Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[N:5]2[CH:11]=1.[I:12]N1C(=O)CCC1=O.C(#N)C>C(Cl)Cl>[I:12][C:11]1[N:5]2[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:4]2=[N:3][C:2]=1[CH3:1]
Reactant: Cc1cn2c(C)cccc2n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Solvent: ClCCl
Product: Cc1nc2cccc(C)n2c1I
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 2,5-dimethylimidazo[1,2-a]pyridine (0.5 g, 3.4 mmol), N-iodosuccinimide (770 mg, 3.4 mmol) and ACN (5 ml) is stirred at RT for 45 minutes. The mixture is diluted with DCM and extracted with an aqueous solution sodium thiosulfate. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 775 mg (83%). HPLC-MS: M+H=273; tR=1.02 min (METHOD—1).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][C:8]=1[OH:9])[CH3:2].[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1.O>CN(C=O)C>[Si:13]([O:9][C:8]1[CH:7]=[CH:6][C:5]([C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[CH2:1][CH3:2])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCc1cc(C(C)=O)ccc1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc(C(C)=O)ccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
To a stirred solution of 1-(3-ethyl-4-hydroxyphenyl)-1-ethanone (9.24 g, 56.27 mmol) in DMF (60 ml) was added tert-butyldimethylsilyl chloride (9.33 g, 61.9 mmol), imidazole (4.6 g, 67.52 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water. The whole was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was fractionally distilled under reduced pressure (180° C., 0.5 mmHg) to give title compound (12.3 g, 78% yield).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].Cl.Cl.[NH:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][C:27]=2[O:28][CH3:29])[N:24]=[CH:23][N:22]=[C:21]3[NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=2[F:38])[CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:37][C:33]1[C:32]([F:38])=[C:31]([CH:36]=[CH:35][CH:34]=1)[NH:30][C:21]1[C:20]2[C:25](=[CH:26][C:27]([O:28][CH3:29])=[C:18]([O:17][CH:14]3[CH2:15][CH2:16][N:11]([S:5]([CH2:4][CH2:3][CH2:2][Cl:1])(=[O:7])=[O:6])[CH2:12][CH2:13]3)[CH:19]=2)[N:24]=[CH:23][N:22]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(S(=O)(=O)CCCCl)CC1
Reaction time: 16 h
Yield: 69.1 %

Procedure:
3-chloropropanesulfonylchloride (174 mg) was added to a solution of 6-(piperidin-4-yloxy)-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline dihydrochloride (190 mg; starting material for Example 16) and diisopropylethylamine (140 mg) in methylene chloride (5 ml) at ambient temperature and the reaction mixture was stirred for 16 hours. The reaction mixture was adsorbed onto silica and the residue was purified by column chromatography on silica eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 94/6). The fractions containing the expected product were combined and evaporated under vacuum to give 4-(3-chloro-2-fluoroanilino)-6-{1-[3-chloropropylsulfonyl]piperidin-4-yloxy}-7-methoxyquinazoline as a brown gum (0.15 g); Mass Spectrum: (M+H)+ 543.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH:7]([N:10]([CH:29]([CH3:31])[CH3:30])[CH2:11][CH2:12][C@@H:13]([C:20]1[CH:25]=[C:24]([CH2:26][OH:27])[CH:23]=[CH:22][C:21]=1[OH:28])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:9])[CH3:8]>ClCCl>[CH3:3][CH:2]([C:1]([O:28][C:21]1[CH:22]=[CH:23][C:24]([CH2:26][OH:27])=[CH:25][C:20]=1[C@@H:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:12][CH2:11][N:10]([CH:7]([CH3:9])[CH3:8])[CH:29]([CH3:31])[CH3:30])=[O:5])[CH3:4]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CO)ccc1O)C(C)C
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Product: CC(C)C(=O)Oc1ccc(CO)cc1[C@H](CCN(C(C)C)C(C)C)c1ccccc1
Temperature: -3 °C

Procedure:
Drops of a solution of 18.6 g isobutyric acid chloride in 250 ml dichloromethane were added in approximately 10 minutes to a solution of 59.8 g (175.1 mol) (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenol cooled to −3° C. (A, see FIG. 1) dissolved in 750 ml dichloromethane with agitation and cooling by ice bath. A white substance precipitated after approximately 5 minutes. For this purpose, drops of a solution of 17.7 g triethylamine in 250 ml dichloromethane were added in 5 minutes under agitation and ice bath cooling. The batch was washed once with each of 250 ml water, 250 ml approximate 5% aqueous NaHCO3 solution and 250 ml water. The dichloromethane extract dried over Na2SO4 was evaporated to a low small bulk on a rotary evaporator to constant weight, whereby a sallow, high viscosity oil was left. Raw yield: 63.7 g (88.5% of the theory).
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[NH2:24][CH2:25][C@@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].CCN(CC)CC>CCO>[CH3:37][C:34]([O:33][C:31]([N:27]1[CH2:28][CH2:29][CH2:30][C@H:26]1[CH2:25][NH:24][C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:9][C:10]([F:12])([F:13])[F:11])[CH2:14][C:15]([F:16])([F:18])[F:17])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22])=[O:32])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ccc(C(=O)N(CC(F)(F)F)CC(F)(F)F)cc1[N+](=O)[O-]

Procedure:
Following the general procedure for Intermediate 2 using 4-fluoro-3-nitro-N,N-bis(2,2,2-trifluoroethyl)benzamide (130 mg, 0.373 mmol) and (S)-2-aminomethyl-1-Boc-pyrrolidine (82 mg, 0.410 mmol) in 3 mL of EtOH containing Et3N (0.080 mL, 0.559 mmol). The product was purified by flash chromatography on silica gel using 3:1/hexanes:EtOAc as eluent. Yield: 165 mg (84%); 1H NMR (CDCl3) 1.47 (brs, 9H), 1.83 (m, 1H), 1.90 (m, 2H), 2.03 (m, 1H), 3.31 (m, 1H), 3.37 (m, 2H), 3.62 (m, 1H), 4.09 (m, 2H), 4.24 (m, 6H), 7.26 (m, 1H), 7.50 (m, 1H), 8.27 (s, 1H), 8.55 (brs, 1H); MS (ESI) 529.38 (MH+).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C([O:10][C:11](=[O:42])[CH:12]([CH2:36][C:37]([O:39]CC)=[O:38])[S:13][C:14](=[O:35])[CH:15]([CH3:34])[CH2:16][C:17]1[O:18][C:19]([C:22]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31](=[NH:33])[NH2:32])=[CH:27][CH:26]=2)=[O:23])=[CH:20][CH:21]=1)C.Cl.O1CCOCC1>O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:31]([C:28]1[CH:27]=[CH:26][C:25]([O:24][C:22]([C:19]2[O:18][C:17]([CH2:16][CH:15]([CH3:34])[C:14]([S:13][CH:12]([CH2:36][C:37]([OH:39])=[O:38])[C:11]([OH:42])=[O:10])=[O:35])=[CH:21][CH:20]=2)=[O:23])=[CH:30][CH:29]=1)(=[NH:32])[NH2:33]
Reactant: CCOC(=O)CC(SC(=O)C(C)Cc1ccc(C(=O)Oc2ccc(C(=N)N)cc2)o1)C(=O)OCC
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: O
Product: CC(Cc1ccc(C(=O)Oc2ccc(C(=N)N)cc2)o1)C(=O)SC(CC(=O)O)C(=O)O
Yield: 27.4 %

Procedure:
To S-{3-[5-(4-amidinophenoxycarbonyl)furan-2-yl]-2-methylpropionyl}thiomalic acid diethyl ester trifluoroacetic acid salt (40 mg, 0.065 mmol) obtained in step 1 was added 4N hydrochloric acid/dioxane solution:water=3:1 (500 μL), and the mixture was stirred at 60° C. overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by high performance liquid chromatography (acetonitrile-water, each containing 0.1% trifluoroacetic acid, 10-45%) to give the title compound (5.0 mg, 0.0089 mmol, 14%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:43])[CH2:4][C:5]1[CH:42]=[CH:41][CH:40]=[CH:39][C:6]=1[CH2:7][CH2:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[N:10]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][NH:2][C:3](=[O:43])[CH2:4][C:5]1[CH:42]=[CH:41][CH:40]=[CH:39][C:6]=1[CH2:7][CH2:8][C:9]1[C:14]([C:15]([F:18])([F:16])[F:17])=[CH:13][N:12]=[C:11]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:24][CH:25]=2)[N:10]=1
Reactant: CNC(=O)Cc1ccccc1CCc1nc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)Cc1ccccc1CCc1nc(Nc2ccc(N3CCNCC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 94 %

Procedure:
tert-Butyl 4-(4-((4-(2-(2-(methylamino)-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (I56) (0.087 g, 0.15 mmol) was dissolved in DCM (5 mL) under an atmosphere of nitrogen. Trifluoroacetic acid (0.222 mL, 2.906 mmol) was added to the solution and the reaction was stirred at room temperature for 6 hours. Volatiles were removed in vacuo, EtOAc (70 mL) and 2 M aq. NaOH (70 mL) were added to the residue and the layers were separated. The aqueous layer was extracted with EtOAc (2×70 mL), the combined organics were washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo to give a solid which was taken up in DCM (˜10 mL) and methanol (˜1 mL) and concentrated in vacuo. The process was repeated with only DCM twice after which the sample was further dried on high-vacuum to give the title compound (I4) (0.068 g, 94% yield) as a pale yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 9.97 (s, 1H), 8.60 (s, 1H), 7.93-7.85 (m, 1H), 7.60-7.53 (m, 2H), 7.23-7.12 (m, 4H), 6.91-6.86 (m, 2H), 3.50 (s, 2H), 3.14-3.06 (m, 2H), 3.02-2.93 (m, 6H), 2.87-2.80 (m, 4H), 2.56 (d, J=4.6 Hz, 3H). LCMS Method A: rt 4.37 min; m/z 499.6 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:16]([CH3:25])=[C:17]([CH:21]=[C:22]([Cl:24])[CH:23]=2)[C:18]([OH:20])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:27][CH2:28][C:29]1[C:34](=[O:35])[CH:33]=[C:32]([CH3:36])[NH:31][C:30]=1[CH3:37].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>CN(C)C=O>[Cl:24][C:22]1[CH:21]=[C:17]([C:18](=[O:20])[NH:27][CH2:28][C:29]2[C:34](=[O:35])[CH:33]=[C:32]([CH3:36])[NH:31][C:30]=2[CH3:37])[C:16]([CH3:25])=[C:15]([CH:23]=1)[O:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1
Reactant: Cc1cc(=O)c(CN)c(C)[nH]1
Reactant: Cc1c(OC2CCN(C(=O)OC(C)(C)C)CC2)cc(Cl)cc1C(=O)O
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cc(=O)c(CNC(=O)c2cc(Cl)cc(OC3CCN(C(=O)OC(C)(C)C)CC3)c2C)c(C)[nH]1
Temperature: 0 °C
Yield: 49.9 %

Procedure:
A solution of 3-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-5-chloro-2-methylbenzoic acid (140 mg, 0.379 mmol), 3-(aminomethyl)-2,6-dimethylpyridin-4(1H)-one, hydrochloride (71.4 mg, 0.379 mmol), 1-hydroxy-7-azabenzotriazole (HOAT) (77 mg, 0.568 mmol), EDC (109 mg, 0.568 mmol) and N-methylmorpholine (166 μl, 1.514 mmol) was stirred for 18 h at RT in N,N-Dimethylformamide (DMF) (3619 μl) under nitrogen. Upon completion, the reaction was poured into stirring ice-water. White solid precipitated out of solution, which was filtered and dried under high vacuum to give tert-butyl 4-(5-chloro-3-(((2,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yl)methyl)carbamoyl)-2-methylphenoxy)piperidine-1-carboxylate (0.095 g, 0.189 mmol, 50% yield). 1H NMR (400 MHz, DMSO-d6) δ 1.41 (s, 9 H) 1.50-1.60 (m, 2 H) 1.79-1.90 (m, 2 H) 2.06 (s, 3 H) 2.16 (s, 3 H) 2.31 (s, 3 H) 3.20-3.31 (m, 2 H) 3.49-3.63 (m, 2 H) 4.19 (d, J=4.80 Hz, 2 H) 4.59-4.78 (m, 1 H) 5.87 (s, 1 H) 6.81 (d, J=2.02 Hz, 1 H) 7.15 (d, J=1.77 Hz, 1 H) 8.22 (t, J=5.05 Hz, 1 H) 11.01 (br. s., 1 H). MS(ES) [M+H]+ 504.4.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:13][CH:14]1[NH:18][C:17](=[O:19])[CH2:16][CH2:15]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCCCCC.O1CCCC1>[C:20]([N:18]1[CH:14]([O:13][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:15][CH2:16][C:17]1=[O:19])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCCCCOC1CCC(=O)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCOC1CCC(=O)N1C(=O)c1ccccc1
Reaction time: 0.33 h

Procedure:
16.5 cm3 of a 15% solution butyllithium in hexane is added at -60° C. to 4.98 g of 5-n-heptyloxy pyrrolidin-2-one in solution in 100 cm3 of tetrahydrofuran. After 20 minutes of agitation at -60° C., 3.5 g of benzoyl chloride in 25 cm3 of tetra-hydrofuran is added at this temperature. Agitation is carried out for 4 hours, allowing the mixture to return to ambient temperature. After concentration at 40° C., the residue is taken up in water, extracted with ether and concentrated to dryness. The residue is chromatographed on silica (eluent: toluene-ethyl acetate 8-2) and 1.2 g of the product sought is obtained.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:20]([O:24][C:25]([N:27]([CH2:31][CH2:32]Cl)[CH2:28][CH2:29]Cl)=[O:26])([CH3:23])([CH3:22])[CH3:21]>O1CCCC1>[C:20]([O:24][C:25]([N:27]1[CH2:31][CH2:32][C:1]2([C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: C1=Cc2ccccc2C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(C=Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
To a solution of indene (5.1 ml, 0.04 mol) in dry tetrahydrofuran (15 ml), cooled in an ice bath and maintained under an atmosphere of nitrogen, was added lithium bis (trimethylsilyl) amide (82 ml of a 1.0M solution in tetrahydrofuran, 0.08 mol), over 15 minutes. The mixture was stirred in the cold for 30 minutes, then added dropwise to a solution of N-tert-butyloxycarbonylbis (2-chloroethyl)amine (9.9 g, 0.04 mol) in tetrahydrofuran (200 ml), at 0° C. The mixture was stirred for 2 hours at this temperature, then allowed to warm to ambient temperature and stirred for a further 30 minutes. The solvent was removed in vacuo to leave a dark oil, which was chromatographed using 5:1 petrol:ether as the eluant, to give 1'-(tert-butyloxycarbonyl)spiro[indene-1,4'-piperidine] (7.1 g, 58%) as a pale yellow solid. N.M.R. (CDCl3)δ 1.28 (2H, d, J=12 Hz), 1.50 (9H, s), 2.00 (2H, t of d, J=12 and 4 Hz), 3.13 (2H, t of d, J=12 and 2 Hz), 4.20 (2H, m), 6.79 (1H, d, J=6 Hz), 6.84 (1H, d, J=6 Hz), 7.30 (4H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:32]=[C:33]([CH3:36])[C:34]=1[NH2:35])[O:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:24][CH2:23][C:22]4[CH:25]=[C:26]([O:29][CH3:30])[CH:27]=[CH:28][C:21]=4[NH:20][C:19]3=[O:31])[CH2:14][CH2:13]2)[CH:7]=1.[F:37][C:38]([F:44])([F:43])[CH2:39][C:40](O)=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(O)(=O)C>CN(C=O)C>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:21]2[NH:20][C:19](=[O:31])[N:18]([CH:15]3[CH2:14][CH2:13][N:12]([C:8]4[CH:7]=[C:6]([O:5][C:4]5[CH:32]=[C:33]([CH3:36])[C:34]6[N:35]=[C:40]([CH2:39][C:38]([F:44])([F:43])[F:37])[NH:1][C:2]=6[CH:3]=5)[N:11]=[CH:10][N:9]=4)[CH2:17][CH2:16]3)[CH2:24][CH2:23][C:22]=2[CH:25]=1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c(N)c(N)c4)ncn3)CC1)C(=O)N2
Reactant: O=C(O)CC(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c5nc(CC(F)(F)F)[nH]c5c4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.20 g (0.42 mmol) 3-{1-[6-(3,4-diamino-5-methyl-phenoxy)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one, 60 mg (0.46 mmol) 3,3,3-tri-fluoropropionic acid, 0.15 g (0.47 mmol) TBTU and 0.14 mL (1.0 mmol) TEA in 2.0 mL DMF were stirred for 4 h at RT. Then 2.0 mL glacial acetic acid was added and the mixture was stirred overnight at RT. In addition the reaction mixture was stirred for 1 h at 100° C., then cooled and purified by preparative HPLC-MS. The product-containing fractions were combined and the acetonitrile was evaporated down. The residue was made alkaline with 4N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried under HV.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[N:3]=1.[CH3:10][NH:11][CH3:12]>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([N:11]([CH3:12])[CH3:10])[CH:5]=[CH:6][C:7]=1[CH3:8].[Cl:9][C:4]1[N:3]=[C:2]([N:11]([CH3:12])[CH3:10])[C:7]([CH3:8])=[CH:6][CH:5]=1
Reactant: Cc1ccc(Cl)nc1Cl
Reactant: CNC
Solvent: ClCCl
Product: Cc1ccc(Cl)nc1N(C)C
Product: Cc1ccc(N(C)C)nc1Cl
Temperature: 80 °C
Reaction time: 16 h

Procedure:
2,6-Dichloro-3-methylpyridine (250 mg, 1.5 mmol) was dissolved in a 40% aqueous solution of dimethylamine (0.2 mL, 1.5 mmol) and stirred at 80° C. in a sealed tube for 16 hours. Then DCM was added. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo to yield (6-chloro-5-methyl-pyridin-2-yl)-dimethyl-amine and (6-chloro-3-methyl-pyridin-2-yl)-dimethyl-amine as a colorless oil that was used in the next step without further purification.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[C@@H:34]([OH:35])[CH2:33][CH2:32][NH:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.C([O:39][CH2:40][C:41](Cl)=[O:42])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[C@@H:34]([OH:35])[CH2:33][CH2:32][N:31]([C:40](=[O:39])[CH2:41][OH:42])[CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CNCC[C@@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CN(C(=O)CO)CC[C@@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-N-[(3S*,4S*)-4-hydroxypiperidin-3-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f39) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH3:37][O:38][C:39]1[CH:49]=[CH:48][C:47](/[CH:50]=[CH:51]/[C:52](=[O:65])[C:53]2[CH:58]=[C:57]([O:59][CH3:60])[C:56]([O:61][CH3:62])=[C:55]([O:63][CH3:64])[CH:54]=2)=[CH:46][C:40]=1[O:41][CH2:42][C:43](O)=[O:44]>ClCCl.O>[F:15][C:2]([F:1])([F:14])[O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([NH:11][C:43](=[O:44])[CH2:42][O:41][C:40]3[CH:46]=[C:47](/[CH:50]=[CH:51]/[C:52](=[O:65])[C:53]4[CH:54]=[C:55]([O:63][CH3:64])[C:56]([O:61][CH3:62])=[C:57]([O:59][CH3:60])[CH:58]=4)[CH:48]=[CH:49][C:39]=3[O:38][CH3:37])[S:10][C:6]=2[CH:5]=1
Reactant: COc1ccc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)cc1OCC(=O)O
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COc1ccc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)cc1OCC(=O)Nc1nc2ccc(OC(F)(F)F)cc2s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 805.1 %

Procedure:
To a solution of 6-(trifluoromethoxy)-2-aminobenzothiazole (234 mg, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{2-methoxy-5-[(E)-3-oxo-3-(3-(3,4,5-trimethoxy phenyl)-1-propenyl]phenoxy}acetic acid (2) (402 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (9j) (498 mg, 80% yield)
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][CH:34]=[CH:33][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][C:16]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:19]3[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=3[N:17]=2)[CH2:11][CH2:10]1)=[O:5].[C:37]([O:40][C:41](=[O:43])[CH3:42])(=O)[CH3:38].[OH-:44].[NH4+]>O>[C:41]([OH:40])(=[O:43])/[CH:42]=[CH:3]/[C:4]([OH:5])=[O:44].[F:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:20]2[C:19]3[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=3[N:17]=[C:16]2[CH2:15][CH:12]2[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][N:6]3[C:4](=[O:5])[C:3]4[C:2](=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:1]=[C:37]3[CH3:38])[CH2:10][CH2:11]2)=[CH:27][CH:26]=1
Reactant: [OH-]
Reactant: Nc1ccccc1C(=O)NCCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: CC(=O)OC(C)=O
Agent: [NH4+]
Solvent: O
Product: Cc1nc2ccccc2c(=O)n1CCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Product: O=C(O)/C=C/C(=O)O
Temperature: 120 °C
Yield: 72 %

Procedure:
A mixture of 4 parts of 2-amino-N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl)methyl]-1-piperidinyl]ethyl]benzamide, 20 parts of acetic acid anhydride and 40 parts of water was stirred and heated overnight at 120° C. After cooling, ice water was added. The whole was treated with ammonium hydroxide. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was converted into the (E)-2-butenedioate salt in ethanol. The salt was filtered off and dried, yielding 3.7 parts (72%) of 3-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]ethyl]-2-methyl-4(3H)-quinazolinone (E)-2-butenedioate (1:1); mp. 210.3° C. (481).
Reaction SMILES: [OH:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.N1C=CC=CC=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>C(Cl)Cl.O>[Br:9][C:5]1[CH:6]=[C:7]([NH:8][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([C:17]([F:16])([F:27])[F:28])=[CH:19][CH:20]=2)[C:2]([OH:1])=[N:3][CH:4]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Nc1cc(Br)cnc1O
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cc(Br)cnc1O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
4-(Trifluoromethyl)benzoic acid (2.45 g, 12.9 mmol) dissolved in DCM (30 ml), cooled to 0° C. and added oxalyl chloride (3.4 ml, 38.6 mmol). Catalytic amount of DMF was added to this mixture and stirred at rt for 30 mins. After 30 mins, DCM removed on rotavapour and co-distilled the residue two times with DCM to obtain 4-(trifluoromethyl)benzoyl chloride quantitatively. 2-Hydroxy-3-amino-5-bromopyridine (2.4 g, 11.1 mmol) dissolved in DCM (15 ml) and added Pyridine (1.74 g, 22 mmol) under nitrogen atmosphere. This mixture stirred at rt for 30 mins and added 4-(trifluoromethyl)benzoyl chloride (2.4 g, 13.3 mmol). After continuing stirring at rt for 30 mins, reaction mass diluted with water and extracted with DCM. DCM removed on rotavapour to obtain the crude. Crude was purified on column using 60-120 mesh silica gel and a gradient mixture of MeOH and DCM (2:98) as eluent to afford the titled compound (2.1 g) as a brown solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.43 (bs, 1H), 9.58 (s, 1H), 8.37 (d, J 2.6, 1H), 8.09 (d, J 8.2, 2H), 7.91 (d, J 8.2, 2H), 7.48 (d, J 2.6, 1H).