Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC1C(C)=C2C(C(=O)C(C3C=CC(OC)=CC=3)CO2)=CC=1.C(OC(=O)C)(=O)C.[C:29]([O:32][C:33]1[CH:54]=[CH:53][C:36]([C:37]2[C:46](=[O:47])[C:45]3[C:40](=[C:41]([CH3:52])[C:42]([O:48][C:49](=[O:51])[CH3:50])=[CH:43][CH:44]=3)[O:39][CH:38]=2)=[CH:35][CH:34]=1)(=O)C>N1C=CC=CC=1>[C:49]([O:48][C:42]1[C:41]([CH3:52])=[C:40]2[C:45]([C:46](=[O:47])[C:37]([C:36]3[CH:35]=[CH:34][C:33]([O:32][CH3:29])=[CH:54][CH:53]=3)=[CH:38][O:39]2)=[CH:44][CH:43]=1)(=[O:51])[CH3:50]
Reactant: CC(=O)Oc1ccc(-c2coc3c(C)c(OC(C)=O)ccc3c2=O)cc1
Agent: COc1ccc(C2COc3c(ccc(O)c3C)C2=O)cc1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(-c2coc3c(C)c(OC(C)=O)ccc3c2=O)cc1

Procedure:
7-Acetoxy-4′-methoxy-8-methylisoflavone was prepared from 7-hydroxy-4′-methoxy-8-methylisoflavanone (3.0 g, 10.6 mmol), acetic anhydride (10 ml) and pyridine (2.0 ml) as described for 4′,7-diacetoxy-8-methylisoflavone. Yield: (2.0 g, 58%) m.p. 190-192° C. 1H NMR (CDCl3): δ 2.31 (s, 3H, CH3), 2.38 (s, 3H, OCOCH3), 3.84 (s, 3H, OMe), 6.98 (d, 2H, J 8.7 Hz, ArH), 7.12 (d, 1H, J 8.6 Hz, H6), 7.52 (d, 2H, J 8.7 Hz, ArH), 8.03 (s, 1H, H2), 8.18 (d, 1H, J 8.6 Hz, H5). Mass spectrum: 325 (M+1, 13%); 324 (M, 58%); 282 (100); 281 (42).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[C:7](=[O:12])O[C:5]2=[O:13].[NH2:14][CH2:15][C:16]([OH:18])=[O:17]>C1(C)C(C)=CC=CC=1>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4](=[CH:3][C:2]=1[Cl:1])[C:5](=[O:13])[N:14]([CH2:15][C:16]([OH:18])=[O:17])[C:7]2=[O:12]
Reactant: NCC(=O)O
Reactant: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Solvent: Cc1ccccc1C
Product: O=C(O)CN1C(=O)c2cc(Cl)c(Cl)cc2C1=O
Temperature: 160 °C
Yield: 92.2 %

Procedure:
To a solution of 5,6-dichloroisobenzofuran-1,3-dione (2 g, 9.22 mmol) in xylene (10 ml), 2-aminoacetic acid (0.761 g, 10.14 mmol) was added, and the reaction was heated at 160° C. for 40 hours. The precipitate that formed during the reaction was filtered, washed with water and hexanes and dried affording 2-(5,6-dichloro-1,3-dioxoisoindolin-2-yl)acetic acid (2.33 g, 8.50 mmol, 92% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.O=S(Cl)Cl.CCOC(C)=O.[NH4+:25].[OH-]>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[C:5]([C:6]([NH2:25])=[O:7])=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: O=C(O)c1cnc(Cl)cc1C(F)(F)F
Agent: [OH-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: NC(=O)c1cnc(Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
6-Chloro-4-(trifluoromethyl)nicotinic acid (1.0 g, 4.4 mmol, Oakwood) was dissolved in DCM (44 mL) to give a clear solution. SOCl2 (3.2 mL, 44 mmol) was added drop-wise and the reaction mixture was stirred at room temperature overnight and then at reflux for about 16 h. The mixture was concentrated under reduced pressure to give a yellow oil that was dissolved into EtOAc (10 mL). The solution was added drop-wise to a rapidly stirred mixture of EtOAc (20 mL) and concentrated aqueous NH4OH (22 mL, 580 mmol). The resulting cloudy mixture was stirred for about 2 h and separated. The aqueous layer was further extracted with EtOAc (30 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 6-chloro-4-(trifluoromethyl)nicotinamide (0.85 g, 85%) as off-white solid: LC/MS (Table 2, Method a) Rt=1.62 min; MS m/z: 223 (M+H)+.
Reaction SMILES: C(=[N:8][N:9]=[C:10]1[N:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:13](=[O:21])[CH2:12][N:11]1[CH2:22][C:23]([O:25]C)=O)C1C=CC=CC=1>Cl>[CH2:19]([O:18][C:16]([CH2:15][N:14]1[C:13](=[O:21])[CH2:12][N:11]2[C:10]1=[N:9][NH:8][C:23](=[O:25])[CH2:22]2)=[O:17])[CH3:20]
Reactant: CCOC(=O)CN1C(=O)CN(CC(=O)OC)C1=NN=Cc1ccccc1
Agent: Cl
Product: CCOC(=O)CN1C(=O)CN2CC(=O)NN=C21
Yield: 39.1 %

Procedure:
To 230 mg of the 2-benzylidenehydrazono-3-ethoxycarbonylmethyl-1-methoxycarbonylmethylimidazolidin-4-one obtained in the above Referential Example 2 was added 10 ml of 0.5N hydrochloric acid and the mixture was steam-distilled for 40 minutes. After cooling, the reaction mixture was concentrated under reduced pressure and the residue was charged on silica gel column chromatography, followed by elution with a mixed solvent of chloroform and ethyl acetate (1:2 (v/v)). Thus 60 mg of 7-ethoxycarbonylmethyl-1,4,5,7-tetraazabicyclo[4.3.0]nonan-5-en-3,8-dione was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:23]=[C:22]([O:24][CH3:25])[C:21]([F:26])=[CH:20][C:11]=1[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13].[C:27](OC(=O)C)(=O)C.C([O-])([O-])OCC.C(OCC)(=O)C>O1CCOCC1.C(OCC)C.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:10]2[C:11](=[CH:20][C:21]([F:26])=[C:22]([O:24][CH3:25])[N:23]=2)[C:12](=[O:13])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:27]1
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CC(=O)c1cc(F)c(OC)nc1Nc1ccc(F)cc1F
Agent: CCOC([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(OC)c(F)cc2c1=O
Yield: 43.8 %

Procedure:
In 1 ml of dioxane were dissolved 100 mg of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-methoxynicotinoyl]acetate, 55 mg of acetic anhydride and 60 mg of ethyl ortho-formate, and the resulting solution was subjected to reaction under reflux for 7 hours. Subsequently, the reaction mixture was added to a mixture of 3 ml of ethyl acetate and 3 ml of water, and the organic layer was separated, washed successively with 3 ml of water and 3 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the crystalline material thus obtained was added 1 ml of diethyl ether, after which crystals were collected by filtration to obtain 45 mg (yield 43.8%) of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-7-methoxy-4-oxo-1,8-naphthyridine-3-carboxylate. The physical properties of this compound were identical with those of the compound obtained in Example 41.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][N:6]([CH:13]([CH2:17][CH2:18][C:19](=[O:21])[NH2:20])[C:14](O)=[O:15])[C:7]2=[O:12])#[N:2]>C(#N)C>[O:15]=[C:14]1[CH:13]([N:6]2[CH2:5][C:4]3[C:3]([C:1]#[N:2])=[CH:11][CH:10]=[CH:9][C:8]=3[C:7]2=[O:12])[CH2:17][CH2:18][C:19](=[O:21])[NH:20]1
Reactant: N#Cc1cccc2c1CN(C(CCC(N)=O)C(=O)O)C2=O
Solvent: CC#N
Product: N#Cc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Yield: 78.2 %

Procedure:
A mixture of 2-(4-cyano-1-oxoisoindolin-2-yl)-4carbamoylbutanoic acid (0.6 g, 2.09 mmol) and 1,1-carbonyldiimidazole (0.44 g, 2.72 mmol) in acetonitrile (20 mL) was heated to reflux for 2 hours. The mixture was cooled to room temperature and filtered to give 2-(2,6-dioxo(3-piperidyl))-1-oxoisoindoline-4-carbonitrile (0.44 g, 83%) as a white solid: mp 312-314° C.; 1H NMR (DMSO-d6) δ 11.04 (s, 1H), 8.16 (d, J=7.0 Hz, 1H), 8.06 (d, J=7.1 Hz, 1H), 7.74 (t, J=7.7 Hz, 1H), 5.20-5.13 (dd, J=5.2 and 13.2 Hz, 1H), 4.69 (d, J=18.1 Hz, 1H), 4.57 (d, J=18.1 Hz, 1H), 2.97-2.85 (m, 1H), 2.64-2.45 (m, 2H), 2.05-1.97 (m, 1H); 13C NMR (DMSO-d6) δ 172.81, 170.69, 166.49, 145.36, 135.37, 132.85, 129.36, 127.91, 116.01, 107.09, 51.77, 46.72, 31.14, 22.22; Anal. Calcd. For C14H11N3O3: C, 62.45; H, 4.12; N, 15.61. Found: C, 62.26; H, 4.10; N, 15.51.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[O:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]>FC(F)(F)C(O)=O.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[O:24][CH2:23][CH2:22][NH:21][CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](CN2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C[C@H]2CNCCO2)CC1
Reaction time: 1 h
Yield: 161.2 %

Procedure:
Trifluoroacetic acid/Dichloromethane (20 ml, 1:1) was added to tert-butyl (2S)-2-[(4-{[(3,4-dichlorophenyl)amino]-carbonyl}piperazin-1-yl)methyl]morpholine-4-carboxylate (2.10 g) under argon and stirred for 1 h. The solvent was then removed on a rotavapor and azeotroped (2×20 ml) with toluene and dried for 24 h under high vacuum to afford the title compound (2.67 g) as a brown oil which was used without further purification.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.Cl.CN.C[CH2:27][N:28](C(C)C)C(C)C>>[CH3:22][C:3]1[C:2]([NH:28][CH3:27])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Product: CNc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1C
Temperature: 100 °C
Yield: 16 %

Procedure:
Prepared similarly to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 67 mg, 0.226 mmol), methanamine hydrochloride (30.5 mg, 0.452 mmol; Sigma-Aldrich), and DIPEA (197 μl, 1.131 mmol), heating at 100° C. for 3 h. Purification by silica gel (100% DCM to 5% 2 M NH3 in MeOH/DCM) provided 2-(2-methyl-3-(methylamino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (16% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.53 (s, 3H) 2.88 (t, J=6.85 Hz, 2H) 3.05 (d, J=4.50 Hz, 3H) 3.43 (td, J=6.80, 2.25 Hz, 2H) 6.94-6.98 (m, 1H) 7.13 (d, J=1.96 Hz, 1H) 7.32 (t, J=7.73 Hz, 1H) 7.37-7.43 (m, 1H) 7.58 (d, J=6.85 Hz, 1H) 7.90 (d, J=6.46 Hz, 1H) 12.24 (br. s., 1H). MS (ESI, pos. ion) m/z: 308.1 (M+1).
Reaction SMILES: FC(F)(F)S(O[CH2:7][C:8]([F:18])([F:17])[CH2:9][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)(=O)=O.[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.[K]>CN(C)C=O>[F:17][C:8]([F:18])([CH2:7][N:25]1[C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]2[C:21]1=[O:31])[CH2:9][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=S(=O)(OCC(F)(F)COC1CCCCO1)C(F)(F)F
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC(F)(F)COC1CCCCO1
Temperature: 85 °C

Procedure:
A mixture of 2,2-difluoro-3-tetrahydropyranyloxypropyl trifluoromethanesulfonate (2.3 g, 7 mmol), potassium phthalimide (1.4 g, 7.7 mmol) and anhydrous dimethylformamide (50 ml) under nitrogen was stirred and heated at 85° C. overnight. After cooling, salts are filtered off, and the solvent was removed in vacuo. The residue was taken up in dichloromethane (100 ml), washed with 0.5M NaOH (30 ml) and brine. The organic phase was separated, dried over magnesium sulfate and concentrated. The desired compound 2,2-difluoro-3-phthalimido-1-tetrahydropyranyloxypropane was purified by flash chromatography on silica gel (ethyl acetate:hexane; 20:80) (2 g, 90%).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[C:13]12([C:23](=[O:32])[CH2:24][CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2.CI>C1COCC1.CCCCCC>[C:13]12([C:23](=[O:32])[CH:24]([CH3:1])[CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2
Reactant: O=C(CCc1cccnc1)C12CC3CC(CC(C3)C1)C2
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC(Cc1cccnc1)C(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 73 %

Procedure:
To a stirred solution of diisopropylamine (0.42 ml, 3.0 mmol) in THF (10 ml) at 0° C. was added butyllithium (1.6M; 1.87 ml, 3.0 ml) in hexane followed after 5 minutes by a solution of 1-(1-adamantyl)-3-(3-pyridyl)propan-1-one in THF (8 ml). After stirring for a further 20 min at 0° C., methyl iodide (0.19 ml, 3.0 mmol) was added dropwise and the solution was allowed to attain room temperature. After 1 hr the mixture was partitioned between ether and water. The ether extracts were dried (Na2CO3) and concentrated. Chromatography on elution with petrol-ether-triethylamine 100:50:1 afforded the title compound (0.62g, 73%), which crystallised from pentane, m.p 69-70 C; IR νmax 1696 cm-1 ; 1H-NMR (CDCl3) δ1.06 (3H,d,J 6.7 Hz, CHCH3) 1.51-1.72 (12H, m, adamantyl CH2), 1.96 (3H, s, adamantyl CH), 2.57 and 2.92 (2H, m, CHCH2), 3.28 (1H, m, CHCH3), 7.18 (1H, m, Py 5-H), 7.43 (1H, m, Py 4-H), 8.43 (2H, m, Py 6-H and 2-H); MS m/z 283 (M+). Anal. Calcd: C, 80.52; H, 8.89; N, 4.94. Found: C, 80.56; H, 8.95; N, 4.91%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[N:20]=[C:19]3[N:21]([CH3:35])[C:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][C:23]=4[C:18]3=[CH:17][CH:16]=2)[C:11](=[O:36])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[N:20]=[C:19]3[N:21]([CH3:35])[C:22]4[CH2:27][CH2:26][NH:25][CH2:24][C:23]=4[C:18]3=[CH:17][CH:16]=2)[C:11](=[O:36])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)nc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CO
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)nc31)CNCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.5 %

Procedure:
tert-Butyl 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-9-methyl-5,7,8,9-tetrahydro-6H-pyrido[3′,4′:4,5]pyrrolo[2,3-b]pyridine-6-carboxylate (0.51 g, 1.1 mmol) was treated with 1.25 M HCl in MeOH (25 mL), and the resulting solution was stirred at ambient temperature for 18 h. The solution was concentrated to dryness under reduced pressure. The resulting residue was diluted with CH2Cl2 (30 mL) and washed with saturated NaHCO3 solution (50 mL). The resulting layers were separated, and the aqueous phase was extracted with CH2Cl2 (3×30 mL). The combined organic extractions were dried over Na2SO4 and concentrated under reduced pressure to dryness. Flash chromatography (40 g ISCO column, CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 4 column volumes, increased to 0:100 over 4 column volumes and held for 10 column volumes) provided the title compound (0.24 g, 59%) as an off-white film: 1H NMR (300 MHz, DMSO-d6) δ 7.87 (d, J=8.1 Hz, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.49-7.37 (m, 5H), 7.23 (d, J=8.1 Hz, 1H), 6.15 (dd, J=7.5, 2.7 Hz, 1H), 5.98 (d, J=2.7 Hz, 1H), 5.16 (s, 2H), 3.87 (s, 2H), 3.65 (s, 3H), 3.07 (t, J=5.1 Hz, 2H), 2.79-2.61 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8]([CH2:12][OH:13])=[C:7]([CH3:14])[C:6]=2[CH:15]=1.[C:16]([C:18]1[CH:19]=[CH:20][C:21]([C:24](O)=[O:25])=[N:22][CH:23]=1)#[N:17]>>[C:16]([C:18]1[CH:19]=[CH:20][C:21]([C:24]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH2:9][C:8]([CH2:12][OH:13])=[C:7]([CH3:14])[C:6]=3[CH:15]=2)=[O:25])=[N:22][CH:23]=1)#[N:17]
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: CC1=C(CO)CCCc2ccc(N)cc21
Product: CC1=C(CO)CCCc2ccc(NC(=O)c3ccc(C#N)cn3)cc21

Procedure:
In a manner similar to the procedure of step 3A, (E)-(2-amino-9-methyl-6,7-dihydro-5H-benzo[7]annulen-8-yl)methanol from preparation J was coupled with 5-cyanopicolinic acid to afford the titled compound of Step 44A. 1H NMR (500 HMz, chloroform-d) δ 9.84 (s, 1H), 8.90 (dd, J=2.0, 0.8 Hz, 1H), 8.45 (dd, J=8.1, 0.8 Hz, 1H), 8.21 (dd, J=8.1, 2.0 Hz, 1H), 7.68 (d, J=2.3 Hz, 1H), 7.56 (dd, J=8.1, 2.3 Hz, 1H), 7.21 (d, J=8.2 Hz, 1H), 4.41 (s, 2H), 2.56 (t, J=7.0 Hz, 2H), 2.16 (s, 3H), 2.12 (quin, J=7.1 Hz, 2H), 2.02-1.96 (m, 2H), 1.57 (br. s., 1H).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[N:66]1[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=1[CH2:72][NH2:73]>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:73][CH2:72][C:67]5[CH:68]=[CH:69][CH:70]=[CH:71][N:66]=5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCc1ccccn1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc(C(=O)NCc2ccccn2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.08 h
Yield: 70.7 %

Procedure:
A mixture of 0.045 g (0.1 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (I-22), 0.042 g (0.110 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.052 ml (0.300 mmole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.013 g (0.12 mmole) 2-pyridinemethanamine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with water-acetonitrile (gradient, 0:100-80:20) to give 0.038 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-pyridin-2-ylmethyl-benzamide (I-109) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:21][CH:20]=2)[C:7]2[C:12]([C:13]=1[C:14]([O:16][CH3:17])=[O:15])=[CH:11][C:10]([OH:18])=[CH:9][CH:8]=2)=[O:4].[Cl:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1>>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:23][CH:24]=2)[C:7]2[C:12]([C:13]=1[C:14]([O:16][CH3:17])=[O:15])=[CH:11][C:10]([O:18][C:34]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:29])[CH:35]=1)=[CH:9][CH:8]=2)=[O:4]
Reactant: COC(=O)c1c(C(=O)OC)n(-c2ccc(OC(C)C)cc2)c2ccc(O)cc12
Reactant: OB(O)c1cccc(Cl)c1
Product: COC(=O)c1c(C(=O)OC)n(-c2ccc(OC(C)C)cc2)c2ccc(Oc3cccc(Cl)c3)cc12

Procedure:
The sub-title compound was prepared in accordance with step (a) Example 18 from 5-hydroxyindole-1-(4-isopropoxyphenyl)-2,3-dicarboxylic acid dimethyl ester (150 mg-0.39 mmol, see step (a) Example 19) and 3-chlorophenylboronic acid (120 mg, 0.78 mmol). Yield 93 mg (49%).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]([CH3:39])[C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([NH:21][C:22]3[N:27]=[C:26]([C:28]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]([CH3:37])[CH:29]=4)[CH:25]=[CH:24][N:23]=3)=[CH:15][C:14]=2[NH2:38])[CH2:9]1>C(Cl)Cl>[CH3:39][N:7]([CH3:6])[C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([NH:21][C:22]3[N:27]=[C:26]([C:28]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]([CH3:37])[CH:29]=4)[CH:25]=[CH:24][N:23]=3)=[CH:15][C:14]=2[NH:38][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:9]1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CC[C@H](N(C)C)C2)c(N)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cn(C)c4ccccc34)n2)c(OC)cc1N1CC[C@H](N(C)C)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 36.4 %

Procedure:
A solution of acryloyl chloride (1M in CH2Cl2, 0.36 mL, 0.36 mmol) was added dropwise to a solution of 4-[(3S)-3-dimethylaminopyrrolidin-1-yl]-6-methoxy-N-[4-(1-methy-lindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 148, 183 mg, 0.40 mmol) in CH2Cl2 (5 mL) at −10° C. over a period of 2 minutes under an atmosphere of N2. The resulting mixture was stirred at 0° C. for 10 minutes and was then allowed to warm to r.t. over 20 minutes. The mixture was then washed with sat. NaHCO3 (2 mL), dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 3-25% CH3OH in CH2Cl2 gave an oil which later crystallised. This solid was triturated and washed with EtOAc (3 mL) to give the title compound (67 mg, 33%) as a pale yellow solid; 1H NMR: 1.77 (1H, m), 2.08 (1H, s), 2.18 (6H, s), 2.72 (1H, m), 3.17 (1H, s), 3.21 (2H, d), 3.32-3.45 (1H, m), 3.87 (3H, s), 3.89 (3H, s), 5.70 (1H, d), 6.22 (1H, d), 6.48-6.58 (1H, m), 6.59 (1H, s), 7.20 (3H, m), 7.51 (1H, d), 7.76 (1H, s), 8.17 (1H, s), 8.28 (1H, d), 8.32 (1H, d), 8.39 (1H, s), 9.33 (1H, s); m/z: ES+ MH+ 512.7.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>[Cl:1][CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=1
Reactant: O=C(CCl)Nc1ccccc1Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: ClCc1nc2ccccc2n1-c1ccccc1
Temperature: 25 °C
Yield: 36.5 %

Procedure:
A solution of 2-chloro-N-(2-anilinophenyl)acetamide (10 g) and p-toluenesulfonic acid monohydrate (4.5 g) in benzene (250 ml) was refluxed for 1.5 hours under an azeotropic dehydration. After being cooled to ambient temperature, the reaction mixture was diluted with an aqueous sodium bicarbonate solution and extracted with ethyl acetate three times. The combined organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel (100 g) with dichloromethane as an eluent to afford 2-chloromethyl-1-phenyl-1H-benzimidazole (3.4 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH2:17][O:18][CH3:19])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[CH:35]=[CH:34][N:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:11]1[C:12]([N:14]([CH2:16][CH2:17][O:18][CH3:19])[CH3:15])=[CH:13][C:8]2[N:7]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[CH:35]=[CH:34][N:33]=[N:32]4)[CH:26]=3)[CH2:23][C:22](=[O:37])[NH:21][C:9]=2[CH:10]=1
Reactant: COCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3ccnn3)c1)=N2

Procedure:
The title compound was prepared from {4-chloro-5-[(2-methoxy-ethyl)-methyl-amino]-2-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert.-butyl ester (Example M14) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (69 mg).
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[F:14][C:15]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18].[Cl:25]C(Cl)(Cl)C(Cl)(Cl)Cl.Cl>CCCCCC.O1CCCC1.O>[F:14][C:15]1[C:23]([Cl:25])=[C:22]([F:24])[CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18]
Reactant: O=C(O)c1ccc(F)cc1F
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(F)c(Cl)c1F
Temperature: -70 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
294 ml (0.471 mol) of a 1.6N solution of n-butyllithium in hexane are added dropwise and at -70° C. to a solution of 71 ml (0.471 mol) of tetramethylethylenediamine (TMEDA) in 300 ml of dry tetrahydrofuran (THF). 33.8 g (0.214 mol) of 2,4-difluorobenzoic acid, in 100 ml of dry tetrahydrofuran (THF), are added dropwise with stirring, under argon and at -70° C., to the above solution. After stirring for one hour, 111.5 g (0.471 mol) of hexachloroethane in solution in 150 ml of dry THF are run in. After two hours at -70° C., the temperature is allowed to return to 10° C. The reaction mixture is hydrolysed with 150 ml of ice-cooled water and brought to a pH of approximately 1 by addition of 3N hydrochloric acid. The aqueous phase is extracted with ether, dried over magnesium sulphate and concentrated. The residue is recrystallised from heptane/ether. 16.5 g (yield 40%) of 2,4-difluoro-3-chlorobenzoic acid are obtained.