Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11](Cl)=[O:12])[CH2:7]1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27][NH2:28]>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]([NH:28][CH2:27][CH2:26][CH2:25][N:24]([CH3:29])[CH3:23])=[O:12])[CH2:7]1
Reactant: O=C(Cl)N1CCC(Oc2cccc(Cl)c2)C1
Reactant: CN(C)CCCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN(C)CCCNC(=O)N1CCC(Oc2cccc(Cl)c2)C1
Temperature: 0 °C
Reaction time: 72 h
Yield: 43 %

Procedure:
A solution, 13 g (0.05 mole) of 3-(3-chlorophenoxy)-1-pyrrolidinecarbonyl chloride in 100 ml of chloroform was stirred at 0° C. for 5 min. Then, the following were added in order: 25 g of ice, 12.8 g of sodium carbonate; and 5.62 g (0.055 mole) of N,N-dimethyl-1,3-propanediamine. The resulting mixture was allowed to come to room temperature and stirred for 72 hours. At this time the reaction mixture was diluted with excess water and the organic phase separated. The chloroform solution was washed with water and extracted with 50 ml of 3N hydrochloric acid. The chloroform portion was washed with 2×25 ml of water. The hydrochloric acid portion was combined with the last 2 washes and the pH adjusted to neutral with 3N sodium hydroxide. The resulting solution was extracted with 3×30 ml of chloroform and the chloroform extracts were combined, dried over magnesium sulfate and concentrated to a dark oil, 13.2 g. All of the samples were converted to the free base, charcoaled, and chromatographed on 25 g of silica gel. Elution with chloroform gave after concentrating a dark orange oil. Trituration of this oil with ethyl ether and concentration of the triturates gave 7 g of a pale yellow viscous oil. This oil was pumped under high vacuum for 24 hours. The oil upon standing crystallized and was recrystallized from ethyl ether/30-60 petroleum ether to give 3.2 g of fine white crystals; m.p. 60°-61° C.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:5](=[C:6]3[C:11](=[CH:12][CH:13]=2)[N:10]=[CH:9][CH:8]=[CH:7]3)[N:4]=[C:3]1[CH:15]([CH3:20])[CH2:16][C:17](O)=[O:18].CN(C=O)C.C(Cl)(=O)C([Cl:29])=O>C(Cl)Cl>[CH3:1][N:2]1[C:14]2[C:5](=[C:6]3[C:11](=[CH:12][CH:13]=2)[N:10]=[CH:9][CH:8]=[CH:7]3)[N:4]=[C:3]1[CH:15]([CH3:20])[CH2:16][C:17]([Cl:29])=[O:18]
Reactant: CC(CC(=O)O)c1nc2c3cccnc3ccc2n1C
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(CC(=O)Cl)c1nc2c3cccnc3ccc2n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of 3-(3-methyl-3H-imidazo[4,5-f]quinolin-2-yl)butanoic acid (200 mg, 0.74 mmol) in oxalyl chloride (8 mL) and DCM (8 mL) was added DMF (5 mg). The mixture was stirred at room temperature for 2 h. The mixture was concentrated to dryness to give the product as a yellow solid (160 mg, 75% yield). See, e.g., Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 2000, 294-296; Tetrahedron Letters, 2000, 4165-4168.
Reaction SMILES: [CH2:1]([CH2:8][NH:9][CH2:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:14]=1)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]C=1.S(=O)(=O)(O)O.[OH-].[Na+].Cl[CH2:32]Cl>>[CH3:32][N:9]1[CH2:10][CH:11]([C:13]2[CH:14]=[C:15]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:16]=[CH:17][CH:18]=2)[C:2]2[C:1](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:8]1
Reactant: COC(=O)Cc1cccc(C(O)CNCCc2ccccc2)c1
Reactant: ClCCl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)Cc1cccc(C2CN(C)Cc3ccccc32)c1

Procedure:
1.5 g (4.8 mmol) of 2-benzylmethylamino-l-(3-methoxycarbonylmethylphenyl)ethanol are dissolved in 13 ml of dichloromethane. 3.7 ml of conc. sulfuric acid are added dropwise to this solution with cooling and stirring. It is stirred at room temperature for three hours. The reaction solution is diluted with dichloromethane and treated with ice. This solution is then adjusted to an alkaline pH using NaOH solution. The deposited organic phase is separated off. The aqueous phase is extracted twice more with dichloromethane. The combined organic phases are dried and the solvent is distilled off. The residue is taken up in ether and the solution is filtered. Methyl 3-[2-methyl-1,2,3,4-tetrahydro-4-(R,S)-isoquinolinyl]phenyl-acetate is obtained as an oil.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][OH:7])[CH2:2][CH3:3].C(N(CC)CC)C.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>ClCCl.O>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:7][CH2:6][CH2:5][O:4][CH2:1][CH2:2][CH3:3])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: CCCOCCO
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCCOCCOS(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.3 %

Procedure:
To a solution of 2-propoxy-1-ethanol (1.5 g, 14.4 mmol) and triethylamine (2.2 g, 21.6 mmol) in dichloromethane (20 mL) at 0° C. was added 4-bromobenzenesulfonyl chloride (3.86 g, 15.1 mmol) in dichloromethane (10 mL) dropwise over 30 minutes. The reaction was then warmed to room temperature and stirred for 16 hours. The mixture was then poured into water (50 mL) and acidified with 2N aqueous hydrochloric acid (15 mL). The aqueous layer was extracted with dichloromethane and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give a crude residue. This was purified by column chromatography on silica gel (50 g), eluting with hexane:ethyl acetate (9:3), to give the title compound (2.2 g, 48%) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]2([C:15]#[N:16])[CH2:14][CH2:13]2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].O1CCCC1.CO>O>[Cl:1][C:2]1[C:11]([C:12]2([C:15]#[N:16])[CH2:14][CH2:13]2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cccc(C2(C#N)CC2)c1Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: N#CC1(c2cccc(C(=O)O)c2Cl)CC1
Yield: 71.1 %

Procedure:
Using methyl 2-chloro-3-(1-cyanocyclopropyl)benzoate (684 mg, 2.90 mmol), lithium hydroxide•monohydrate (207 mg, 4.93 mmol), tetrahydrofuran (10 mL), methanol (3 mL) and water (3 mL) as starting materials, and in the same manner as in Example A1(iii), the title compound (457 mg, 71%) was obtained as a white powder.
Reaction SMILES: [CH2:1]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C([Li])CCC.[C:22](OCC)(=[O:24])[CH3:23].Cl>O1CCCC1.CCCCCC.O>[C:22]([CH:14]([CH2:13][CH2:12][CH2:11][O:10][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[C:15]#[N:16])(=[O:24])[CH3:23]
Reactant: CCCCCCCCCOCCCCC#N
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCOCCCC(C#N)C(C)=O
Temperature: -60 °C
Reaction time: 4 h

Procedure:
35.0 g (156 millimoles) of 5-(n-nonyloxy)-valeronitrile in 500 ml of absolute tetrahydrofuran are initially taken, in the absence of water and under an inert gas atmosphere, and the mixture is cooled to -60° C. 162 millimoles of n-butyl-lithium in n-hexane are slowly added to the stirred mixture, which is then left for 4 hours at -60° C. A solution of 13.1 g (155 millimoles) of dry ethyl acetate in tetrahydrofuran is then added dropwise, stirring is continued for 3 hours at -60° C., and the mixture is allowed to warm up slowly to room temperature. First water and then 2N hydrochloric acid are added while cooling with ice, until the pH of the solution reaches 4. The organic phase which separates out is isolated, washed with water, dried and evaporated down. The oil which remains (41 g; 99%) is more than 90% pure according to gas chromatography, and can be reacted without further purification.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][CH2:27][O:28][C:21]=5[CH:20]=4)[C:15]([C:29]4C=C[CH:32]=[CH:31][CH:30]=4)=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1.C1COC2C=CC(NC3N=C(NC4C=CC5OCCOC=5C=4)C(Br)=CN=3)=CC=2[O:36]1.O1C=CC=C1B(O)O>>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][CH2:27][O:28][C:21]=5[CH:20]=4)[C:15]([C:29]4[O:36][CH:32]=[CH:31][CH:30]=4)=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1
Reactant: c1ccc(-c2cnc(Nc3ccc4c(c3)OCCO4)nc2Nc2ccc3c(c2)OCCO3)cc1
Reactant: Brc1cnc(Nc2ccc3c(c2)OCCO3)nc1Nc1ccc2c(c1)OCCO2
Agent: OB(O)c1ccco1
Product: c1coc(-c2cnc(Nc3ccc4c(c3)OCCO4)nc2Nc2ccc3c(c2)OCCO3)c1

Procedure:
In a manner similar to the preparation of N2,N4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine, N2,N4-bis(3,4-ethylenedioxyphenyl)-5-bromo-2,4-pyrimidinediamine and furan-2-boronic acid were reacted to yield N2,N4-bis(3,4-ethylenedioxyphenyl)-5-(2-furanyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 8.13 (s, 1H), 7.61 (d, 1H, J=1.8 Hz), 7.12 (d, 1H, J=2.4 Hz), 7.08 (d, 1H, J=2.4 Hz), 6.93 (td, 2H, J=2.4 and 8.7 Hz), 6.78 (d, 1H, J=8.7 Hz), 6.68 (d, 1H, J=8.7 Hz), 6.58 (d, 1H, J=2.4 Hz), 6.54 (dd, 1H, J=1.8 and 3.6), 4.24 (s, 4H), 4.20 (bs, 4H); LCMS: ret. time: 15.03 min.; purity: 88%; MS (m/e): 445 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:28]=[CH:27][C:18]3[CH2:19][CH2:20][CH:21]([C:23]([O:25][CH3:26])=[O:24])[O:22][C:17]=3[C:16]=2[CH2:29][CH2:30][CH3:31])=[C:6]([CH2:34][CH2:35][CH3:36])[C:5]=1[OH:37])(=[O:3])[CH3:2].[CH3:38]C(C)=O.S(OC)(OC)(=O)=O>[OH-].[K+]>[C:1]([C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:28]=[CH:27][C:18]3[CH2:19][CH2:20][CH:21]([C:23]([O:25][CH3:26])=[O:24])[O:22][C:17]=3[C:16]=2[CH2:29][CH2:30][CH3:31])=[C:6]([CH2:34][CH2:35][CH3:36])[C:5]=1[O:37][CH3:38])(=[O:3])[CH3:2]
Reactant: CC(C)=O
Reactant: CCCc1c(OCCCCCOc2ccc3c(c2CCC)OC(C(=O)OC)CC3)ccc(C(C)=O)c1O
Agent: [K+]
Agent: [OH-]
Solvent: COS(=O)(=O)OC
Product: CCCc1c(OCCCCCOc2ccc(C(C)=O)c(OC)c2CCC)ccc2c1OC(C(=O)OC)CC2
Temperature: 40 °C

Procedure:
Methyl 7-[[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyl]oxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylate (1 mMol), prepared as described in U.S. Pat. No. 4,565,882, was dissolved in acetone containing 2.5 equivalents of potassium hydroxide and 3 equivalents of dimethyl sulfate. The mixture was heated at 40° C. for 10 hours and then cooled; the solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic layer was separated and dried over magnesium sulfate. Evaporation of the volatiles in vacuo afforded the methyl ether.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[NH:21][S:22]([CH2:25][CH2:26][CH3:27])(=[O:24])=[O:23].CN(C)[CH:30]=[O:31].Cl>O1CCCC1.O>[F:13][C:14]1[C:19]([CH:30]=[O:31])=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[NH:21][S:22]([CH2:25][CH2:26][CH3:27])(=[O:24])=[O:23]
Reactant: CCCS(=O)(=O)Nc1ccc(F)cc1F
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C=O)c1F
Reaction time: 0.5 h

Procedure:
To diisopropyl amine (0.210 mL, 1.49 mmol) in tetrahydrofuran (3 mL) was added n-butyllithium (2.50 M in hexane, 0.600 mL, 1.49 mmol) at −78° C. under an atmosphere of nitrogen. After 30 minutes, propane-1-sulfonic acid (2,4-difluoro-phenyl)-amide (9, 113 mg, 0.480 mmol) in tetrahydrofuran (2 mL) was added at −78° C. under am atmosphere of nitrogen. After 1 hour, N,N-dimethylformamide (0.050 mL, 0.64 mmol) was added. The reaction was stirred for 1 hour, then allowed to come to room temperature for 15 minutes. The reaction was poured into water, acidified with 1M HCl (aq.) to pH=1, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated and purified by silica gel column chromatography eluting with 30% ethyl acetate in hexane to give a solid (10, 25 mg, 20%). MS (ESI) [M−H+]−=262.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:18]=[N:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:5]2=[N:6][C:7]=1[O:8][CH2:9][C:10]1[N:11]([CH3:15])[N:12]=[CH:13][N:14]=1.[CH3:25][Sn](C)(C)C>CN(C)C(=O)C.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.Cl[Pd]Cl>[CH3:25][C:2]1[CH:3]=[C:4]2[CH:18]=[N:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:5]2=[N:6][C:7]=1[O:8][CH2:9][C:10]1[N:11]([CH3:15])[N:12]=[CH:13][N:14]=1
Reactant: C[Sn](C)(C)C
Reactant: Cn1ncnc1COc1nc2c(cnn2-c2ccccc2)cc1Br
Agent: Cl[Pd]Cl
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC(=O)N(C)C
Product: Cc1cc2cnn(-c3ccccc3)c2nc1OCc1ncnn1C
Temperature: 90 °C
Yield: 28.4 %

Procedure:
To a de-gassed solution of 5-bromo-6-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-1-phenyl-1H-pyrazolo[3,4-b]pyridine (84 mg, 0.22 mmol) in N,N-dimethylacetamide (2 ml) was added tetramethyltin (60 μl, 0.43 mmol) followed by dichlorobis(tri-ortho-tolylphosphine)palladium(II) (8.6 mg, 0.01 mmol). The reaction mixture was heated at 90° C. in a sealed tube for 20 h. The mixture was allowed to cool, quenched with saturated aqueous ammonium chloride solution and the product extracted into diethyl ether (×3). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by preparative thin layer chromatography, eluting with 55% ethyl acetate-hexane, afforded the title compound as a white solid (20 mg, 29%), m.p. 145-146° C. δH (400 MHz; CDCl3) 2.32 (3H, s), 3.96 (3H, s), 5.66 (2H, s), 7.31 (1H, t, J=7), 7.50-7.54 (2H, m), 7.82 (1H, s), 7.91 (1H, s), 8.02 (1H, s), 8.19-8.22 (2H, m); m/z (ES+) 321 (M+H+).
Reaction SMILES: CO.[CH2:3](C1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1SCCCC)[C:4]1C=CC=CC=1.[CH2:28]([C:35]1[C:43]([S:44](=[O:47])(=[O:46])[NH2:45])=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][C:36]=1[S:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(O)C>[CH2:28]([C:35]1[C:43]([S:44](=[O:47])(=[O:46])[NH2:45])=[CH:42][C:38]([C:39]([O:41][CH2:3][CH3:4])=[O:40])=[CH:37][C:36]=1[S:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCCCSc1cc(C(=O)O)cc(S(N)(=O)=O)c1Cc1ccccc1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(SCc2ccccc2)c1Cc1ccccc1
Solvent: CO
Solvent: CCO
Product: CCOC(=O)c1cc(SCc2ccccc2)c(Cc2ccccc2)c(S(N)(=O)=O)c1

Procedure:
By replacing in Example 124, methanol with ethanol and 4-benzyl-3-n-butylthio-5-sulfamylbenzoic acid with 4-benzyl-3-benzylthio-5-sulfamylbenzoic acid and following the procedure described, ethyl 4-benzyl-3-benzylthio-5-sulfamylbenzoate is obtained with a melting point of 108°-110° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH2:11][CH3:12])[CH:3]=1.[CH:13]([N:16](C(C)C)CC)(C)[CH3:14].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:8][CH:14]=[CH:13][N:16]=2)=[C:4]([CH2:11][CH3:12])[CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCc1cc(Br)ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1cc(Br)ccc1-c1ncco1
Temperature: 135 °C

Procedure:
4-Bromo-2-ethyl-benzoic acid (6.8 g, 30 mmol), diisopropylethylamine (7.8 mL, 44.7 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 14 g, 37 mmol), and aminoacetaldehyde dimethyl ether (4 mL, 37 mmol) in 2:1 dichlormethane/dimethylformamide (120 mL) 5 h at room temperature. The solution was washed with several portions of water, then 1N HCl(aq) and saturated sodium chloride, dried (Na2SO4), filtered, and concentrated in vacuo to a crude light yellow oil. The residue was redissolved in Eaton's reagent (P2O5 in methanesulfonic acid, 100 mL), and the solution was heated at 135° C. under argon for 6 h. The solution was cooled to room temperature and carefully poured onto ice. The mixture was extracted with dichloromethane, and the organic layer was backwashed with saturated sodium chloride, dried (Na2SO4), filtered, and concentrated in vacuo to a crude oil. The residue was redissolved in ethyl acetate and washed with saturated sodium bicarbonate, then saturated sodium chloride, dried (Na2SO4), filtered, and concentrated in vacuo to pure brown liquid (3.16 g, 44%) 1H NMR (300 MHz, CDCl3): δ ppm 1.24 (t, J=7.54 Hz, 3 H) 3.09 (q, J=7.54 Hz, 2 H) 7.27 (s, 1 H) 7.42 (dd, J=8.38, 1.98 Hz, 1 H) 7.48 (d, J=2.07 Hz, 1 H) 7.74 (s, 1 H) 7.81 (d, J=8.48 Hz, 1 H).
Reaction SMILES: CS(C)=O.[CH:5]([C:7]1[O:11][C:10](B(O)O)=[CH:9][CH:8]=1)=[O:6].C(O[K])(C)=O.I[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][NH:25][C:24]2=[O:31]>CC([O-])=O.CC([O-])=O.[Pd+2].O>[O:31]=[C:24]1[C:23]2[C:28](=[CH:29][CH:30]=[C:21]([C:10]3[O:11][C:7]([CH:5]=[O:6])=[CH:8][CH:9]=3)[CH:22]=2)[N:27]=[CH:26][NH:25]1
Reactant: O=c1[nH]cnc2ccc(I)cc12
Reactant: O=Cc1ccc(B(O)O)o1
Agent: [Pd+2]
Agent: CC(=O)O[K]
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccc(-c2ccc3nc[nH]c(=O)c3c2)o1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98 %

Procedure:
A 5:2 v/v mixture of DMSO and H2O (1400 mL) was degassed for 30 min at ambient temperature using nitrogen. 5-Formylfuran-2-ylboronic acid ((VIa); 26.8 g, 193 mmol) was added dissolved in this mixture. [HP(t-Bu)3]BF4 (840 mg, 2.94 mmol) and Pd(OAc)2 (680 mg, 2.94 mmol) was added and the mixture was stirred at ambient temperature under an atmosphere of nitrogen for 20 min AcOK (18.8 g, 192 mmol) was added into the reactor and was stirred for 20 min at ambient temperature. 6-Iodoquinazolin-4(3H)-one ((Va); 40 g, 147 mmol) was added and heated to 80±5° C. (internal temperature) in an oil bath under nitrogen. Upon completion of the reaction (HPLC), the reaction mixture was hot-filtered, then hot water (400 mL, 80±5° C.) was added into the filtrate. This was slowly cooled to 0-15° C. (solid started to precipitate at 70° C. (internal temperature) and was then filtered. The filter cake was washed with H2O (80 mL), then with MeCN (60 mL), and dried in vacuo at 60±5° C. for 6 h to provide 5-(4-oxo-3,4-dihydroquinazolin-6-yl)-furan-2-carbaldehyde ((IX); 34.6 g, 144 mmol) with 99.7% HPLC purity in 97.6% HPLC yield. 1H NMR (300 MHz, d6-DMSO): δ 7.47 (d, J=3.8 Hz, 1H), 7.69 (d, J=3.8 Hz, 1H), 7.77 (d, J=8.6 Hz, 1H), 8.17 (s, 1H), 8.27 (dd, J=8.6, 2.1 Hz, 1H), 8.52 (d, J=2.1 Hz, 1H), 9.66 (s, 1H); 13C NMR (75 MHz, CDCl3): δ 110.5, 122.6, 123.9, 126.0, 127.5, 129.0, 131.4, 147.1, 150.1, 152.7, 157.6, 161.2, 178.8; ESI-MS, Pos: [M+H]+ m/z 241; IR (cm−1): 1713, 1671, 1604,1462; m.p.: 267° C. See FIG. 2 for the DSC/TGA of the compound of formula (IX); See FIG. 3 for the X-ray powder diffraction pattern of the compound of formula (IX); Residual concentration of palladium: 230 ppm.
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+].[N:67]1([C:72]2[CH:79]=[CH:78][C:75]([CH:76]=O)=[CH:74][CH:73]=2)[CH:71]=[CH:70][N:69]=[CH:68]1>C(O)C.CN(C=O)C>[N:67]1([C:72]2[CH:79]=[CH:78][C:75]([C:76]3[NH:42][C:39]4=[N:40][CH:41]=[C:36]([Br:35])[C:37]([N:46]5[CH2:51][CH2:50][N:49]([CH2:52][C:53]6[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=6)[CH2:48][CH2:47]5)=[C:38]4[N:43]=3)=[CH:74][CH:73]=2)[CH:71]=[CH:70][N:69]=[CH:68]1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccc(-n2ccnc2)cc1
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: CN(C)C=O
Solvent: CCO
Product: Brc1cnc2[nH]c(-c3ccc(-n4ccnc4)cc3)nc2c1N1CCN(Cc2cccnc2)CC1
Reaction time: 6 h
Yield: 26.6 %

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 (20 mg, 0.051 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.15 mmol, 0.15 mL) and 4-(1H-imidazol-1-yl)benzaldehyde (1.1 eq, 0.056 mmol, 10 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 9:1) gave the product (7 mg, 27%) as a colourless solid; δH (500 MHz, DMSO-d6) 2.64 (s, br, 4H, piperazine N(CH2)2), 3.63 (s, br, 2H, CH2), 3.70 (t, J=4.4 Hz, 4H, piperazine N(CH2)2), 7.16 (s, 1H, imidazole H-2), 7.39 (dd, J=7.8, 4.8 Hz, 1H, pyridine H-5), 7.79 (td, J=7.8, 1.5 Hz, 1H, pyridine H-4), 7.85 (s, br, 1H, imidazole H-4 or H-5), 7.86 (d, J=8.7 Hz, 2H, phenyl H-2 & H-6), 8.26 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.30 (d, J=8.7 Hz, 2H, phenyl H-3 & H-5), 8.39 (s, br, 1H, imidazole H-4 or H-5), 8.50 (dd, J=4.7, 1.5 Hz, 1H, pyridine H-6), 8.57 (d, J=1.5 Hz, 1H, pyridine H-2), 13.59 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[C:28]([S:31][CH2:32][CH:33]([C:37]([F:40])([F:39])[F:38])[C:34](O)=[O:35])(=[O:30])[CH3:29]>ClCCl>[C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:34](=[O:35])[CH:33]([C:37]([F:38])([F:39])[F:40])[CH2:32][S:31][C:28](=[O:30])[CH3:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: CC(=O)SCC(C(=O)O)C(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(=O)SCC(C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)C(F)(F)F
Temperature: 0 °C

Procedure:
L-proline tert-butyl ester (5.1 g.) is dissolved in dichloromethane (40 mg.) and the solution is stirred and chilled in an ice bath. Dicyclohexylcarbodiimide (6.2 g.) dissolved in dichloromethane (15 ml.) is added followed immediately by a solution of 3-acetylthio-2-trifluoromethylpropanoic acid (6.5 g.) in dichloromethane (5 ml.). After fifteen minutes stirring in the ice bath and sixteen hours at room temperature, the precipitate formed is filtered off and the filtrate is concentrated to dryness in vacuo. The residue is dissolved in ethyl acetate and washed neutral. The organic phase is dried over magnesium sulfate and concentrated to dryness in vacuo to give 1-(3-acetylthio-2-trifluoromethylpropanoyl)-L-proline tert-butyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:26]([OH:28])=O)=[N:11][N:12]2[CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:16][N:15]([CH3:24])[C:14](=[O:25])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(CC)CC.[F:50][C:51]1[CH:58]=[CH:57][C:54]([CH2:55][NH2:56])=[CH:53][CH:52]=1>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10]([C:26]([NH:56][CH2:55][C:54]2[CH:57]=[CH:58][C:51]([F:50])=[CH:52][CH:53]=2)=[O:28])=[N:11][N:12]2[CH:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:16][N:15]([CH3:24])[C:14](=[O:25])[C:13]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccc(F)cc1
Reactant: CN1CC(c2ccccc2)n2nc(C(=O)O)c(OCc3ccccc3)c2C1=O
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN1CC(c2ccccc2)n2nc(C(=O)NCc3ccc(F)cc3)c(OCc3ccccc3)c2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-benzyloxy-5-methyl-4-oxo-7-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylic acid (20 mg, 0.053 mmol) in anhydrous DMF were added HOBT (11 mg, 0.079 mmol), EDC (15 mg, 0.079 mmol), Et3N (7 μL, 0.053 mmol), and 4-fluorobenzylamine (7 μL, 0.064 mmol). The reaction mixture was stirred at room temperature for 1 hour. Purification was achieved by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA). Collection and concentration of the appropriate fractions yielded the title product as a white solid. ES MS (M+1)=485.