74, 131.48, 127.70, 119.48, 119.27, 119.09, 112.19, 111.76, 63.76, 58.32, 55.48, 48.90, 44.27, 43.47, 29.87, 14.69; Anal. Calcd. For C26H30N3O6Cl: C, 59.58; H, 6.00; N, 8.34; Cl, 7.03. Found: C, 59.18; H, 6.03; N, 8.14; Cl, 6.68.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[CH:12])[CH:6]=1)[CH3:2].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](Cl)=[N:22][OH:23])=[CH:17][CH:16]=1.N1C=CC=CC=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[O:23][N:22]=[C:21]([C:18]3[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=3)[CH:12]=2)[CH:6]=1)[CH3:2]
Reactant: ON=C(Cl)c1ccc(Cl)cc1
Reactant: C#Cc1cccc(C(=O)OCC)c1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cccc(-c2cc(-c3ccc(Cl)cc3)no2)c1
Temperature: 25 °C

Procedure:
In a 10 ml round flask, 500 mg (2.9 mmol) of 3-ethynyl-benzoic acid ethyl ester and 652 mg (3.5 mmol, 1.2 eq.) of 4-chloro-N-hydroxy-benzenecarboximidoyl chloride are dissolved in 4 ml of CHCl3. To this solution, 11 mg (0.14 mmol, 0.05 eq.) of pyridine and 290 mg (2.9 mmol) of triethyl amine are added at 0° C. under a nitrogen atmosphere. The orange solution is stirred under warming to room temperature for 20 h. The suspension is filtered and the solution concentrated in vacuo. Chromatographical purification (100 g SiO2; eluent: hexane/ethyl acetate 9:1) yields the title compound as a white solid. Mass spectrum: m/z (M+H)+: 328.2; 330.2
Reaction SMILES: [Cl:1][SiH:2]([CH2:4][SiH](Cl)Cl)[Cl:3].[CH2:8]([Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:9]=[CH2:10]>C(O)(C)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH3:12][Si:11]([CH3:14])([CH3:13])[CH2:8][CH2:9][CH2:10][Si:2]([CH3:4])([Cl:3])[Cl:1]
Reactant: Cl[SiH](Cl)C[SiH](Cl)Cl
Reactant: C=CC[Si](C)(C)C
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: C[Si](C)(C)CCC[Si](C)(Cl)Cl
Yield: 145 %

Procedure:
In the same apparatus and procedures as EXAMPLE 1, 9.3 g (0.04 mole) of bisdichlorosilylmethane, 13.7 g (0.12 mole) of allyltrimethylsilane, and 80 μl of 1% chloroplatinic acid solution in isopropanol were placed and reacted for 2 hours at reflux under the dry nitrogen atmosphere. Vacuum distillation gave 13.3 g (134°-136° C./0.05 mmHg) of [{3-(trimethylsilyl)propyl}dichlorosilyl]methane in 75.1% yield.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:11][CH:12]=[C:13]([C:15]2[C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:17][O:18][C:19]=2[CH3:20])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1>>[CH2:1]([O:8][CH2:9][C:10]1[N:11]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)[CH:12]=[C:13]([C:15]2[C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:17][O:18][C:19]=2[CH3:20])[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]c(COCc2ccccc2)n1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(COCc2ccccc2)n1
Yield: 80 %

Procedure:
As described for Example 63, 4-(2-benzyloxymethyl-1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (38 mg, 0.11 mmol) using 1-fluoro-4-nitrobenzene instead of 4-fluoroacetophenone was converted to the title compound (41 mg, 80%) which was obtained as a yellow solid. MS: m/e=467.0 [M+H]+.
Reaction SMILES: CN(C)[C:3]1[CH:4]=[C:5]([CH2:9]O)[CH:6]=[CH:7][CH:8]=1.[Br:12][C:13]1[C:14]([CH3:20])=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1.[CH3:21]C1(C)C(C)(C)OB(C2C=NNC=2)O1>>[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:3]2[CH2:8][CH2:7][CH2:6][C:5]([CH3:9])([CH3:21])[CH2:4]2)[C:14]=1[CH3:20]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Cc1c(O)cccc1Br
Reactant: CN(C)c1cccc(CO)c1
Product: Cc1c(Br)cccc1OC1CCCC(C)(C)C1

Procedure:
The title compound was prepared by substituting 3,3-dimethylcyclohexanol for (3-(dimethylamino)phenyl)methanol and 3-bromo-2-methylphenol for 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE 34A.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[F:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:16][CH2:15][N:14]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(C2=CCNCC2)cc1F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C2=CCN(S(C)(=O)=O)CC2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.4 %

Procedure:
4-(3-Fluoro-4-methoxy-phenyl)-1,2,3,6-tetrahydro-pyridine hydrochloride salt (462.00 mg, 1.90 mmol) is suspended in dichloromethane (10 mL). Triethylamine (479.58 mg, 660.57 μL, 4.74 mmol) and methanesulfonyl chloride (260.59 mg, 176.07 μL, 2.27 mmol) are added and the reaction is capped and stirred at room temperature for 16 h. The reaction is partitioned between dichloromethane and water. The aqueous layer is extracted with dichloromethane. The combined organic layers are washed with brine, dried over magnesium sulfate, filtered, and concentrated to dryness. The crude material is purified by chromatography using a 5 g silica gel cartridge eluting with dichloromethane to provide 349 mg of the title compound as a white solid. MS (m/z) 286 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:28])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:15][CH:14]=2)=[C:6]([CH2:31][CH2:32][CH3:33])[C:5]=1[OH:34])(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=O)C=1.[OH-:46].[Ca+2].[OH-:48]>C(Cl)Cl>[C:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:28])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:15][CH:14]=2)(=[O:48])=[O:46])=[C:6]([CH2:31][CH2:32][CH3:33])[C:5]=1[OH:34])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCSc2ccc(C(=O)CCCCC(=O)OC)cc2)ccc(C(C)=O)c1O
Reactant: [OH-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Solvent: ClCCl
Product: CCCc1c(OCCCS(=O)(=O)c2ccc(C(=O)CCCCC(=O)OC)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The compound of Step B above, (1.0 g, 2.05 mmoles) was dissolved in dry methylene chloride (25 ml) to which was added one equivalent of m-chloroperbenzoic acid in methylene chloride (10 ml). After 1 hour stirring at room temperature, additional m-CPBA (450 mg) was added. The reaction was complete in two hours Calcium hydroxide (1.0 g) was added and the reaction mixture was stirred for 10 minutes. The mixture was filtered and the filtrate concentrated. The residue was purified by chromatography to yield the title compound. NMR (CDCl3): 0.90 (3H, m), 1.50 (2H, m), 1.74 (4H, m), 2.33 (6H, m), 2.55 (3H, s), 3.03 (2H, m), 3.37 (2H, m), 3.68 (3H, s), 4.12 (2H, m), 6.39 (2H, d), 7.60 (2H, d), 8.12 (4H, m), 12.73 (1H, s).
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[C:16](=[C:17](Cl)[CH:18]=[CH:19][CH:20]=5)[C:15](=[O:23])[N:14]([CH3:24])[C:13]=34)[N:5]=2)[CH2:3][CH2:2]1.[Cl:25][C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1.[H-].[Na+].O>CN(C)C=O.CCOCC>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[C:16](=[C:17]([O:32][C:28]6[CH:29]=[CH:30][CH:31]=[C:26]([Cl:25])[CH:27]=6)[CH:18]=[CH:19][CH:20]=5)[C:15](=[O:23])[N:14]([CH3:24])[C:13]=34)[N:5]=2)[CH2:2][CH2:3]1
Reactant: Oc1cccc(Cl)c1
Reactant: Cn1c(=O)c2c(Cl)cccc2n2cnc(-c3noc(C4CC4)n3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: Cn1c(=O)c2c(Oc3cccc(Cl)c3)cccc2n2cnc(-c3noc(C4CC4)n3)c12
Temperature: 110 °C
Reaction time: 8 h
Yield: 53.8 %

Procedure:
A mixture of 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methyl-5-oxo-6-chloro-4,5-dihydro-imidazo(1,5-a)quinazoline (0.4 g, 1.2 mmol), 3-chlorophenol (0.4 g, 3 mmol), and sodium hydride (55% dispension in oil, 0.14 g, 3 mmol) in 20 ml of dry dimethylformamide was stirred for 8 h at 110° C., cooled to room temperature and poured into 30 ml of water and 5 ml of ether. The mixture was then stirred for 30 min. at 0° C. and the precipitate was filtered off, rinsed with water and dried giving 0.28 g (57%) of 3-(5-cyclopropyl-1,2,4- oxadiazol-3-yl)-4-methyl-5-oxo-6-(3-chlorophenoxy)-4,5-dihydroimidazo(1, 5-a) quinazoline, M.p. 201°-203° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[CH:5]=[C:4]([CH3:12])[N:3]=1.Cl.[CH2:14]([O:16][C:17](=[O:27])[CH2:18][C@@H:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:15].CCN(C(C)C)C(C)C>CC(N(C)C)=O.C(OCC)(=O)C>[CH2:14]([O:16][C:17](=[O:27])[CH2:18][C@@H:19]([NH:26][C:6]1[CH:5]=[C:4]([CH3:12])[N:3]=[C:2]([Cl:1])[C:7]=1[N+:8]([O-:10])=[O:9])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH3:15]
Reactant: CCOC(=O)C[C@@H](N)c1ccccc1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(Cl)n1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C[C@@H](Nc1cc(C)nc(Cl)c1[N+](=O)[O-])c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.3 %

Procedure:
To a solution of 2,4-dichloro-6-methyl-3-nitropyridine (900 mg, 4.35 mmol) in DMA (8 mL) were added (R)-3-amino-3-phenylpropionic acid ethyl ester HCl (799 mg, 3.48 mmol) and DIPEA (1.6 mL, 8.70 mmol). The reaction mixture was stirred at room temperature for 12 hours. The reaction was then diluted with ethyl acetate and washed with water twice. The organic phase was dried over Na2SO4 and concentrated to give yellow oil. The resulting oily residue was purified by silica gel preparative TLC using 99:1 CH2Cl2:MeOH as an eluent to afford 650 mg (51%) of the title compound as a light orange oil. LCMS, M++1, m/z: 364.15.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:17])[C:7]=2[N:6]=[CH:5]1.[C:18]1([S-:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Na+]>CS(C)=O>[C:18]1([S:24][CH2:2][CH2:3][N:4]2[C:16]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]=[C:8]([NH2:17])[C:7]=3[N:6]=[CH:5]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1nc2ccccc2c2c1ncn2CCCl
Reactant: [S-]c1ccccc1
Agent: [Na+]
Solvent: CS(C)=O
Product: Nc1nc2ccccc2c2c1ncn2CCSc1ccccc1
Temperature: 100 °C
Yield: 80 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, 1-(2-chloroethyl)-1H-imidazo[4,5-c]quinolin-4-amine (2.0 g, 8.11 mmol), sodium benzenethiolate (1.79 g, 12.16 mmol), and anhydrous dimethyl sulfoxide (40 mL) under a nitrogen atmosphere. The reaction mixture was heated to 100° C. to give a homogeneous solution that was maintained at 100° C. for 30 minutes at which time the starting material was completely consumed. The hot solution was poured into rapidly stirred water (300 mL) which caused a solid to precipitate out of solution. The solid was collected by filtration to afford an off-white solid. The material was triturated with acetonitrile and collected by filtration to give 1-[2-(phenylthio)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine (2.08 g, 6.49 mmol) as an off-white powder, m.p. 233-235° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[S:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[Br:23][C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:33]2[CH2:32][CH2:31][N:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([Br:23])[CH:25]=3)[CH2:35][CH2:34]2)=[S:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2nc1NC(=S)Oc1ccccc1
Reactant: Brc1cccc(N2CCNCC2)c1
Product: COc1nc2ccccc2nc1NC(=S)N1CCN(c2cccc(Br)c2)CC1
Yield: 57.5 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)thiocarbamate and 1-(3-bromophenyl)piperazine were reacted by the same way with the example 63 to obtain the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([NH:14][CH2:15][C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[OH-].[K+].C1COCC1.Cl>O.CO>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([NH:14][CH2:15][C:16]3[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(CNc2cc(-c3ccc(OC)nc3)n[nH]2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(-c2cc(NCc3ccc(C(=O)O)cc3)[nH]n2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
A solution of 384 (672 mg, 1.99 mmol) and KOH (300 mg, 5.35 mmol) in 1:1:1 mixture of THF, MeOH and water (9 mL) was stirred at room temperature overnight. The reaction mixture was acidified to pH=4 by addition of 1M HCl and concentrated in vacuo. The residue was triturated with water and the solid was collected by filtration and dried to afford the title compound (640 mg, 99% yield). LRMS: (calc) 324.1; (found) 325.2 (M+H1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([CH3:13])=[CH:5]2.[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:6]1[C:7]([CH3:12])=[N:8][C:9]2[C:4]([CH:5]=1)=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2cc(Cl)ccc2nc1C
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nc2ccc(Cl)cc2cc1CBr
Temperature: 25 °C
Yield: 31.7 %

Procedure:
To a solution of 6-chloro-2,3-dimethylquinoline (2.0 g, 10.5 mmol) in carbon tetrachloride (80 ml) benzoyl peroxide (100 mg) and N-bromosuccinimide (3.7 g, 21.0 mmol) were added. The reaction mixture was refluxed for 4 hours, and then cooled to room temperature. The precipitate was removed by filtration and the filtrate was evaporated in vacuo. The residue was flash chromatographed on silica gel with ethyl acetate/petroleum ether as the eluent to give 0.90 g 3-bromomethyl-6-chloro-2-methylquinoline.
Reaction SMILES: [C:1]([S:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)(=[O:3])[CH3:2].C([O:20][C:21](=[O:29])[CH2:22][NH:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)(C)(C)C.[I-].[Na+].Cl[Si](C)(C)C>C(Cl)Cl.C(#N)C>[C:1]([S:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([N:23]([CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)[CH2:22][C:21]([OH:29])=[O:20])=[O:9])(=[O:3])[CH3:2]
Reactant: COc1cccc(C(=O)O)c1SC(C)=O
Reactant: CC(C)(C)OC(=O)CNC1CCCC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: COc1cccc(C(=O)N(CC(=O)O)C2CCCC2)c1SC(C)=O
Reaction time: 8 h

Procedure:
N,N1 -Dicyclohexylcarbodiimide (10.3 g, 50 mmol) in methylene chloride (80 ml) was added to 2-acetylthio-3-methoxybenzoic acid (11.3 g, 50 mmol) and N-cyclopentylglycine t-butyl ester (10.0 g, 50 mmol) in methylene chloride (300 ml) at 0°-5° C. Overnight stirring was followed by filtration and washing of the filtrate with dilute hydrochloric acid, sodium bicarbonate solution and brine. Drying and concentration gave a gum which was dissolved in acetonitrile (65 ml), combined with sodium iodide (11.2 g, 75 mmol) and heated to 40°-50° C. Chlorotrimethylsilane (8.1 g, 75 mmol) was introduced and the mixture was heated for 30 minutes, then quenched with water. The organic phase was washed with water, aqueous sodium thiosulfate and brine then concentrated. Aqueous sodium bicarbonate was added to the residue and the resulting solution was washed with methylene chloride and ether, then acidified and extracted with ethyl acetate. The organic portion was dried and concentrated and the residue passed through a silica gel column to provide the amorphous product.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:33])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][OH:43])[CH2:37][CH2:36]1.O1CCN(CCO)CC1>>[CH:30]1([C:26]2[N:25]=[C:24]([CH2:23][N:18]3[C:19]4[C:15](=[C:14]([NH:13][C:11]([C:8]5[N:5]6[CH:6]=[CH:7][C:2]([O:43][CH2:42][CH2:41][N:38]7[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]7)=[CH:3][C:4]6=[N:10][CH:9]=5)=[O:12])[CH:22]=[CH:21][CH:20]=4)[C:16]([CH3:33])=[N:17]3)[CH:29]=[CH:28][CH:27]=2)[CH2:32][CH2:31]1
Reactant: CN1CCN(CCO)CC1
Reactant: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(F)ccn34)c12
Agent: OCCN1CCOCC1
Product: Cc1nn(Cc2cccc(C3CC3)n2)c2cccc(NC(=O)c3cnc4cc(OCCN5CCN(C)CC5)ccn34)c12
Yield: 45 %

Procedure:
Prepared according to Example 1, Step B, substituting N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide for 7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide and 2-(4-methylpiperazin-1-yl)ethanol for 2-morpholinoethanol, to give the final product (45%). MS (APCI), positive scan, m/z=565.3 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[C:7]3[CH:13]=[C:12]([C:14]4[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=4)[C:17]([OH:19])=O)[N:11]([S:23]([C:26]4[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=4)(=[O:25])=[O:24])[C:8]3=[N:9][CH:10]=[C:5]2[CH:4]=[N:3]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:66]1[CH2:71][CH2:70][N:69]([CH2:72][CH2:73][NH2:74])[CH2:68][CH2:67]1>CCOC(C)=O.CN(C=O)C>[CH3:1][N:2]1[C:6]2=[C:7]3[CH:13]=[C:12]([C:14]4[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=4)[C:17]([NH:74][CH2:73][CH2:72][N:69]4[CH2:70][CH2:71][O:66][CH2:67][CH2:68]4)=[O:19])[N:11]([S:23]([C:26]4[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=4)(=[O:24])=[O:25])[C:8]3=[N:9][CH:10]=[C:5]2[CH:4]=[N:3]1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cccc(C(=O)O)c3)cc3c4c(cnc32)cnn4C)cc1
Reactant: NCCN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2c(-c3cccc(C(=O)NCCN4CCOCC4)c3)cc3c4c(cnc32)cnn4C)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
A flask was charged with 3-(1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)benzoic acid (0.10 g, 0.22 mmol, prepared using D from Preparation #1 with 3-boronobenzoic acid), DIEA (0.039 mL, 0.224 mmol), HATU (0.085 g, 0.224 mmol) and DMF (3 mL). The mixture was stirred at about 40° C. for about 30 min. To the mixture was added 2-morpholinoethanamine (0.038 mL, 0.291 mmol). The mixture was allowed to stir at about 40° C. for about 2 h. The mixture was stirred overnight at rt and then diluted with EtOAc (10 mL) and washed with water (10 mL). The aqueous layer was further extracted with EtOAc (2×10 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography with an elution gradient of 0 to 7.5% MeOH/DCM to give 3-(1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)-N-(2-morpholinoethyl)benzamide (0.123 g, 98%): LC/MS (Table 2, Method c) Rt=1.20 min; MS m/z 559 (M+H)+.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH:13]1[C:17]([CH2:18][CH2:19][CH2:20][OH:21])=[CH:16][N:15]=[CH:14]1.O.Cl.Cl.[CH2:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH:26]1[NH:34][C:35]1[N:36]=[CH:37][C:38]2[CH2:43][NH:42][CH2:41][C:39]=2[N:40]=1>CN(C)C=O>[CH2:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:25][CH:26]1[NH:34][C:35]1[N:36]=[CH:37][C:38]2[CH2:43][N:42]([C:1]([O:21][CH2:20][CH2:19][CH2:18][C:17]3[NH:13][CH:14]=[N:15][CH:16]=3)=[O:2])[CH2:41][C:39]=2[N:40]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OCCCc1cnc[nH]1
Reactant: c1ccc2c(c1)CC(Nc1ncc3c(n1)CNC3)C2
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCCCc1cnc[nH]1)N1Cc2cnc(NC3Cc4ccccc4C3)nc2C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 3.9 %

Procedure:
Add 1,1′-carbonyldiimidazole (0.51 g; 1.2 equiv; 3.15 mmoles) to a solution of 3-(1H-imidazol-5-yl)propan-1-ol (0.50 g; 1.0 equiv; 2.62 mmoles) in dimethylformamide (8.5 mL) and stir for 1 hour. Slowly add N-(2,3-dihydro-1H-inden-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride hydrate (0.94 g; 1.10 equiv; 2.89 mmoles) to the aforementioned solution. Stir for 16 hours at ambient temperature and then heat to 60° C. for an additional 16 hours. Partition the reaction mixture between water and chloroform and separate the layers. Further extract the aqueous layer with chloroform (2×). Dry the combined organic extracts over magnesium sulfate, filter, and concentrate to a viscous liquid. Purify the crude product by column chromatography (0 to 20% methanol in dichloromethane) to afford 3-(1H-imidazol-5-yl)propyl 2-(2,3-dihydro-1H-inden-2-ylamino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (0.041 g; 4%) as a brown solid: MS (m/z): 405(M+1).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C@@H:10]([CH3:28])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[NH:21][C:22]1[CH:27]=[N:26][CH:25]=[CH:24][N:23]=1)=[O:12].Cl[C:30]1[N:38]=[CH:37][N:36]=[C:35]2[C:31]=1[N:32]=[CH:33][N:34]2[CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][O:40]1.O>CC(O)C>[F:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:11](=[O:12])[C@@H:10]([NH:9][C:30]2[N:38]=[CH:37][N:36]=[C:35]3[C:31]=2[N:32]=[CH:33][N:34]3[CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][O:40]2)[CH3:28])=[C:15]([NH:21][C:22]2[CH:27]=[N:26][CH:25]=[CH:24][N:23]=2)[CH:16]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)C(=O)Nc1ccc(F)cc1Nc1cnccn1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Solvent: CCN(CC)CC
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)C(=O)Nc1ccc(F)cc1Nc1cnccn1
Temperature: 80 °C

Procedure:
Triethylamine (211 μl, 1.52 mol) was added to (S)-2-amino-N-[4-fluoro-2-(pyrazin-2-ylamino)phenyl]propionamide hydrochloride (118 mg, 0.38 mmol) and 6-chloro-9-(tetrahydro-2-pyranyl)purine (109 mg, 0.45 mol) in IPA (5.0 ml) and heated at 80° C. overnight. The reaction was poured into water and the aqueous layer extracted into EtOAc (×3). The combined organic fractions were washed with brine, dried (Na2SO4) and concentrated in vacuo. The product was purified by chromatography (SiO2, 0-10% 2M ammonia methanol/DCM) to yield the title compound as a 1:1 mixture of diastereomers (100 mg, 0.21 mmol, 55%). LCMS (Method C): RT 2.55 min [M+H]+ 478.2. 1H NMR (MeOD, 400 MHz): δ 8.26 (2H, m), 7.84 (2H, m), 7.58 (2H, m), 7.32 (1H, ddd, J 11.9, 10.1, 2.8 Hz), 6.92 (1H, ddd, J 8.9, 8.1, 2.9 Hz), 5.70 (1H, m), 4.16 (1H, m), 4.80 (1H, m), 3.80 (1H, m), 2.18 (3H, m), 1.80 (2H, m), 1.61 (4H, m).