Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:10][CH2:11][C@H:12]([CH2:16][N:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[N:19][C:18]2=[O:27])[C@H:13]([OH:15])[CH3:14])=[CH:5][CH:4]=1.N1[C-]=NN=N1.C([NH2+]C(C)C)(C)C.[CH:54]([N:57]([CH:71]([CH3:73])[CH3:72])[P:58](N(C(C)C)C(C)C)[O:59][CH2:60][CH2:61][C:62]#[N:63])([CH3:56])[CH3:55]>ClCCl>[CH:71]([N:57]([CH:54]([CH3:56])[CH3:55])[P:58]([O:59][CH2:60][CH2:61][C:62]#[N:63])[O:15][C@H:13]([CH3:14])[C@@H:12]([CH2:16][N:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[N:19][C:18]1=[O:27])[CH2:11][O:10][C:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:73])[CH3:72]
Reactant: CC(C)N(C(C)C)P(OCCC#N)N(C(C)C)C(C)C
Reactant: COc1ccc(C(OC[C@H](Cn2ccc(NC(C)=O)nc2=O)[C@@H](C)O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: CC(C)[NH2+]C(C)C
Agent: [c-]1nnn[nH]1
Solvent: ClCCl
Product: COc1ccc(C(OC[C@H](Cn2ccc(NC(C)=O)nc2=O)[C@@H](C)OP(OCCC#N)N(C(C)C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.9 %

Procedure:
To a stirred solution of 47 (0.98 g, 1.75 mmol) in 30 ml of anhydrous dichloromethane was added diisopropylammonium tetrazolide (0.3 g) followed by 0.8 g (2.66 mmol) of 2-cyanoethyl N,N,N′,N′-tetraisopropylphosphordiamidite. After being stirred at room temperature for 20 hrs the reaction was concentrated, and the residue portioned between ethyl acetate and saturated NaHCO3. The organic phase was washed with saturated NaCl, dried over Na2SO4 and concentrated in vacuo. The crude phosphoramidite was p twice by re-dissolving in small (˜10 ml) amount of ethyl acetate, diluting with hexane (100 ml), allowing precipitate as an oil and decanting the liquid. Drying in vacuo afforded 1.1 g (83%) of 48 as an amorphous white solid. 31P NMR (DMSO-d6): δ 145.84, 144.94.
Reaction SMILES: C[O:2][C:3](=[O:32])[C@H:4]([CH2:6][CH:7]([CH2:9][C:10](=[O:31])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[C:12]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:8])[NH2:5].[Li+].[OH-]>C1COCC1.O>[N:22]1[CH:23]=[CH:24][C:19]([CH2:18][NH:17][C:13]2[C:12]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[C:11]([CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:9][CH:7]([CH3:8])[CH2:6][C@@H:4]([C:3]([OH:32])=[O:2])[NH2:5])=[O:31])=[CH:20][CH:21]=1
Reactant: COC(=O)[C@@H](N)CC(C)CC(=O)c1cccc(NCc2ccncc2)c1-c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(CC(=O)c1cccc(NCc2ccncc2)c1-c1ccccc1)C[C@H](N)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
The product of Example 389A (0.22 g, 0.51 mmoles) was dissolved in 10 mL THF/H2O (2:1), cooled to 0° C. and LiOH (0.04 g, 1.02 mmoles) added. The reaction was stirred at 0° C. for 1 h, followed by stirring at room temperature for 2 hours. The solvents were evaporated and the residue passed through a bed of silica gel and eluted with CH2Cl2:CH3OH (9:1) to afford the title compound (0.19 g, 90%) as a white solid. 1H NMR (300 MHz, DMSO-d6) 0.79 (t, 6H), 1.19 (m, 2H), 1.42 (m, 1H), 4.06 (m, 1H), 4.36 (d, 2H), 6.53 (dd, 1H), 6.81 (m, 2H), 7.04 (d, 1H), 7.17-7.31 (m, 6H), 7.59 (d, 1H), 8.46 (d, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][NH:10][C:11]([NH2:13])=[S:12])([CH3:4])([CH3:3])[CH3:2].Br[CH:16]([CH3:20])[C:17](=O)[CH3:18].CCN(C(C)C)C(C)C>C(O)C>[C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][NH:10][C:11]1[S:12][C:16]([CH3:20])=[C:17]([CH3:18])[N:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCNC(N)=S
Reactant: CC(=O)C(C)Br
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(NCCNC(=O)OC(C)(C)C)sc1C

Procedure:
A solution of (2-thioureido-ethyl)-carbamic acid tert-butyl ester [CAS 331779-96-5] (3.6 g), 3-bromo-2-butanone (2.45 g), and DIPEA (5.5 ml) in ethanol (100 ml) was stirred overnight at RT and refluxed 1 hour. The mixture was concentrated. Ethyl acetate was added. Insoluble parts were filtered off and the remaining solution was extracted with brine. The organic layer was dried, evaporated and purified by flash chromatography yielding after crystallization 0.86 g of white crystals.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[CH2:38]([O:37][C:35](=[O:36])[NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)[CH3:39]
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from trans-4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A140) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=[O:2].[CH2:6]([N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N+:15]([O-])=[CH:14][C:13]=2[N:12]=[CH:11]1)[CH:7]([CH3:9])[CH3:8].[OH-].[NH4+]>CN(C)C=O>[OH2:2].[Cl:3][C:14]1[C:13]2[N:12]=[CH:11][N:10]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)Cn1cnc2c[n+]([O-])c3ccccc3c21
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)Cn1cnc2c(Cl)nc3ccccc3c21
Product: O
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4.8 g (0.0311 mole) of phosphorus oxychloride in 20 ml of N,N-dimethylformamide was added, in small portions, 5.0 g (0.207 mole) of 1-isobutyl-1H-imidazo[4,5-c]quinoline-5-oxide. The solution was stirred for 15 minutes at 20° C., then heated on a steam bath for 15 minutes. The solution was cooled to 20° C., then poured into stirred ice. The solution was basified to pH 8 with concentrated ammonium hydroxide. The yellow solid precipitate was separated by filtration, washed sequentially with water and diethyl ether, and dried to provide 4-chloro-1-isobutyl-1H-imidazo[4,5-c]quinoline hydrate, m.p. 103°-107° C. Recrystallization twice from ethyl acetate with drying provided 4-chloro-1-isobutyl-1H-imidazo[4,5-c]quinoline, m.p. 135°-137° C. Analysis: Calculated for C14H14ClN3 : %C, 64.7; %H, 5.4; %N, 16.2; Found: %C, 64.6; %H, 5.5; %N, 16.1.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Br[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>>[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:5][CH:4]=1
Reactant: OCc1ccc(O)cc1
Reactant: CCOC(=O)CCCBr
Product: CCOC(=O)CCCOc1ccc(CO)cc1

Procedure:
Ethyl 4-(4-(hydroxymethyl)phenoxy)butanoate 29b was prepared by reacting 4-(hydroxymethyl)phenol 27b with ethyl 4-bromobutyrate 28b according to protocol described for the compound 29a in Example 24 (Scheme 9). The ester 29b was isolated as colorless oil 96% yield (2.26 g). 1H NMR (400 MHz, CDCl3): δ 1.24 (3H, t, J=7.2 Hz); 2.07 (2H, m); 2.15 (2H, t, J=7.2 Hz)); 3.97 (2H, t, J=6.4 Hz); 4.10 (2H, q, J=7.2 Hz); 4.59 (2H, s); 6.88 (1H, s); 6.87 (1H, s); 7.24-7.27 (2H, m).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH2:15])[S:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:16]([O:20][C:21](=[O:27])[CH2:22][S:23](Cl)(=[O:25])=[O:24])([CH3:19])([CH3:18])[CH3:17]>CN(C1C=CN=CC=1)C>[C:16]([O:20][C:21](=[O:27])[CH2:22][S:23](=[O:24])(=[O:25])[NH:15][C:12]1[S:13][CH:14]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=2)[N:11]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)c1ccc(-c2csc(N)n2)cc1
Reactant: CC(C)(C)OC(=O)CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Product: CC(C)c1ccc(-c2csc(NS(=O)(=O)CC(=O)OC(C)(C)C)n2)cc1

Procedure:
4-(4-Isopropyl-phenyl)-thiazol-2-ylamine, chlorosulfonyl-acetic acid tert-butyl ester, DMAP (10 mol %) were combined using general procedure C (method 2) to afford [4-(4-Isopropyl-phenyl)-thiazol-2-ylsulfamoyl]-acetic acid tert-butyl ester. LCMS m/z: 398 (M+1)+; 1H NMR (CDCl3, 400 MHz): δ 1.27 (d, 6H); 1.44 (s, 9H); 2.95 (m, 1H); 4.06 (s, 2H); 6.48 (s, 1H); 7.32 (d, 2H); 7.39 (d, 2H); 10.5 (brs, 1H).
Reaction SMILES: Cl[C:2]([CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][CH2:12][CH:13]1[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])=[O:3].[NH2:26][C:27]1[CH:35]=[C:34]([Br:36])[CH:33]=[CH:32][C:28]=1[C:29]([NH2:31])=[O:30].CCN(CC)CC>C1COCC1.O>[Br:36][C:34]1[CH:33]=[CH:32][C:28]([C:29](=[O:30])[NH2:31])=[C:27]([NH:26][C:2]([CH:4]2[CH2:8][CH2:7][CH2:6][N:5]2[C:9]([O:11][CH2:12][CH:13]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:19]3[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:10])=[O:3])[CH:35]=1
Reactant: NC(=O)c1ccc(Br)cc1N
Reactant: O=C(Cl)C1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: NC(=O)c1ccc(Br)cc1NC(=O)C1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
A solution of (9H-fluoren-9-yl)methyl 2-(chlorocarbonyl)pyrrolidine-1-carboxylate (600 mg, 1.8 mmol), 2-amino-4-bromobenzamide (400 mg, 1.8 mmol), and Et3N (2 mL) in THF was stirred at room temperature. The reaction was monitored by TLC. After diluting with H2O (50 mL), the mixture was extracted with ethyl acetate (3×100 mL). The organic layers were dried over Na2SO4 and concentrated to give yellow residue, which was purified by column chromatography. MS (ESI): 534, 536 (MH+)
Reaction SMILES: F[C:2](F)(F)[C:3](O)=O.N1(CC(O)=O)CCOCC1.[S:18]1[CH:22]=C[N:20]=[N:19]1.[C:23](N)([NH2:26])=[N:24]N.C(OC=C(C(OCC)=O)C(OCC)=O)C>>[N:20]1[C:3]2[CH:2]=[N:24][CH:23]=[N:26][C:22]=2[S:18][N:19]=1
Reactant: O=C(O)C(F)(F)F
Reactant: NN=C(N)N
Reactant: c1csnn1
Agent: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: O=C(O)CN1CCOCC1
Product: c1ncc2nnsc2n1

Procedure:
5-Hydroxy-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidine-6-carboxamides. As described in Chart BL, (4-morpholinyl)acetic acid trifluoroacetic acid salt BL.1 (J. Med. Chem. 1994, 37, 4538-4554) is cyclized to the thiadiazole BL.2 with aminoguanidine in polyphosphoric acid. Condensation of BL.2 with diethyl ethoxymethylenemalonate followed by thermal cyclization affords thiadiazolopyrimidine BL.3. The resulting ester BL.3 is then saponified to afford the corresponding acid BL.4 which is then coupled with a benzylamine (e.g. 4-chlorobenzylamine) mediated by 1,1′-carbonyldiimidazole (or other suitable carboxylic acid activating agent) to provide amides of the general formula BL.5. A specific example of heterocycle W19.2 in which R8=OH is also prepared as described in Chart BL. Thiadiazole BL.2 is heated in xylenes with diethyl 2-(((4-chlorobenzyl)amino) carbonyl)malonate (prepared by the reaction of 4-chlorobenzyl-amine with triethyl methanetricarboxylate) to afford thiadiazolopyrimidine BL.6.
Reaction SMILES: C[Li].[CH-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.Cl[Ti:14]Cl.O>CCOCC>[CH3:8][C-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[C-:8]1([CH3:3])[CH:12]=[CH:11][CH:10]=[CH:9]1.[Ti+2:14]
Reactant: Cl[Ti]Cl
Reactant: c1cc[cH-]c1
Agent: [Li]C
Solvent: CCOCC
Solvent: O
Product: C[c-]1cccc1
Product: [Ti+2]
Temperature: 0 °C

Procedure:
In a standard procedure, methyllithium (2 equivalents) was added to an ice-cooled suspension of Cp2TiCl2 in dry ether (15 ml per gram of Cp2TiCl2). After stirring for one half hour, a small amount of water was added to quench the reaction. The contents were transferred to a separatory funnel and the orange organic layer washed once with water. Drying with anhydrous MgSO4, filtration, and removal of the solvent with a rotary evaporator provided bright orange crystals of dimethyl titanocene. Yields are typically greater then 95%. Due to its thermal instability and light sensitivity over time in the solid form, this compound is best stored as a 0.5M tetrahydrofuran or toluene solution kept in the dark, and preferably cold. The compound can be exposed to water during the normal workup procedure or to air during weighing and handling. Moreover, the reagent can be stored in the dark as, e.g., a toluene or THF solution for several months without significant decomposition, as indicated by NMR
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH:9]1([C:13]#[N:14])[CH2:12][CH2:11][CH2:10]1.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]Br)=[C:18]([I:24])[CH:17]=1>C1COCC1>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:9]2([C:13]#[N:14])[CH2:12][CH2:11][CH2:10]2)=[C:18]([I:24])[CH:17]=1
Reactant: N#CC1CCC1
Reactant: BrCc1ccc(Br)cc1I
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC1(Cc2ccc(Br)cc2I)CCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Lithium diisopropylamide (3.34 mL, 6.68 mmol), was added dropwise to a solution of cyclobutanecarbonitrile (0.417 g, 5.14 mmol) in THF (20 mL) at −78° C. under an argon atmosphere. The reaction mixture was stirred at −78° C. for 30 min, then was a solution of 4-bromo-1-(bromomethyl)-2-iodobenzene (see Caruso, A.; Tovar, J., D. J. Org. Chem. 2011, 76, 2227-2239, 2.51 g, 6.68 mmol) in THF (8 mL) slowly added dropwise and the reaction was allowed to reach r.t. The mixture was stirred for another 3 h and then quenched with water. The reaction mixture was partitioned between water and EtOAc, the organic layer was dried over MgSO4 and concentrated to give a crude product which was purified by flash chromatography (eluent: heptane/ethylacetae 12:1) to afford the title compound (1.71 g, 89% yield): 1H NMR (500 MHz, CDCl3) δ ppm 2.08-2.34 (m, 4 H), 2.47-2.58 (m, 2 H), 3.18-3.23 (m, 2 H), 7.29 (s, 1 H), 7.49 (dd, 1 H), 8.03 (d, 1 H); GC MS (EI) m/z 375 M+.
Reaction SMILES: [CH2:1]([O:5]C(Cl)=O)[CH:2](C)C.C(O)(=O)C.C(N(CC)CC)C.[NH2:20][C@H:21]([CH3:39])[CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[C:35](=[O:36])[C:34]2[N:33]([CH3:37])[CH:32]=[N:31][C:30]=2[N:29]([CH3:38])[C:27]1=[O:28]>ClCCl>[C:1]([NH:20][C@H:21]([CH3:39])[CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[C:35](=[O:36])[C:34]2[N:33]([CH3:37])[CH:32]=[N:31][C:30]=2[N:29]([CH3:38])[C:27]1=[O:28])(=[O:5])[CH3:2]
Reactant: C[C@@H](N)CCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reactant: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)N[C@H](C)CCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.1 %

Procedure:
Isobutylchloroformate (341 mg, 2.5 mmol) was added slowly to a solution of acetic acid (146 mg, 2.5 mmol) and triethylamine (252.75 mg, 2.5 mmol) in dichloromethane (20 ml) at −15° C. After warming to room temperature over 15 minutes, a solution of (R)-1-(5-aminohexyl)-3,7-dimethylxanthine (prepared as described for CT11558) (558 mg, 2 mmol) in dichloromethane (10 ml) was added. After stirring al room temperature for 12 hours, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 13% methanol-ethyl acetate to provide (R)-1-(5-acetamidohexyl)-3,7-dimethylxanthine (CT12538) (380 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:25]=[C:26]([CH2:30]OS(C)(=O)=O)[CH:27]=[N:28][CH:29]=2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>C1COCC1.O>[NH3:8].[CH3:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:29]=[N:28][CH:27]=[C:26]([CH2:30][N:40]3[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]3)[CH:25]=2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:17][CH:18]=1)[CH2:7]2
Reactant: CN1CCNCC1
Reactant: Cc1cc(-c2cncc(COS(C)(=O)=O)c2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(-c2cncc(CN3CCN(C)CC3)c2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Product: N
Temperature: 50 °C
Reaction time: 18 h
Yield: 5 %
Yield: 132.4 %

Procedure:
Methanesulfonic acid 5-[7-methyl-1-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindol-5-yl]-pyridin-3-ylmethyl ester (36 mg, 0.071 mmol) was dissolved in THF (5 mL). N-Methyl piperazine (24 uL, 0.213 mmol) was added and the mixture stirred at 50° C. for 18 hrs. The mixture was cooled, diluted with water, and extracted with ethyl acetate. The organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (5% 2M NH3 in MeOH/CH2Cl2) provided the title compound (24 mg, 67%) as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 8.73 (s, 1H), 8.56 (s, 1H), 7.86 (s, 1H), 7.42 (d, 2H), 7.37 (d, 2H), 7.19 (d, 2H), 4.82 (s, 2H), 4.32 (s, 2H), 3.60 (s, 2H), 2.85 (s, 3H), 2.52-2.42 (br s, 8H), 2.30 (s, 3H).
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[C:31]([CH2:33]Br)[CH:30]=[CH:29][C:28]=2[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:25])[C:6]1=[O:39])[CH2:2][CH2:3][CH3:4].[NH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1.O>C1COCC1>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[C:31]([CH2:33][N:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[CH:30]=[CH:29][C:28]=2[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:25])[C:6]1=[O:39])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2cc(CBr)ccc2C(C)(C)C)c(-c2cccc(OC)c2)c2cccnc21
Reactant: C1CCNC1
Solvent: C1CCOC1
Solvent: O
Product: CCCCn1c(=O)c(NC(=O)Nc2cc(CN3CCCC3)ccc2C(C)(C)C)c(-c2cccc(OC)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To a solution of N-[1-butyl-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N′-[2-tert-butyl-5-(bromomethyl)phenyl]urea (330 mg, 0.56 mmol) in THF (tetrahydrofuran, 5 ml) is added pyrrolidine (362 mg, 5.09 mmol), and the mixture is stirred at room temperature for 3 hours. The mixture is poured into water, and the mixture is extracted with ethyl acetate. The extract is washed with water and a saturated brine, and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, and the resulting residue is purified by silica gel column chromatography (5-10% methanol/chloroform) to give the title compound (234 mg, 0.42 mmol) as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:45]=[C:46]([F:48])[CH:47]=1)[CH2:5][N:6]1[C:10](C)=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([O:32][CH3:33])=[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:26]=4)[CH:19]=3)[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH:13]=2)[C:8](C)=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:48][C:46]1[CH:45]=[C:4]([CH:3]=[C:2]([F:1])[CH:47]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([O:32][CH3:33])=[C:25]([NH:27][S:28]([CH3:31])(=[O:29])=[O:30])[CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH:8]=[N:7]1
Reactant: COc1ccc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cc(F)cc(F)c4)c2C)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2cnc3[nH]cc(-c4cnn(Cc5cc(F)cc(F)c5)c4)c3c2)cc1NS(C)(=O)=O
Yield: 1 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(5-(3-(1-(3,5-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxy phenyl) methanesulfonamide (210 mg, 0.3 mmol) was hydrolyzed by lithium hydroxide (34.2 mg, 0.91 mmol), THF/Methanol/water (4/6/1 mL) to afford 1.6 mg of the titled compound after purification by preparative TLC (SiO2-1000 micron) eluted by 3% MeOH in CHCl3). 1H NMR (CDCl3, 300 MHz): δ 8.9 (b, 1H), 8.5 (s, 1H), 7.84 (m, 1H), 7.78 (m, 1H), 7.0 (m, 1H), 6.85 (m, 1H), 6.78-6.7 (m, 3H), 5.29 (s, 2H), 3.93 (s, 3H), 2.98 (s, 3H), 2.51 (s, 3H), 2.17 (s, 3H). MS: m/z=538.1 (M+1), HPLC: 86.27% in method B.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.[NH:12]1[CH2:18][CH2:17][CH2:16][CH:15]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[CH2:14][CH2:13]1.OC1C2N=NNC=2C=CC=1.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C.CN(C=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([N:12]1[CH2:18][CH2:17][CH2:16][CH:15]([C:19]2[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=2)[CH2:14][CH2:13]1)=[O:7]
Reactant: Cc1ccc(C(=O)O)cc1N
Reactant: N#Cc1ccc(C2CCCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)N2CCCC(c3ccc(C#N)cc3)CC2)cc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
To a 4-mL vial was added 3-amino-4-methylbenzoic acid (27 mg, 0.18 mmol, 1.0 equiv), 4-(azepan-4-yl)benzonitrile (compound 40.4, 40 mg, 0.2 mmol, 1.1 equiv), hydroxybenzotriazole (39 mg of 20 wt % H2O, 0.23 mmol, 1.3 equiv), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (44 mg, 0.23 mmol, 1.3 equiv), DMF (1 mL) and N,N-diisopropylethylamine (93 μL, 0.54 mmol, 3.0 equiv). The mixture was stirred at room temperature for 4 hours then diluted into ethyl acetate (10 mL) and washed with brine (10 mL). The aqueous was extracted with ethyl acetate (3 mL) and the combined organics were washed with brine (10 mL), 1 M NaH2PO4 (5 mL) and brine (10 mL). The organics were dried (Na2SO4), filtered and concentrated to obtain the title compound as a brown solid (45 mg, 74%). m/z (ES+) 334 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[Cl:16][C:17]1[N:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(Cl)Cl>[Cl:16][C:17]1[N:22]=[CH:21][C:20]([S:23]([N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: CNc1ccccn1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(c1ccccn1)S(=O)(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1.3 g (11.8 mmol) of N-methylpyridin-2-amine in 25 mL of DCM are added, at 0° C., 3.3 mL (23.6 mmol) of triethylamine and then, portionwise, 2.5 g (11.8 mmol) of 6-chloropyridine-3-sulfonyl chloride (prepared according to document WO 98/40332). After stirring for 12 hours at room temperature, the reaction medium is taken up in 100 mL of DCM, washed successively with 100 mL of water and 30 mL of brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, eluting with a 4/1 cyclohexane/EtOAc mixture. After concentrating under reduced pressure, 2.8 g of 6-chloro-N-methyl-N-pyridin-2-ylpyridine-3-sulfonamide are obtained in the form of a brown solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[N:19]=[C:18]([C:28]([N:30]3[CH2:34][C:33](=[O:35])[NH:32][CH2:31]3)=[O:29])[CH:17]=2)[CH:11]=1)(=O)=O.[CH2:36]([NH2:38])[CH3:37].[CH:39]([OH:41])=[O:40].ClC1C=C(N2C(C3C=CC=C(OCCCN(C)C)C=3)=CC(C(N3CC(=O)NC3)=O)=N2)C=CC=1>O1CCCC1>[CH:39]([OH:41])=[O:40].[Cl:27][C:23]1[CH:22]=[C:21]([N:20]2[C:16]([C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:8][CH2:7][CH2:6][NH:38][CH2:36][CH3:37])[CH:11]=3)=[CH:17][C:18]([C:28]([N:30]3[CH2:34][C:33](=[O:35])[NH:32][CH2:31]3)=[O:29])=[N:19]2)[CH:26]=[CH:25][CH:24]=1
Reactant: CS(=O)(=O)OCCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Reactant: CCN
Agent: CN(C)CCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Solvent: O=CO
Solvent: C1CCOC1
Product: CCNCCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 120A and ethylamine without the addition of tetrahydrofuran in analogy to the synthesis of the compound of Example 29. 23 mg (21% of theory) of the title compound are obtained.