Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:21][CH2:22][CH2:23][O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1>CN(C=O)C>[O:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH:25]1[O:24][CH2:23][CH2:22][CH2:21][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5]1
Reactant: Oc1cccc(N2CCNCC2)c1
Reactant: BrCCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Oc1cccc(N2CCN(CCCOC3CCCCO3)CC2)c1
Yield: 49.4 %

Procedure:
712 mg (4 mmol) 3-Piperazin-1-yl-phenol are dissolved in 30 mL DMF under argon and cooled below 5° C. After addition of 1.38 g (2.5 eq.) K2CO3, 166 mg (0.25 eq.) KI and 888 mg (1 eq.) 2-(3-bromo-propoxy)-tetrahydro-pyran, the suspension is stirred at room temperature for 20 hours, then extracted with AcOEt after dilution with saline. The organic phase is dried over sodium sulfate, evaporated and the residue column chromatographed (silica gel, AcOEt/EtOH 95:5) to yield 630 mg (48%) desired product as a light yellowish resin.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:36])([CH2:33][CH2:34][CH3:35])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:32])=[N:15][N:16]2[C:21]([O:22][CH2:23][C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[F:31])=[CH:20][CH:19]=[CH:18][C:17]=12)=[O:12])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]([CH3:36])([CH2:33][CH2:34][CH3:35])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:32])=[N:15][N:16]2[C:21]([O:22][CH2:23][C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[F:31])=[CH:20][CH:19]=[CH:18][C:17]=12)=[O:12]
Reactant: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3c(F)cccc3F)cccc12)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC(C)(N)CNC(=O)c1c(C)nn2c(OCc3c(F)cccc3F)cccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.9 %

Procedure:
A solution of 45 mg (0.046 mmol, 53% pure) of rac-{1-[({7-[(2,6-difluorobenzyl)oxy]-2-methylpyrazolo[1,5-a]pyridin-3-yl}carbonyl)amino]-2-methylpentan-2-yl}carbamic acid tert-butyl ester (Example 131A) in 4 ml of dichloromethane was admixed with 0.5 ml (6.49 mmol) of trifluoroacetic acid. The resulting solution was stirred at room temperature for 2 h. The solvent was drawn off under reduced pressure and the residue was purified by preparative HPLC chromatography (Method 21), which gave 6.5 mg (34% yield) of the target compound as a white powder.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][C:6](=[O:8])[CH2:5][CH:4]1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].[BH4-].[Na+].[NH4+].[Cl-]>CO>[CH2:1]([CH:3]1[CH2:7][CH:6]([OH:8])[CH2:5][CH:4]1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2]
Reactant: CCOC(=O)C1CC(=O)CC1CC
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CCOC(=O)C1CC(O)CC1CC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl 2-ethyl-4-oxocyclopentanecarboxylate (12.82 g, 69.6 mmol, 86% ee, predominantly 1S,2R) in MeOH (183 mL) was added sodium borohydride (3.29 g, 87 mmol) portion-wise. The suspension was stirred at ambient temperature for about 16 h. Saturated aqueous NH4Cl (200 mL) was added and the reaction was stirred for about 3 h. The white precipitate that formed was filtered and washed with Et2O (100 mL). The filtrate was poured into Et2O (300 mL). The solid was filtered and washed with Et2O (50 mL). The layers were separated and the aqueous layer was extracted with Et2O (2×150 mL). The combined organic layers were washed with brine (2×150 mL), dried over anhydrous MgSO4, filtered and concd under reduce pressure (keeping bath temperature about 25° C. and vacuum >50 psi) to give a crude product as a thick light yellow oil. The oil was washed with pentane (5×80 mL). The combined pentane layers were dried over anhydrous MgSO4, filtered and concd to give an oil which was purified by silica gel chromatography using 1:1 EtOAc:pentane to give ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate as a scalemic mixture of diastereomers predominantly (1S,2R,4S)-ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate (12.38 g, 96%) as a clear oil; 1H NMR (400 MHz, CDCl3) δ 4.34-4.25 (m, 1H), 4.23-4.09 (m, 2H), 3.43-3.17 (m, 1H), 2.88 (td, J=7.1, 2.2, 1H), 2.40 (dt, J=14.0, 7.8, 1H), 2.09-1.91 (m, 3H), 1.33-1.24 (m, 4H), 0.95 (t, J=7.4, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][C:9]2[N:13]([CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:12]3[CH:21]=[CH:22][C:23]([N+:25]([O-])=O)=[CH:24][C:11]=3[N:10]=2)=[CH:6][CH:5]=1)[CH3:2].Br.C(S[C:39]([C:41]1[CH:45]=[CH:44][S:43][CH:42]=1)=[NH:40])C1C=CC=CC=1>>[CH2:17]([N:16]([CH2:19][CH3:20])[CH2:15][CH2:14][N:13]1[C:12]2[CH:21]=[CH:22][C:23]([NH:25][C:39]([C:41]3[CH:45]=[CH:44][S:43][CH:42]=3)=[NH:40])=[CH:24][C:11]=2[N:10]=[C:9]1[CH2:8][C:7]1[CH:28]=[CH:29][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=1)[CH3:18]
Reactant: N=C(SCc1ccccc1)c1ccsc1
Reactant: CCOc1ccc(Cc2nc3cc([N+](=O)[O-])ccc3n2CCN(CC)CC)cc1
Agent: Br
Product: CCOc1ccc(Cc2nc3cc(NC(=N)c4ccsc4)ccc3n2CCN(CC)CC)cc1
Temperature: 25 °C
Reaction time: 108 h

Procedure:
{2-[2-(4-Ethoxy-benzyl)-5-nitro-benzoimidazol-1-yl]-ethyl}-diethyl-amine 7a (108 mg, 0.273 mmol) was reduced to the amine 8a as outlined above and the resulting ethanolic solution charged to a small, argon purged flask fitted with a magnetic stirbar. Thiophene-3-carboximidothioic acid benzyl ester hydrobromide 9f (182 mg, 0.575 mmol) is added to the flask and the reaction was stirred under Ar at ambient temperature for 108 hours. The solvent was evaporated and the residue partitioned between H2O and ethyl acetate and 3M sodium hydroxide solution added to adjust pH to 10. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine (twice), dried over magnesium sulphate, filtered and concentrated to afford crude. The product was purified using silica gel dry column chromatography eluting with 5% 2M NH3 in methanol/95% dichloromethane then purified using a second silica gel column eluting with 60% methanol/40% dichloromethane to afford a pale yellow solid 16 N-(1-(2-(diethylamino)ethyl)-2-(4-ethoxybenzyl)-1H-benzo[d]imidazol-5-yl)thiophene-3-carboximidamide. Yield: 40 mg (30.8%) 1H NMR (DMSO) δ; 0.83 (t, 6H, J=7.0), 1.30 (t, 3H, J=6.9), 2.38-2.50 (2×m, 6H), 3.97 (q, 2H, J=7.0), 4.10 (t, 2H, J=6.5), 4.22 (s, 2H), 6.12 (br, 2H), 6.73 (d, 1H, J=8.3), 6.86 (d, 2H, J=8.4), 6.97 (d, 1H, J=1.8), 7.19 (d, 2H, J=8.6), 7.34 (d, 1H, J=8.4), 7.53-7.55 (m, 1H), 7.61-7.66 (m, 1H), 8.13 (d, 1H, J=3.0). MS (ESI): 476 (MH+, 25%), 377 (100%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([F:24])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.Cl[C:35]([O:37][CH3:38])=[O:36]>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:35]([O:37][CH3:38])=[O:36])[CH2:9]2)=[N:4][C:3]=1[C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([F:24])[CH:15]=1
Reactant: COC(=O)c1ccc(-c2nc(C3CCCNC3)cnc2N)cc1F
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(-c2nc(C3CCCN(C(=O)OC)C3)cnc2N)cc1F
Reaction time: 0.5 h

Procedure:
To methyl 4-(3-amino-6-(piperidin-3-yl)pyrazin-2-yl)-2-fluorobenzoate (55 mg, 0.166 mmol) (for synthesis, see Example 34, Step 7) in DCM (3 mL) in ice bath was added DIEA (0.116 mL, 0.666 mmol) and methyl chloroformate (0.013 mL, 0.166 mmol). The reaction mixture was stirred at in ice bath for 30 min. The reaction mixture was partitioned between DCM and water. The DCM layer was separated, washed with brine, dried over sodium sulfate, filtered and evaporated. The residue (50 mg, 77%) was taken to the next step without further purification. LCMS (m/z): 389.2 (MH+), 0.785 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:16]([CH2:17][CH2:18][CH2:19][OH:20])=[N:15][O:14][N:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:20][CH2:19][CH2:18][CH2:17][C:16]1[C:12]([C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=2)=[O:11])=[N:13][O:14][N:15]=1)(=[O:24])=[O:23]
Reactant: O=C(Nc1ccc(F)c(Cl)c1)c1nonc1CCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)OCCCc1nonc1C(=O)Nc1ccc(F)c(Cl)c1
Temperature: 0 °C
Yield: 79.4 %

Procedure:
N-(3-Chloro-4-fluorophenyl)-4-(3-hydroxypropyl)-1,2,5-oxadiazole-3-carboxamide (60 mg, 0.20 mmol) was dissolved in anhydrous DCM (2 mL), followed by addition of TEA (57 μL, 0.41 mmol). The reaction was stirred and cooled to 0° C., and methanesulfonyl chloride (29 μL, 0.37 mmol) was added drop-wise. The reaction was quenched with water and diluted with DCM. The organic layer was separated, dried over Na2SO4, filtered, concentrated and purified by silica gel chromatography (25%-75% EtOAc/hexane) to give the desired product (60 mg, 80%). LCMS for C13H14ClFN3O5S (M+H)+: m/z=378.
Reaction SMILES: [N:1]1[N:2]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH2:20][CH2:19][C:18]3=[O:22])=[CH:13][CH:12]=2)[CH:3]=[C:4]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6][C:5]=12.[CH:23]1([CH2:26]C=O)[CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.CO>[CH:23]1([CH2:26][N:8]2[CH2:9][CH2:10][C:4]3=[CH:3][N:2]([C:11]4[CH:12]=[CH:13][C:14]([N:17]5[CH2:21][CH2:20][CH2:19][C:18]5=[O:22])=[CH:15][CH:16]=4)[N:1]=[C:5]3[CH2:6][CH2:7]2)[CH2:25][CH2:24]1
Reactant: O=CCC1CC1
Reactant: O=C1CCCN1c1ccc(-n2cc3c(n2)CCNCC3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: O=C1CCCN1c1ccc(-n2cc3c(n2)CCN(CC2CC2)CC3)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1-[4-(5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)phenyl]-2-pyrrolidinone (may be prepared as described in Description 22) (55 mg, 0.10 mmol) in dichloromethane (5 ml) was added cyclopropylacetaldehyde (26 mg, 0.30 mmol) and acetic acid (3 drops). The resulting mixture was stirred at room temperature, under argon, for 20 minutes. Sodium triacetoxyborohydride (64 mg, 0.30 mmol) was added and stirring continued for 18 hours. The resulting crude mixture was diluted with methanol and then purified by SCX, eluting with methanol and then with 2M ammonia/methanol. The basic fractions were collected and solvent evaporated in vacuo. Crude product was triturated with ethyl acetate to afford the title compound (E19). MS (ES+) m/e 351 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1.[CH:20]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.[Cl-].[Na+]>C(O)CO>[Br:1][C:2]1[CH:7]=[N:6][C:5]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:4]=2[C:3]=1[NH:26][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NC1CCCCC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)c(Br)cnc21
Agent: [Cl-]
Agent: [Na+]
Solvent: OCCO
Product: C[Si](C)(C)CCOCn1ccc2c(NC3CCCCC3)c(Br)cnc21
Temperature: 25 °C
Yield: 80 %

Procedure:
5-Bromo-4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine (150 mg, 0.415 mmol) and cyclohexylamine (1 mL, 9 mmol) in ethylene glycol (1 mL) were stirred at 200° C. for 2 hour under microwave irradiation. The reaction mixture was allowed to cool to room temperature and, after addition of saturated aqueous sodium chloride, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1 (v/v)) to give the title compound as an orange oil (141 mg, yield 80%).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19]C)=[O:18])[CH:15]=3)[C:10]([CH3:21])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+].Cl>CO>[CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=3)[C:10]([CH3:21])=[CH:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C)cn(CC3CCCCC3)c2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1cn(CC2CCCCC2)c2cc(C(=O)O)ccc12
Temperature: 70 °C
Yield: 85.3 %

Procedure:
A mixture of methyl 1-cyclohexylmethyl-3-methyl-1H-indole-6-carboxylate [9.0 g, Reference Example 29(a)] and lithium hydroxide (8.0 g) in aqueous methanol (300 ml, 1:2, v/v) was heated at 70° C. for 4 hours. The reaction mixture was cooled to room temperature, then acidified by addition of dilute hydrochloric acid and then extracted three times with ethyl acetate (150 ml). The combined extracts were dried over sodium sulphate then evaporated to give the title compound as a white solid (7.3 g). M+271.
Reaction SMILES: [Cl:1][C:2]1[C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][N:5]=[C:4]2[N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=[CH:19][C:3]=12.Br[C:29]1[CH:30]=[C:31]([CH:35]([OH:41])[C:36]([N:38]([CH3:40])[CH3:39])=[O:37])[CH:32]=[N:33][CH:34]=1>C1COCC1.C(#N)C.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[Cl:1][C:2]1[C:7]([C:29]2[CH:30]=[C:31]([CH:35]([OH:41])[C:36]([N:38]([CH3:39])[CH3:40])=[O:37])[CH:32]=[N:33][CH:34]=2)=[CH:6][N:5]=[C:4]2[N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:26])[CH3:27])[CH:18]=[CH:19][C:3]=12
Reactant: CN(C)C(=O)C(O)c1cncc(Br)c1
Reactant: CC1(C)OB(c2cnc3c(ccn3COCC[Si](C)(C)C)c2Cl)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [CH]1[CH][CH][C]([PH+](c2ccccc2)c2ccccc2)[CH]1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CC#N
Product: CN(C)C(=O)C(O)c1cncc(-c2cnc3c(ccn3COCC[Si](C)(C)C)c2Cl)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
A mixture of 4-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (1.3 g, 3.3 mmol), 2-(5-bromo-pyridin-3-yl)-2-hydroxy-N,N-dimethyl-acetamide (0.8 g, 3.3 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (133 mg, 0.2 mmol) in THF/Acetonitrile/saturated NaHCO3 (20 ml/20 ml/20 ml) was stirred at 70° C. overnight. The mixture was allowed to cool down to room temperature and then extracted with ethyl acetate (2×). The combined organic layers were extracted with brine, dried with Na2SO4, decanted, and concentrated to dryness. Silica chromatography of the crude using a gradient of ethyl acetate and hexane afforded 2-{5-[4-chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]pyridine-3-yl}-2-hydroxy-N,N-dimethyl-acetamide (1.3 g, 85% yield). 1H NMR (500 MHz, DMSO-d6) δ 0.05 (s, 9H), 0.92 (t, 2H), 2.95 (d, 6H), 3.62 (t, 2H), 5.68 (s, 1H), 6.77 (s, 1H), 7.96, (s, 1H), 7.98 (s, 1H), 8.41 (s, 1H), 8.71 (s, 1H), 8.72 (s, 1H). MS: m/z 461.3 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].C([O-])([O-])=O.[K+].[K+].[C:13]([O:17][C:18]([N:20]([CH3:30])[CH2:21][CH2:22][CH2:23][CH2:24]OS(C)(=O)=O)=[O:19])([CH3:16])([CH3:15])[CH3:14]>C(#N)C>[C:13]([O:17][C:18](=[O:19])[N:20]([CH2:21][CH2:22][CH2:23][CH2:24][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6])[CH3:30])([CH3:16])([CH3:15])[CH3:14]
Reactant: CN(CCCCOS(C)(=O)=O)C(=O)OC(C)(C)C
Reactant: NCCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCCCNCCCCN)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
Putrescine (9.45 g, 107 mmol) was dissolved in acetonitrile (200 mL) with K2CO3 (14.79 g, 107 mmol) and stirred under N2. Mesylate 22 (6.03 g, 21.4 mmol) dissolved in acetonitrile (60 mL) was added dropwise over 30 min while stirring under N2. After 30 min, the reaction mixture was brought to reflux and stirred overnight. The reaction mixture was then cooled, solid K2CO3 was filtered off and the filtrate concentrated in vacuo. The residue was re-dissolved in CH2Cl2 (200 mL) and washed six times with sat. aqueous Na2CO3 to remove the unreacted putrescine. The organic layer was then dried over anhydrous Na2SO4, filtered, and concentrated to give the product 23 as a clear oil that was used in the next step without further purification, yield: 5.31 g (90%); 1H NMR (CDCl3) δ 3.21 (t, 2H), 2.84 (s, 3H), 2.71 (t, 2H), 2.62 (t, 4H), 1.40-1.60 (m, 17H).
Reaction SMILES: [C:1](=[O:13])([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[O:2][CH:3](Cl)[CH3:4].[C:14]([NH:17][C:18]1[C:19]([I:34])=[C:20]([N:29]([C:31](=[O:33])[CH3:32])[CH3:30])[C:21]([I:28])=[C:22]([C:25]([O-:27])=[O:26])[C:23]=1[I:24])(=[O:16])[CH3:15].[K+].[I-].[Na+]>CN(C=O)C>[C:14]([NH:17][C:18]1[C:19]([I:34])=[C:20]([N:29]([C:31](=[O:33])[CH3:32])[CH3:30])[C:21]([I:28])=[C:22]([C:25]([O:27][CH:3]([O:2][C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:13])[CH3:4])=[O:26])[C:23]=1[I:24])(=[O:16])[CH3:15]
Reactant: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(N(C)C(C)=O)c1I
Reactant: CCCCCCOC(=O)OC(C)Cl
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCOC(=O)OC(C)OC(=O)c1c(I)c(NC(C)=O)c(I)c(N(C)C(C)=O)c1I
Temperature: 60 °C
Reaction time: 18 h

Procedure:
1-Chloroethyl hexyl carbonate (0.47 g, 2.3 mmol) was added at room temperature to a solution of potassium 5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate (1.51 g, 2.3 mmol) and sodium iodide (0.036 g, 0.24 mmol) in dry DMF (12 ml). After stirring at 60° C. for 3 hours and at room temperature for 18 hours the solvent was removed at reduced pressure. The residue was suspended in chloroform (20 ml) and washed three times with a saturated sodium hydrogen carbonate solution and finally twice with water. After drying with magnesium sulfate the solution was evaporated to dryness. Yield: 0.88 g, Purity by HPLC: 95.2% 1H-NMR (DMSO-d6); delta=0.86 (CH2CH3); 1.22-1.36 (CH2CH2CH2CH3); 1.62 (OCH2CH2); 1.64 (CHCH3); 1.66 (NCH3COCH3); 2.04 (NHCOCH3); 2.95 (NCH3); 4.16 (OCH2); 6.96 (CH); 10.11 ppm (NH). FAB/MS: 801 ((M+H)+).
Reaction SMILES: CN1CC[CH2:4][C:3]1=[O:7].C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)(=O)C.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH:26][C:27]([O:29]C)=[O:28])=[C:21]([NH:31][C:32]([NH:34][C:35](=[O:45])[C:36]2[CH:41]=[C:40]([F:42])[C:39]([F:43])=[CH:38][C:37]=2[Cl:44])=[O:33])[CH:20]=1>O>[C:3]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH:26][C:27]([OH:29])=[O:28])=[C:21]([NH:31][C:32]([NH:34][C:35](=[O:45])[C:36]2[CH:41]=[C:40]([F:42])[C:39]([F:43])=[CH:38][C:37]=2[Cl:44])=[O:33])[CH:20]=1)(=[O:7])[CH3:4]
Reactant: COC(=O)C=Cc1ccc(N)cc1NC(=O)NC(=O)c1cc(F)c(F)cc1Cl
Reactant: CN1CCCC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)Cl
Product: CC(=O)Nc1ccc(C=CC(=O)O)c(NC(=O)NC(=O)c2cc(F)c(F)cc2Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
6 ml of N-methylpyrrolidone, 1.11 g (3.4 mmol) of cesium carbonate and 0.27 g (3.4 mmol) of acetyl chloride were added to 0.70 g (1.7 mmol) of methyl 3-{4-amino-2-[3-(2-chloro-4,5-difluorobenzoyl)ureido]phenyl}acrylate and the mixture was stirred at room temperature for 30 minutes. It was then diluted with H2O and extracted with ethyl acetate. The organic phase was washed with H2O, dried and concentrated. 0.65 g (85%) of the desired product was obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24]C)[CH:19]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2].Cl.N1C=CC=CC=1>[OH-].[Na+]>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2]
Reactant: CCn1ncc2c(NCc3cccc(OC)c3)c3ccccc3nc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CCn1ncc2c(NCc3cccc(O)c3)c3ccccc3nc21
Temperature: 200 °C

Procedure:
A mixture of 1-ethyl-N-(3-methoxyphenylmethyl)-1H-pyrazolo [3,4-b]quinolin-4-amine (3.8 g, 0.0114 mol) and pyridine hydrochloride (10 g) was heated at about 200° C. for 3 hours. The reaction mixture was cooled and then 10% NaOH (70 mL) was added. The mixture was washed with ether (2×30 mL) and then the aqueous layer was acidified with acetic acid to a pH of about 5. The solid which formed was collected by filtration and dried in vacuo to afford 2.5-3 g of 1-ethyl-N-(3-hydroxyphenylmethyl)-1H-pyrazolo [3,4-b]quinolin-4-amine, as an off-white solid, m.p. 273-275° C.
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([C:19]#[N:20])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:21]C)=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].Cl.N1C=CC=CC=1>>[CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([C:19]#[N:20])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([OH:21])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12CCC(=O)C(C#N)=C1c1ccc(OC)cc1C2
Agent: Cl
Solvent: c1ccncc1
Product: CCCCC12CCC(=O)C(C#N)=C1c1ccc(O)cc1C2
Temperature: 192.5 °C

Procedure:
A mixture of 9a-butyl-4-cyano-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (17 mg) and pyridine hydrochloride (2 g) was placed under a nitrogen atmosphere and heated in an oil bath at 190-195° C. for 1 hour. After cooling to room temperature, the mixture was partitioned between EtOAc (20 ml) and water (30 mL). The organic portion was washed with brine (10 mL), dried over MgSO4, filtered, and evaporated under vacuum to an oil (16 mg). The crude product was purified by preparative layer chromatography on a 0.05×20×20 cm silica gel GF plate using 5% CH3OH n CH2Cl2 as the developing solvent. The UV visible product band was eluted with 10% CH3OH in CH2Cl2, the solvent evaporated under vacuum, and the residue lyophilized from benzene-methanol to afford 9a-butyl-4-cyano-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one as an amorphous solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[O:10][C:9]([CH2:11][N:12]3[CH2:15][CH:14]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:28][C:29]1[NH:33][C:32]2[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=2[N:30]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.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]>[CH3:28][C:29]1[N:33]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[O:10][C:9]([CH2:11][N:12]4[CH2:15][CH:14]([N:16]5[CH2:21][CH2:20][O:19][CH2:18][CH2:17]5)[CH2:13]4)=[CH:8][C:6]=3[N:7]=2)[C:32]2[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=2[N:30]=1
Reactant: Clc1nc(N2CCOCC2)c2oc(CN3CC(N4CCOCC4)C3)cc2n1
Reactant: Cc1nc2ccccc2[nH]1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2oc(CN3CC(N4CCOCC4)C3)cc2n1
Yield: 30.2 %

Procedure:
A mixture of 2-chloro-4-morpholin-4-yl-6-(3-morpholin-4-ylazetidin-1-ylmethyl)furo[3,2-d]pyrimidine (100 mg, 0.25 mmol), 2-methyl-1H-benzoimidazole (38 mg, 0.29 mmol), Pd2dba3 (12 mg, 0.013 mmol), Xphos (13 mg, 0.027 mmol) and cesium carbonate (184 mg, 0.56 mmol) in DMF (2.2 mL) was purged with argon gas then subjected to microwave irradiation at 145° C. for 30 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g), which was washed with MeOH/DCM before the desired product was eluted with 2 M NH3 in MeOH/DCM. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH 100:0 to 97:3 to 95:5 to 90:10) to afford 242 as a tan solid (37 mg, 30%). LCMS (Method G): RT=4.85 min, M+H+=490. 1H NMR (CDCl3, 400 MHz) δ 7.99 (m, 1H); 7.70 (m, 1 H); 7.26 (m, 2 H); 6.72 (s, 1 H); 4.07 (t, J=4.7 Hz, 4 H); 3.90-3.79 (m, 6H); 3.75 (m, 4 H); 3.64 (m, 2 H); 3.17 (m, 1 H); 3.11 (m, 1 H); 2.89 (s, 3 H) and 2.37 (m, 5 H)