Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN1CCOCC1.[NH2:26][C@H:27]([C:31]([N:33]1[CH2:53][CH2:52][CH2:51][C@H:34]1[C:35]([NH:37][C@H:38]([C:42]([C:44]([C:47]([F:50])([F:49])[F:48])([F:46])[F:45])=[O:43])[CH:39]([CH3:41])[CH3:40])=[O:36])=[O:32])[CH:28]([CH3:30])[CH3:29]>C(Cl)Cl>[N:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([C:14]([NH:26][C@H:27]([C:31]([N:33]3[CH2:53][CH2:52][CH2:51][C@H:34]3[C:35]([NH:37][CH:38]([CH:39]([CH3:40])[CH3:41])[C:42](=[O:43])[C:44]([F:45])([F:46])[C:47]([F:48])([F:49])[F:50])=[O:36])=[O:32])[CH:28]([CH3:29])[CH3:30])=[O:16])=[CH:17][CH:18]=2)(=[O:8])=[O:9])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCOCC2)cc1
Reactant: CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)C(F)(F)C(F)(F)F)C(C)C
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)c1ccc(S(=O)(=O)N2CCOCC2)cc1)C(C)C)C(=O)C(F)(F)C(F)(F)F
Temperature: -22 °C
Reaction time: 0.33 h
Yield: 50 %

Procedure:
To a solution of the benzoic acid derivative prepared above (0.240 g, 0.885 mmol) and NMM (0.446 g, 4.43 mmol, 0.489 ml) in CH2Cl2 (8.9 ml) at −22° C. under N2 was added IBCF (0.121 g, 0.885 mmol, 0.115 ml), and the reaction stirred at −22° C. for 20 min. The HCL.Val-Pro-Val-C2F5 (0.400 g, 0.885 mmol) was added in several portions, and the reaction was stirred at −22° C. for 0.5 h, followed by 4 h at room temperature. The reaction was diluted with CH2Cl2 (30 ml) and then washed successively with 10% HCl (2×15 ml), sat. NaHCO3 (2×15 ml), brine (1×15 ml), and dried over MgSO4. Solvent removal under vacuum gave an off-white foam which was purified by flash chromatography (silica gel; 25/75, hexane/EtOAc) to give 0.295 g (50%) of the title compound as a white solid. TLC: Rf 0.49 (EtOAc). 1H NMR: δ8.02-7.93 (m, 2H, aryl), 7.85-7.77 (m, 2.25H, aryl and NH), 7.70 (d, J=7.3 Hz, 0.75H, NH), 6.93 (d, J=9.0 Hz, 1H, NH), 5.04-4.96 (m, 1H, α-CH of Val), 4.86 (dd, J=8.7, 6.7 Hz, 1H, α-CH of Val), 4.71 (dd, J=8.1, 2.0 Hz, 0.25H, α-CH of Pro), 4.61 (dd, J=8.1, 3.0 Hz, 0.75H, α-CH of Pro), 3.92-3.64 (m, 6H, CH2OCH2 and CH2N of Pro), 3.07-2.96 (m, 4H, CH2NCH2), 2.55-1.82 (series of m, 6H, 2×β-CH of Val, CH2CH2 of Pro), 1.12-0.85 (m, 12H, 4×CH3). 19F NMR: δ−82.12 (s, CF3, major), −82.16 (s, CF3, minor), −121.50 and −122.74 (AB quartet, J=296 Hz, CF2, minor), −121.56 and −122.60 (AB quartet, J=299 Hz, CF2, major). MS (DCI/CH4): m/z (rel intensity) 669 (MH+, 55), 317 (100). Anal. (C28H37F5N4O7S.0.33H2O): C, H, N: calcd, 8.30; found, 7.82.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:44]=[CH:45][CH:46]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[CH:23][CH:22]=4)[CH:19]=3)[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH:13]=2)[C:8]([CH3:43])=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:44]=[CH:45][CH:46]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[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]([N:27]5[CH2:28][CH2:29][O:30][CH2:31][CH2:32]5)=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:43])=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCOCC5)cc4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3ccc(N4CCOCC4)cc3)cc12
Yield: 31.7 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 4-(4-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl) morpholine (100 mg, 0.157 mmol) was hydrolyzed by lithium hydroxide (33 mg, 0.786 mmol), THF/Methanol/water (5/5/3 ml) to afford 24 mg (32% yield) of the titled compound. 1H NMR (CDCl3, 300 MHz): δ 9.36 (s, 1H), 8.56 (s, 1H), 7.87 (s, 1H), 7.75-7.52 (d, 2H), 7.40-7.30 (m, 1H), 7.10-6.95 (m, 3H), 6.90-6.80 (d, 1H), 5.32 (s, 2H), 3.91-3.88 (m, 4H), 3.23-3.20 (m, 4H), 2.26 (s, 3H), 2.15 (s, 3H). MS: m/z=482.3 (M+1), HPLC Purity: 99.13% Method: B.
Reaction SMILES: [CH:1]1([S:4](Cl)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH3:8][NH:9][C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH2:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:15]([C:17]([F:20])([F:19])[F:18])=[N:16][C:12]=2[CH:11]=1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:8][N:9]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH2:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:15]([C:17]([F:18])([F:19])[F:20])=[N:16][C:12]=2[CH:11]=1)[S:4]([CH:1]1[CH2:3][CH2:2]1)(=[O:6])=[O:5]
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CNc1ccc2c(c1)nc(C(F)(F)F)n2CC1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(c1ccc2c(c1)nc(C(F)(F)F)n2CC1CCOCC1)S(=O)(=O)C1CC1
Yield: 97 %

Procedure:
Following the procedure in Example 5, using cyclopropanesulfonyl chloride (34 mg, 0.24 mmol), N-methyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-2-(trifluoromethyl)-1H-benzimidazol-5-amine (63 mg, 0.20 mmol) (for preparation, see the step G in example 1), DIPEA (49 uL, 36 mg, 0.28 mmol) and DMAP (5 mg, 0.04 mmol) in DCM (6 mL) at 0° C. The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 81 mg (97%) of a white solid as the title compound. 1HNMR (400 MHz, METHANOL-D4): δ 0.85-0.92 (m, 2 H), 0.93-1.01 (m, 2 H), 1.37-1.52 (m, 4 H), 2.18-2.31 (m, 1 H), 2.55-2.65 (m, 1 H), 3.30-3.36 (m, 2 H), 3.38 (s, 3 H), 3.86-3.95 (m, 2 H), 4.32 (d, J=7.62 Hz, 2 H), 7.58 (dd, J=8.89, 2.05 Hz, 1 H), 7.76 (d, J=8.79 Hz, 1 H) 7.86 (d, J=1.95 Hz, 1 H). MS (ESI) (M+H)+=418.0. Anal. Calcd for C18H22F3N3O3S+0.10 H2O+0.20 CH3OH (425.66): C, 51.36; H, 5.45; N, 9.87. Found: C, 51.39; H, 5.49; N, 9.92.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Li]CCCC.[Li+].[Cl-].[C:16](Cl)(=[O:20])/[CH:17]=[CH:18]/[CH3:19]>C1COCC1.Cl[Cu]>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:16](=[O:20])[CH:17]=[CH:18][CH3:19])=[CH:3][CH:4]=1
Reactant: C/C=C/C(=O)Cl
Reactant: Fc1ccc(Br)cc1
Agent: Cl[Cu]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC=CC(=O)c1ccc(F)cc1
Reaction time: 1 h
Yield: 9.8 %

Procedure:
To a solution of 1-bromo-4-fluorobenzene (28 g, 0.162 mol) in THF (90 mL) was added n-BuLi (70 mL, 2.5 M) at −78° C. and stirred for 1 h under nitrogen. Then to a premixed solution of CuCl (18 g, 0.16 mol) and LiCl (15 g, 0.354 mol) in THF (160 mL) at −78° C. was added the above solution quickly. The formed solution was stirred for 20 minutes, and was treated with crotonyl chloride (21 g, 0.176 mol). The resulting solution was stirred for 30 minutes. The mixture was quenched with aq NH4Cl, the organic phase was separated, concentrated to give the crude product which was purified by column chromatography to afford 1-(4-fluorophenyl)but-2-en-1-one (2.6 g, 10%). 1H NMR (400 MHz, CDCl3): δ=2.02 (d, 3H), 6.88 (m, 1H), 7.10 (m, 3H), 7.98 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]([CH3:20])[CH3:19])/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[NH2:21][C:22]1[S:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[S:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=[C:22]1[NH:21][C:13](=[O:15])/[C:12](/[C:4]1[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=1)=[N:16]/[O:17][CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)O/N=C(/C(=O)O)c1ccc(S(C)(=O)=O)c(Cl)c1
Reactant: Nc1nc2ccccc2s1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)O/N=C(/C(=O)Nc1nc2ccccc2s1)c1ccc(S(C)(=O)=O)c(Cl)c1
Reaction time: 2 h
Yield: 54.2 %

Procedure:
This estimated 80% pure (E)-(3-chloro-4-methanesulfonyl-phenyl)-isopropoxyimino-acetic acid (prepared as in Example 6, 99 mg, 0.31 mmol), 2-aminobenzothiazole (512 mg, 0.34 mmol) and N,N-diisopropylethylamine (162 μL, 0.93 mmol) were combined in acetonitrile (1.25 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (118 mg, 0.31 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 50% ethyl acetate/hexanes) to afford (E)-N-benzothiazol-2-yl-2-(3-chloro-4-methanesulfonyl-phenyl)-2-isopropoxyimino-acetamide (76 mg, 54%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C19H18ClN3O4S2 [M+] 451.04, found 452 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.39 (d, J=6.3 Hz, 6 H, 2×CH3), 3.32 (s, 3 H, SO2CH3), 4.65 (m, J=6.3 Hz, 1 H, OCH), 7.36 (brt, J=7.8 Hz, 1H, Ar), 7.49 (brt, J=7.8 Hz, 1H, Ar), 7.64 (dd, Jo=8.2, Jm=1.6 Hz, 1 H, Ar), 7.74 (d, Jm=1.6 Hz, 1 H, Ar), 7.84 (m, 2H, Ar), 8.24 (d, Jo=8.2 Hz, 1 H, Ar), 10.20 (s, 1 H, NH).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]([C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([CH2:18][CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:13]1)[CH:7]=[C:6]([C:25]([O:27]CC)=[O:26])[C:5]2=[O:30].[CH2:31]([NH:33][C:34](=[O:54])[NH:35][C:36]1[N:41]=[CH:40][C:39](B(O)O)=[C:38]([C:45]2[S:46][CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[N:49]=2)[CH:37]=1)[CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Li+].Cl>O1CCOCC1.O.C1(P([Pd-4](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)C=CC=CC=1>[CH2:21]([N:20]([CH2:23][CH3:24])[CH2:19][CH2:18][N:14]1[CH2:15][CH2:16][CH2:17][C@H:12]([N:8]2[C:9]3[C:4](=[CH:3][C:2]([C:39]4[CH:40]=[N:41][C:36]([NH:35][C:34]([NH:33][CH2:31][CH3:32])=[O:54])=[CH:37][C:38]=4[C:45]4[S:46][CH:47]=[C:48]([C:50]([F:53])([F:51])[F:52])[N:49]=4)=[N:11][CH:10]=3)[C:5](=[O:30])[C:6]([C:25]([OH:27])=[O:26])=[CH:7]2)[CH2:13]1)[CH3:22]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(B(O)O)cn1
Reactant: CCOC(=O)c1cn([C@H]2CCCN(CCN(CC)CC)C2)c2cnc(Br)cc2c1=O
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cc3c(=O)c(C(=O)O)cn([C@H]4CCCN(CCN(CC)CC)C4)c3cn2)cn1
Temperature: 100 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
To a solution of (S)-ethyl 6-bromo-1-(1-(2-(diethylamino)ethyl)piperidin-3-yl)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylate (Intermediate 63, 461 mg, 0.96 mmol, 1 equiv.) and 6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazole-2-yl)pyridine-3-ylboronic acid (WO2009106885, 519 mg, 1.44 mmol, 1.5 equiv.) in 1,4-dioxane (4 mL) was added tetrakis(triphenylphosphino)palladium(0) (111 mg, 0.1 mmol, 0.1 equiv.) followed by a solution of cesium carbonate (627 mg, 1.92 mmol, 2.0 equiv.) in water (1.3 mL). This reaction mixture was stirred at 100° C. for 2 h. 2 M Lithium hydroxide (0.96 mL) was added. The reaction mixture was stirred at 100° C. for 9 h, cooled to room temperature, and diluted with water. 1 N HCl was added until pH 3-4 was reached. The precipitate was washed with water and hexanes and dried. The compound was purified (C18 silica gel chromatography) and concentrated to provide (5)-1-(1-(2-(diethylamino)ethyl)piperidin-3-yl)-6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylic acid as a solid (193 mg, 30%). Calcd for C32H37F3N8O4S [M+H]+: 687.23.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH3:9][O:10][C:11]1[C:18]([O:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:17][C:14]([C:15]#[N:16])=[C:13]([N+:29]([O-])=O)[CH:12]=1.Cl.[OH-].[Na+]>O>[NH2:29][C:13]1[CH:12]=[C:11]([O:10][CH3:9])[C:18]([O:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: COc1cc([N+](=O)[O-])c(C#N)cc1OCCCN1CCOCC1
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc(N)c(C#N)cc1OCCCN1CCOCC1
Temperature: 70 °C
Yield: 104.6 %

Procedure:
Sodium dithionite (89%, 81.4 kg) was added to a stirred slurry of 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzonitrile (48.8 kg) in water (867 liters) and the resultant mixture was heated to 50° C. for approximately 2 hours to complete the reaction. The temperature of the reaction mixture was raised to approximately 70° C. and a concentrated aqueous hydrochloric acid solution (36%, 270 kg) was added over 3 hours. The resultant mixture was cooled to 20-25° C. and sodium hydroxide liquor (47%, 303.7 kg) was added whilst stirring of the reaction mixture was continued. The reaction mixture was extracted with two portions of methylene chloride (1082 kg and 541 kg respectively) and the combined organic extracts were washed with water (510 liters). The organic phase was concentrated by distillation to remove 800 liters of solvent. There was thus obtained a methylene chloride solution (503.5 kg) containing 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzonitrile (46.3 kg, 99% yield) suitable for use in the next stage.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C@@H:11]3[CH2:16][CH2:15][C@H:14]([NH2:17])[CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[CH:18]([N:21]1[C:30]2[N:29]=[C:28]([NH:31][C:32]3[CH:33]=[CH:34][C:35]([C:41](O)=[O:42])=[C:36]4[C:40]=3[O:39][CH2:38][CH2:37]4)[N:27]=[CH:26][C:25]=2[N:24]([CH3:44])[C:23](=[O:45])[C@@H:22]1[CH2:46][CH3:47])([CH3:20])[CH3:19].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.N>ClCCl>[CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C@@H:11]3[CH2:16][CH2:15][C@H:14]([NH:17][C:41]([C:35]4[CH:34]=[CH:33][C:32]([NH:31][C:28]5[N:27]=[CH:26][C:25]6[N:24]([CH3:44])[C:23](=[O:45])[C@H:22]([CH2:46][CH3:47])[N:21]([CH:18]([CH3:19])[CH3:20])[C:30]=6[N:29]=5)=[C:40]5[O:39][CH2:38][CH2:37][C:36]=45)=[O:42])[CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[CH2:2][CH2:3]1
Reactant: N[C@H]1CC[C@@H](N2CCN(CC3CC3)CC2)CC1
Reactant: CC[C@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OCC4)nc2N1C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)N[C@H]4CC[C@@H](N5CCN(CC6CC6)CC5)CC4)c4c3OCC4)nc2N1C(C)C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
(cis)-4-[4-(Cyclopropylmethyl)piperazin-1-yl]cyclohexanamine 12e (577 mg, 2.43 mmol), the crude compound 7-[[(7S)-8-isopropyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylic acid 43e (1 g, 2.43 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetra methyluronium tetrafluoroborate (780 mg, 2.43 mmol) and diisopropylethylamine (690 mg, 5.35 mmol) were dissolved in 60 mL of dichloromethane. The reaction solution was stirred for 2 hours. The resulting mixture was added with 50 mL of aqueous ammonia and extracted with dichloromethane (50 mL×3). The combined organic phase was washed with saturated brine (50 mL×3), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound N-[(cis)-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl]-7-[[(7S)-7-ethyl-8-isopropyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxamide 43 (1.12 g, yield: 74.6%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:36])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH:24][C:25]([NH:27][CH2:28][C:29]([O:31]CC)=[O:30])=[O:26])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:34][CH3:35])=[CH:13][CH:12]=1)=[O:10].[OH-].[K+]>O.CO>[Cl:36][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH:24][C:25]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:26])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:34][CH3:35])=[CH:13][CH:12]=1)=[O:10]
Reactant: CCOC(=O)CNC(=O)Nc1ccc2oc3c(OC)ccc(C(=O)Nc4c(Cl)cncc4Cl)c3c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1oc1ccc(NC(=O)NCC(=O)O)cc12
Yield: 35.5 %

Procedure:
N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(2-ethoxy-2-oxo-ethylamino carbonylamino)-dibenzo[b,d]furan-1-carboxamide (Example 50) (150 mg, 0.28 mmol) was hydrolysed using potassium hydroxide (2 eq.) in 3 ml water and 3 ml methanol for 30 min. at room temperature. The solid precipitated was filtered and washed with methanol to obtain the product as white solid (50 mg). mp: >250° C.
Reaction SMILES: [CH2:1]=O.[NH2:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][N:13]([CH:15]3[CH2:19][NH:18][CH:17]([C:20]([NH:22][CH3:23])=[O:21])[CH2:16]3)[CH:14]=2)=[CH:6][C:5]=1[C:24]1[O:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1.[Na].N>CO.ClCCl>[NH2:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][N:13]([C@H:15]3[CH2:19][N:18]([CH3:1])[C@H:17]([C:20]([NH:22][CH3:23])=[O:21])[CH2:16]3)[CH:14]=2)=[CH:6][C:5]=1[C:24]1[O:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1
Reactant: CNC(=O)C1CC(n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)cn2)CN1
Reactant: C=O
Agent: N
Agent: [Na]
Solvent: ClCCl
Solvent: CO
Product: CNC(=O)[C@@H]1C[C@@H](n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)cn2)CN1C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
TFA (5 ml) was added to (2S,4R)-tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazol-1-yl]-2-(methylcarbamoyl)pyrrolidine-1-carboxylate under argon. The resulting solution was stirred at 25° C. for 1 hour. The solution was evaporated under reduced pressure, adsorbed with ammonia in methanol solution. The crude product was purified by flash chromatography on silica gel eluting with 1 to 6% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness to afford (2S,4R)-4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazol-1-yl]-N-methyl-pyrrolidine-2-carboxamide (38 mg) as a pale yellow solid. 37% Aqueous formaldehyde (8.42 μl) at 0° C. was added to a stirred solution 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazol-1-yl]-N-methyl-pyrrolidine-2-carboxamide (38 mg) dissolved in methanol (2 ml) and dichloromethane (2 ml) over a period of 5 minutes under argon. The resulting solution was stirred at 0° C. for 5 minutes. Sodium triacetoxyhydroborate (23.96 mg, 0.11 mmol) was added and the mixture was stirred 5 minutes at 25° C. A solution of ammonia in methanol 7N (1 ml) was added and the mixture was adsorbed on silica gel. The crude product was purified by flash chromatography on silica gel eluting with 1 to 6% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness to afford (2S,4R)-4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazol-1-yl]-N,1-dimethyl-pyrrolidine-2-carboxamide (30 mg) after overnight stirring in acetonitrile as a solid. NMR Spectrum: (DMSOd6) 2.23-2.32 (m, 1H), 2.35 (s, 3H), 2.47-2.56 (m partially hidden by DMSOd5, 1H), 2.65 (d, 3H), 2.76-2.84 (m, 1H), 3.19-3.27 (m, 1H), 3.47-3.56 (m, 1H), 4.89-4.99 (m, 1H), 7.41-7.50 (m, 2H), 7.67 (bs, 2H), 7.77-7.82 (m, 1H), 7.83-7.87 (m, 1H), 7.90 (q, 1H), 7.97 (s, 1H), 8.37 (s, 1H), 8.44 (d, 1H), 8.53 (d, 1H) Mass spectrum: M+H+ 418
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:38]([CH3:39])[C:37]4[CH:40]=[C:41]([F:44])[CH:42]=[CH:43][C:36]=4[N:35]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:38]([CH3:39])[C:37]4[CH:40]=[C:41]([F:44])[CH:42]=[CH:43][C:36]=4[N:35]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3nc4ccc(F)cc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2c(C)cc(-c3nc4ccc(F)cc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-methyl-6-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.C([Sn](CCCC)(CCCC)[CH:20]1[CH2:25][CH2:24][CH:23]=[CH:22][O:21]1)CCC>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:8][C:6]1[N:7]=[C:2]([C:24]2[CH2:23][CH2:22][O:21][CH2:20][CH:25]=2)[N:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:5]=1
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Reactant: CCCC[Sn](CCCC)(CCCC)C1CCC=CO1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: Clc1nc(C2=CCOCC2)nc(N2CCOCC2)n1
Temperature: 90 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
In a three necked flask under nitrogen equipped was dissolved 2,4-dichloro-6-morpholin-4-yl-[1,3,5]triazine (610 mg, 2.6 mmol), tributyldihydropyranylstannane (1.45 g, 3.89 mmol, 1.5 eq), and (Ph3P)2PdCl2 (150 mg, 0.21 mmol, 0.1 eq) in anhydrous dioxan (5 ml). The reaction mixture was heated under stirring to 90° C. for 16 hrs. For purification silica gel (10 g) was added to the mixture and the solvent was removed to let the product adsorbed on the silica gel. The silica gel plug was placed on a column and the mixture was flash chromatographed with hexane:ethyl acetate (10:1) to give after removal solvent the product as off white solid (345 mg=47% yield); MS (ESI) m/z 281.
Reaction SMILES: Br.Br[CH2:3][CH2:4][C:5]1[C:10](=[O:11])[N:9]2[CH2:12][CH2:13][S:14][C:8]2=[N:7][C:6]=1[CH3:15].Cl.Cl.[F:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:24][NH:25]2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)CC(=O)C>[F:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23]([CH:28]3[CH2:33][CH2:32][N:31]([CH2:3][CH2:4][C:5]4[C:10](=[O:11])[N:9]5[CH2:12][CH2:13][S:14][C:8]5=[N:7][C:6]=4[CH3:15])[CH2:30][CH2:29]3)=[N:24][NH:25]2)=[CH:21][CH:20]=1
Reactant: Fc1ccc2c(C3CCNCC3)n[nH]c2c1
Reactant: Cc1nc2n(c(=O)c1CCBr)CCS2
Agent: Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(=O)CC(C)C
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3n[nH]c4cc(F)ccc34)CC1)CCS2
Reaction time: 6 h
Yield: 48.3 %

Procedure:
A mixture of 4.4 parts of 6-(2-bromoethyl)-2,3-dihydro-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one monohydrobromide, 3.7 parts of 6-fluoro-3-(4-piperidinyl)-1H-indazole dihydrochloride, 4.25 parts of sodium carbonate and 120 parts of 4-methyl-2-pentanone was stirred for 6 hours at reflux temperature. After cooling, the reaction mixture was filtered. The precipitate was stirred in water and the whole was filtered again. The precipitated product was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 2.5 parts (48.3%) of 6-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]ethyl]-2,3-dihydro-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one; mp. 207.6° C. (compound 2).