Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16]O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[Cl:18]CCl.S(Cl)(Cl)=O>O>[Cl:18][CH2:16][CH2:15][CH:12]1[CH2:13][CH2:14][N:9]([C:6]2[N:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:10][CH2:11]1
Reactant: COc1ccc(N2CCC(CCO)CC2)nn1
Reactant: ClCCl
Solvent: O
Solvent: O=S(Cl)Cl
Product: COc1ccc(N2CCC(CCCl)CC2)nn1
Reaction time: 8 h

Procedure:
A solution of 7.3 parts of 1-(6-methoxy-3-pyridazinyl)-4-piperidineethanol in 130 parts of dichloromethane was added dropwise to 7.3 parts of thionyl chloride at room temperature. Upon complete addition, stirring was continued overnight at room temperature. The residue was taken up in water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding a first fraction of 1.8 parts of 3-[4-(2-chloroethyl)-1-piperidinyl]-6-methoxypyridazine. The aqueous layer was neutralized with an ammonium hydroxide solution. The precipitated product was filtered off and taken up in dichloromethane. The organic layer was dried, filtered and evaporated, yielding a second fraction of 4.0 parts of 3-[4-(2-chloroethyl)-1-piperidinyl]-6-methoxypyridazine. Total yield: 5.8 parts (73.4%) of 3-[4-(2-chloroethyl)-1-piperidinyl]-6-methoxypyridazine as a residue (int. 96).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:35]=[C:36]([CH:38]=[CH:39][CH:40]=2)[NH2:37])[CH2:29][CH2:28]1.[OH-].[Na+]>CN(C=O)C.CO>[O:27]1[CH2:28][CH2:29][N:30]([CH2:33][C:34]2[CH:35]=[C:36]([NH:37]/[C:16](=[C:6]3\[C:5](=[O:26])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=4)/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:38]=[CH:39][CH:40]=2)[CH2:31][CH2:32]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: Nc1cccc(CN2CCOCC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1cccc(CN2CCOCC2)c1)c1ccccc1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 3-morpholinomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [CH3:1][N:2]([C:9]1[CH:14]=[C:13]([N+:15]([O-])=O)[C:12]([O:18][CH3:19])=[CH:11][C:10]=1[CH3:20])[C:3](=[O:8])[CH2:4][N:5]([CH3:7])[CH3:6]>[Pd].CO>[NH2:15][C:13]1[C:12]([O:18][CH3:19])=[CH:11][C:10]([CH3:20])=[C:9]([N:2]([CH3:1])[C:3](=[O:8])[CH2:4][N:5]([CH3:7])[CH3:6])[CH:14]=1
Reactant: COc1cc(C)c(N(C)C(=O)CN(C)C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1cc(C)c(N(C)C(=O)CN(C)C)cc1N
Temperature: 25 °C
Yield: 84.9 %

Procedure:
10% palladium on carbon (0.25 g, 8.52 mmol) was placed under N2 atm. MeOH (10 mL) was added, followed by a solution of N1,N2,N2-trimethyl-N1-[2-methyl-4-(methyloxy)-5-nitrophenyl]glycinamide (1.86 g, 6.61 mmol) in MeOH (90 mL). The slurry was purged with N2, then was placed under H2 atm via a rubber balloon and maintained at rt for 2 days. The resulting mixture was filtered through Celite. The filtrate was concentrated. The oily residue was taken up into Et2O and concentrated again to obtain N1-[5-amino-2-methyl-4-(methyloxy)phenyl]-N1,N2,N2-trimethylglycinamide as a white foamy solid (1.41 g, 85%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.00 (s, 3H), 2.11 (s, 6H), 2.58 (d, J=15.57 Hz, 1H), 2.77 (d J=15.57 Hz, 1H), 2.97 (s, 3H), 3.77 (s, 3H), 4.70 (s, 2H), 6.41 (s, 1H), 6.72 (s, 1H); ESIMS (M+H)+=252.10.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]([OH:18])=O)[CH:13]=[CH:12][C:11]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25].[NH2:26][C:27](=[N:40]O)[C:28]1[C:37]([F:38])=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([F:39])[CH:29]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.C1COCC1.CN(C=O)C>[F:39][C:30]1[CH:29]=[C:28]([C:27]2[N:26]=[C:16]([C:14]3[CH:13]=[CH:12][C:11]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[CH3:25])=[C:10]([CH2:9][O:8][CH3:7])[CH:15]=3)[O:18][N:40]=2)[C:37]([F:38])=[CH:36][C:31]=1[C:32]([O:34][CH3:35])=[O:33]
Reactant: COC(=O)c1cc(F)c(C(N)=NO)cc1F
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COCc1cc(-c2nc(-c3cc(F)c(C(=O)OC)cc3F)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (190 mg, 1.50 mmol) was added to a suspension of Intermediate 3 (143 mg, 0.50 mmol) and DMF (catalytic amount) in anhydrous DCM (2 mL) and the resulting mixture was stirred at RT for 1 hour. After evaporation to dryness, the residue was taken up in anhydrous THF (2 mL) and added into a solution of Intermediate 42 (108 mg, 0.50 mmol) and DIEA (193 mg, 1.50 mmol) in anhydrous THF (1 mL). The resulting mixture was heated at 150° C. for 30 minutes under microwave irradiation. It was then filtered through a SPE-NH2 column, which was further washed with THF. After evaporation, the residue was purified by flash chromatography (silica, cHex/EtOAc), affording the title product as an off-white solid. LC/MS (Method B): 451.2 (M+H)+. HPLC (Method A) Rt 6.0 min (Purity: 89.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:13])[O:10][CH2:11][CH3:12])[N:5]=[C:4]2[NH:14][CH:15]=[N:16][C:3]=12.[H-].[Na+].ClCOCC1C=CC=CC=1.ClC1C=C(NC(=O)OCC)N=C2N(COCC3C=CC=CC=3)C=NC=12.ClC1C=C(NC(=O)OCC)N=C2N=CN(COCC3C=CC=CC=3)C=12.[CH:79]1([CH2:85][CH2:86]Br)[CH2:84][CH2:83][CH2:82][CH2:81][CH2:80]1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:86][CH2:85][CH:79]2[CH2:84][CH2:83][CH2:82][CH2:81][CH2:80]2)[C:9](=[O:13])[O:10][CH2:11][CH3:12])[N:5]=[C:4]2[NH:14][CH:15]=[N:16][C:3]=12
Reactant: CCOC(=O)Nc1cc(Cl)c2nc[nH]c2n1
Reactant: BrCCC1CCCCC1
Agent: CCOC(=O)Nc1cc(Cl)c2c(ncn2COCc2ccccc2)n1
Agent: CCOC(=O)Nc1cc(Cl)c2ncn(COCc3ccccc3)c2n1
Agent: ClCOCc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)N(CCC1CCCCC1)c1cc(Cl)c2nc[nH]c2n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 124 mg of ethyl N-(7-chloro-3H-imidazo[4,5-b]pyridin-5-yl)-carbamate in 2 ml of dry dimethylformamide is added 50 mg of sodium hydride (60% dispersion in mineral oil). After stirring for 10 minutes, 0.11 ml of benzyl chloromethyl ether is added, and the reaction is stirred for 3 hours. The reaction is quenched with water and extracted 3 times with ethyl acetate. The organic extract is washed with water, and dried (sodium sulfate). Evaporation of the solvents in vacuo leaves a residue which is purified by flash chromatography on silica gel (ether) to give a mixture of ethyl N-[7-chloro-3-(benzyloxymethyl)-3H-imidazo[4,5-b]pyridin-5-yl]-carbamate and ethyl N-[7-chloro-1-(benzyloxymethyl)-1H-imidazo[4,5-b]pyridin-5-yl]carbamate. To a solution of 100 mg of this mixture in 2 ml of dry dimethylformamide is added 17 mg of sodium hydride (60% dispersion in mineral oil) and 210 mg of 2-cyclohexylethyl bromide. The mixture is heated at 70° for 5 hours, cooled to room temperature, and quenched with water. The mixture is extracted 3 times with ethyl acetate. The organic extract is washed with water, and dried (sodium sulfate). The solvents are evaporated in vacuo, and the residue is then dissolved in 2 ml of ethanol. To this solution is added 0.1 ml of concentrated HCl, and the reaction is heated to 70° for 5 hours. After cooling to room temperature, the reaction is neutralized with saturated aqueous sodium bicarbonate, and extracted 3 times with methylene chloride. The combined organic extracts are dried (sodium sulfate) and the solvents evaporated in vacuo to give a residue which is purified by flash chromatography on silica gel (5% methanol/methylene chloride) to give ethyl N-(7-chloro-3H-imidazo[4,5-b]pyridin-5-yl)-N-(2-cyclohexylethyl)-carbamate.
Reaction SMILES: [C:1]([OH:8])(=O)/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].Br[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.O>O1CCCC1>[C:18]1([C:1](=[O:8])[CH:2]=[CH:3][C:4]([OH:6])=[O:5])[C:19]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)/C=C\C(=O)O
Reactant: Brc1cccc2ccccc12
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C=CC(=O)c1cccc2ccccc12
Temperature: 78 °C
Reaction time: 0.08 h
Yield: 30 %

Procedure:
5.88 g(60 mmol) of dry maleic acid was dissolved in 100 ml of dry tetrahydrofuran and the mixture was cooled down to 78° C. 4.14 g(20 mmol) of 1-bromonaphthalene was dissolved in 100 ml of dry tetrahydrofuran and 13.8 ml of 1.6N n-butyllithium-hexane solution was added thereto at 78° C. This reaction solution was stirred for 5 minutes and then it was added to the dry maleic acid solution prepared in advance using cannula. The resulting mixture was stirred for 10 minutes, and water was added thereto to stop the reaction. The solvent was removed under reduced pressure, and the residue was acidified by 1N aqueous hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with water and aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and subjected to column chromatography(eluent: ethyl acetate/hexane=2/1, v/v) to give 1.35 g(6.0 mmol; Yield 30%) of the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH2:14][CH2:13]2)(=[O:9])=[O:8].CCN(CC)CC.Br[CH2:27][CH2:28][Cl:29]>CN(C=O)C>[Cl:29][CH2:28][CH2:27][N:15]1[C:16]2[C:12](=[CH:11][C:10]([S:7]([NH:6][C:2]3[S:1][CH:5]=[CH:4][N:3]=3)(=[O:9])=[O:8])=[CH:18][CH:17]=2)[CH2:13][CH2:14]1
Reactant: O=S(=O)(Nc1nccs1)c1ccc2c(c1)CCN2
Reactant: ClCCBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1nccs1)c1ccc2c(c1)CCN2CCCl
Temperature: 25 °C
Reaction time: 72 h
Yield: 25.3 %

Procedure:
To a stirring solution of 2,3-dihydro-1H-indole-5-sulfonic acid thiazol-2-ylamide (10.0 g, 35.6 mmol), Et3N (5.0 mL, 3.6 g, 35.6 mmol), and DMF (10.0 mL), under N2, was added 1-bromo-2-chloroethane (2.9 mL, 5.1 grams, 35.6 mmol). The solution was stirred at room temperature for 3 days. The mixture was partitioned between water and ethyl acetate. The organic portion was evaporated to dryness under reduced pressure. The residue was purified via silica gel chromatography using 3% MeOH in CH2Cl2 to obtain the desired amine (3.1 g, 9.0 mmol, 25% yield) as a clear oil. 1H-NMR (DMSO-d6) δ 7.39-7.37 (m, 2H), 6.83 (d, J=4.7 Hz, 1H), 6.43 (d, J=7.3 Hz, 2H), 6.28 (s, 1H), 4.23 (t, J=5.8 Hz, 2H), 3.88 (t, J=5.8 Hz, 2H), 3.47 (t, J=8.7 Hz, 2H), 3.33 (s, 1H), 2.94 (t, J=3.7 Hz, 2H). LC/MS (10-99%) M/Z: M+1 obs=344.0; tR=2.88 min.
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[CH:5]1.[CH:18](=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22]>>[CH2:19]([CH:18]([C:5]1[N:4]([CH2:3][CH:2]([CH3:17])[CH3:1])[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=1)[OH:23])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCC=O
Reactant: CC(C)Cn1cnc2cnc3ccccc3c21
Product: CCCCC(O)c1nc2cnc3ccccc3c2n1CC(C)C

Procedure:
Using the method of Example 45, 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (20 g; 89 mmol) was reacted with valeraldehyde to provide 11.6 g of the desired product as a solid.
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:11]([Br:12])=[CH:10][N:9]=[C:8](Cl)[N:7]=2)=[CH:4][C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]1=2.[NH2:18][CH2:19][CH2:20][N:21]1[C:25]2([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:24](=[O:31])[NH:23][C:22]1=[O:32].C(N(C(C)C)CC)(C)C>C(O)(C)C>[S:1]1[C:5]([C:6]2[C:11]([Br:12])=[CH:10][N:9]=[C:8]([NH:18][CH2:19][CH2:20][N:21]3[C:25]4([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[C:24](=[O:31])[NH:23][C:22]3=[O:32])[N:7]=2)=[CH:4][C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]1=2
Reactant: Clc1ncc(Br)c(-c2cc3ccccc3s2)n1
Reactant: NCCN1C(=O)NC(=O)C12CCCCC2
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=C1NC(=O)C2(CCCCC2)N1CCNc1ncc(Br)c(-c2cc3ccccc3s2)n1
Temperature: 170 °C

Procedure:
A mixture of 4-benzo[b]thiophen-2-yl-5-bromo-2-chloro-pyrimidine (318 mg, 1.0 mmol) and 1-(2-aminoethyl)-1,3-diaza-spiro[4.5]decane-2,4-dione (214 mg, 1.01 equiv.) in isopropyl alcohol (4 mL) was treated with diisopropylethylamine (192 μL, 1.1 equiv.) and heated at 170° C. for 17 min in a Personal Chemistry microwave reactor. Upon cooling, the product was obtained by filtration and washing with isopropyl alcohol, recrystallizing from hot isopropyl alcohol. MS (M+H)+ 500/502.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([OH:35])([C:31]([F:34])([F:33])[F:32])[C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>[Pd].CCO>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([S:11]([N:14]2[CH2:15][CH2:16][N:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([OH:35])([C:27]([F:30])([F:28])[F:29])[C:31]([F:32])([F:33])[F:34])=[CH:22][CH:21]=3)[CH2:18][CH2:19]2)(=[O:12])=[O:13])=[CH:3][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCN(c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)N2CCN(c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Reaction time: 12 h
Yield: 18.1 %

Procedure:
A 100-mL round-bottomed flask was charged 2-(4-(4-((3-fluoro-4-nitrophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (350 mg, 0.66 mmol) and EtOH (40 mL). The reaction was placed under an atmosphere of argon. 10% Pd/C (70.1 mg, 0.66 mmol) was added and the reaction was stirred under a balloon atmosphere of H2 for 12 h. The reaction was carefully filtered through a pad of Celite, rinsing with EtOH. The crude material was concentrated onto silica gel and purified via column chromatography (40 g silica gel, 0 to 10% MeOH in CH2Cl2) to give 2-(4-(4-((4-amino-3-fluorophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (60 mg). 1H NMR (400 MHz, CD3OD) δ=7.54 (d, J=8.6 Hz, 2H), 7.40-7.31 (m, 2H), 7.01-6.95 (m, 2H), 6.94-6.86 (m, 1H), 3.31-3.26 (m, 4H), 3.14-3.00 (m, 4H). m/z (ESI, +ve ion) 502.0 (M+H)+. GK-GKRP IC50 (Binding)=0.999 μM; GK-GKRP EC50 (LC MS/MS-2)=0.642 μM.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@:8]23[C@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:14][C@@H:13]([OH:22])[C@@:12]2([OH:23])[C:11]2[C:24]([O:31][CH2:32][CH3:33])=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[CH:27][C:10]=2[O:9]3)=[CH:4][CH:3]=1.[NH2:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.O1CCOCC1.CS(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:34][C:35]1[CH:36]=[C:37]([C:2]2[CH:3]=[CH:4][C:5]([C@:8]34[C@H:15]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[CH2:14][C@@H:13]([OH:22])[C@@:12]3([OH:23])[C:11]3[C:24]([O:31][CH2:32][CH3:33])=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[CH:27][C:10]=3[O:9]4)=[CH:6][CH:7]=2)[CH:38]=[CH:39][CH:40]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: CCOc1cc(OCC)c2c(c1)O[C@@]1(c3ccc(Br)cc3)[C@H](c3ccccc3)C[C@@H](O)[C@@]21O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CCOc1cc(OCC)c2c(c1)O[C@@]1(c3ccc(-c4cccc(N)c4)cc3)[C@H](c3ccccc3)C[C@@H](O)[C@@]21O

Procedure:
51.1 mg (0.10 mmol) of (1R*,3S*,3aR*,8bS*)-3a-(4-bromophenyl)-6,8-diethoxy-3-phenyl-2,3,3a,8b-tetrahydrocyclopenta[b]benzofuran-1,8b-(1H)-diol (Example 8A), 15.5 mg (0.10 mmol) of 3-aminophenyl boronic acid, 10.6 mg (0.10 mmol) of sodium carbonate and 5.8 mg (0.005 mmol) of tetrakis(triphenylphosphine)palladium(0) are heated in a mixture of 0.1 ml of water and 0.5 ml of dioxane at 80° C. under argon overnight. The mixture is then diluted with DMSO and filtered, and the filtrate is purified by preparative HPLC. 17.4 mg (25% of theory) of the product are obtained.
Reaction SMILES: CO[C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=[CH:5][CH:4]=1.[F:31]C1C=CC(C=O)=CC=1>>[F:31][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=[CH:5][CH:4]=1
Reactant: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Reactant: O=Cc1ccc(F)cc1
Product: O=C(NCCNCc1ccc(F)cc1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]-amide using 4-fluorobenzaldehyde instead of 4-methoxy benzaldehyde. LCMS (ESI) 410 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (1H, br. s.) 10.25 (1H, s) 7.99-8.07 (2H, m) 7.77 (1H, d, J=5.42 Hz) 7.46 (1H, d, J=5.42 Hz) 7.31 (3H, dt, J=5.72, 2.82 Hz) 7.06 (2H, t, J=8.91 Hz) 6.79 (1H, d, J=5.42 Hz) 6.43 (1H, dd, J=3.47, 1.95 Hz) 3.65 (2H, s) 3.34 (2H, d, J=5.86 Hz) 2.62 (2H, t, J=6.49 Hz)
Reaction SMILES: [CH:1]1([CH2:5][OH:6])[CH2:4][CH2:3][CH2:2]1.[CH3:7][S:8](Cl)(=[O:10])=[O:9].C(N(CC)CC)C>CCOCC>[CH3:7][S:8]([O:6][CH2:5][CH:1]1[CH2:4][CH2:3][CH2:2]1)(=[O:10])=[O:9]
Reactant: OCC1CCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCC1
Temperature: 25 °C
Yield: 103.4 %

Procedure:
Cyclobutanemethanol (24.9 g; 0.287 mol) and methanesulfonyl chloride (35.3 g; 0.302 mol) in dry ether (250 ml) was cooled to -20° C. under dry nitrogen. Triethylamine (44 ml; 0.32 mol) was added dropwise over 15 min with external cooling so that the reaction temperature remained below -5° C. The reaction mixture was allowed to warm to room temperature over 1 h and then filtered. The remaining solid was washed with ether. The ether solutions were combined and the ether evaporated, to afford crude cyclobutylmethyl methanesulfonate (48.75 g) as a pale yellow liquid, which was used in the next step without further purification. NMR - d(CDCl3 ; 60 MHz) 1.6-2.9 (7H, m), 3.0 (3H, s) and 4.1 (2H, d, J=7 Hz).
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][C@H:11]2[O:15][C:14]([NH2:16])=[N:13][CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:19](OCC)(=[O:24])[C:20]#[C:21][CH2:22][CH3:23]>C(Cl)(Cl)Cl>[C:1]([C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][C@H:11]2[O:15][C:14]3=[N:16][C:19](=[O:24])[CH:20]=[C:21]([CH2:22][CH3:23])[N:13]3[CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCC#CC(=O)OCC
Reactant: CC(C)(C)c1ccc(OC[C@@H]2CN=C(N)O2)cc1
Solvent: ClC(Cl)Cl
Product: CCc1cc(=O)nc2n1C[C@@H](COc1ccc(C(C)(C)C)cc1)O2

Procedure:
The title compound was prepared from (S)-5-(4-tert-butyl-phenoxymethyl)-4,5-dihydro-oxazol-2-yl-amine and ethyl 2-pentynoate according to the procedures employed for the preparation of the compound in Example 95. [α]D25 −29.20 (c 0.5, CHCl3)
Reaction SMILES: C([O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:24]=[C:25]4[C:31]([C:32]5[C:33]([CH3:46])=[N:34][N:35]([CH2:38][C:39]6[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[CH:40]=6)[C:36]=5[CH3:37])=[CH:30][N:29]([S:47]([C:50]5[CH:56]=[CH:55][C:53]([CH3:54])=[CH:52][CH:51]=5)(=[O:49])=[O:48])[C:26]4=[N:27][CH:28]=3)=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)C1C=CC=CC=1>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[F:45][C:41]1[CH:40]=[C:39]([CH:44]=[CH:43][CH:42]=1)[CH2:38][N:35]1[C:36]([CH3:37])=[C:32]([C:31]2[C:25]3[C:26](=[N:27][CH:28]=[C:23]([C:20]4[CH:21]=[CH:22][C:17]([N:14]5[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][OH:8])[CH2:16][CH2:15]5)=[CH:18][CH:19]=4)[CH:24]=3)[N:29]([S:47]([C:50]3[CH:51]=[CH:52][C:53]([CH3:54])=[CH:55][CH:56]=3)(=[O:48])=[O:49])[CH:30]=2)[C:33]([CH3:46])=[N:34]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCN(CCOCc6ccccc6)CC5)cc4)cnc32)cc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCN(CCO)CC5)cc4)cnc32)cc1
Temperature: 70 °C
Yield: 157.1 %

Procedure:
5-(4-(4-(2-(benzyloxy)ethyl)piperazin-1-yl)phenyl)-3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (150 mg, 0.195 mmol) was dissolved in trifluoroacetic acid/toluene (5/5 ml) and heated to 70° C. for overnight. Solvents evaporated off to yield 208 mg of the crude titled compound.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:13].O.[C:15]([OH:19])(=[O:18])[CH:16]=O.P(=O)(O)(O)O>O>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[CH:16][C:15]([OH:19])=[O:18])[C:7]2=[O:13]
Reactant: O=CC(=O)O
Reactant: O=C1CCCc2c(F)cc(F)cc21
Agent: O=P(O)(O)O
Solvent: O
Product: O=C(O)C=C1CCc2c(F)cc(F)cc2C1=O
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A mixture of 5,7-difluoro-3,4-dihydro-1(2H)-naphthalenone (3.2 g), glyoxylic acid monohydrate (1.6 g) and 85% phosphoric acid (3 ml) was heated with stirring at 90° C. for four hours. After cooling, water was added to the reaction solution, and the precipitated crystals were collected by filtration, washed with water, and dried to give (5,7-difluoro-3,4-dihydro-1-oxo-2(1H)-naphthalenylidene)acetic acid (4.2).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH:3]=1.[H-].[Na+].Cl[C:24]1[S:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=1>>[N:8]1([C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:1][C:24]3[S:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=3)[CH:3]=2)[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1
Reactant: N#Cc1cnc(Cl)s1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(N)ncn2)CC1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1cnc(Nc2cc(N3CCNCC3)ncn2)s1

Procedure:
Tert-butyl 4-(6-aminopyrimidin-4-yl)piperazine-1-carboxylate 12-2 (0.25 g, 0.9 mmol), sodium hydride (0.072 g, 1.8 mmol) and 2-chloro-1,3-thiazole-5-carbonitrile 2-2 (0.129 g, 0.9 mmol) were treated as in Scheme 4 above. The product was purified on a C18 preparative column and evaporated to dryness. The residue was then treated with trifluoroacetic acid and the product was isolated from a sodium carbonate/methyene chloride partition. 1H-NMR (CD3OD): 8.47 ppm (s, 1H); 8.02 ppm (s, 1H); 6.24 ppm (s, 1H); 3.88 ppm (t, 4H); 3.27 ppm (t, 4H).