Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](Cl)=[O:31])=[CH:25][CH:24]=1.[CH2:33](N(CC)CC)C>CN(C)C=O.O>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([NH:2][CH2:3][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:13])[N:8]([C:14]2([CH3:33])[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[CH2:7]3)=[O:31])=[CH:25][CH:24]=1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC1(N2Cc3cc(CNC(=O)Cc4ccc(Cl)cc4)ccc3C2=O)CCC(=O)NC1=O
Reaction time: 2 h
Yield: 45.5 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.4 g, 1.20 mmol) and 4-chlorophenylacetyl chloride (0.23 g, 1.20 mmol) in N,N-dimethylformamide (15 mL), was added triethylamine (0.34 mL, 2.40 mmol) at room temperature under nitrogen. After 2 h, the mixture was diluted with water (10 mL) and the product was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water (3×100 mL), dried (MgSO4) and concentrated in vacuo. The residue was triturated in acetonitrile (20 mL) for 2 h. The solids were isolated by filtration and washed with acetonitrile (10 mL) providing 2-(4-chloro-phenyl)-N-[2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-acetamide as a white solid (0.24 g, 44% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 50/50 CH3CN/0.1% H3PO4, 1.87 min (96.81%); mp: 230-232° C.; 1H NMR (DMSO-d6) δ 1.67 (s, 3H), 1.81-1.95 (m, 1H), 2.52-2.82 (m, 3H), 3.50 (s, 2H), 4.37 (d, J=5.9 Hz, 2H), 4.52-4.74 (m, 2H), 7.25-7.44 (m, 6H), 7.57 (d, J=7.7 Hz, 1H), 8.67 (t, J=5.8 Hz, 1H), 10.85 (s, 1H); 13C NMR (DMSO-d6) δ 20.75, 27.81, 29.01, 41.49, 42.24, 47.60, 57.12, 121.78, 122.55, 127.00, 128.15, 130.92, 130.98, 131.14, 135.28, 142.33, 143.59, 166.91, 169.87, 172.43, 173.55; Anal Calcd for C23H22ClN3O4+0.3H2O: C, 62.04; H, 5.12; N, 9.44. Found: C, 61.98; H, 4.80; N, 9.17.
Reaction SMILES: [CH:1]1([N:4]([CH3:21])[CH:5]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]3[CH:10]=[C:9]([C:17]#[CH:18])[CH:8]=[C:7]([O:19][CH3:20])[C:6]2=3)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24](=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1.C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I>[CH3:22][O:23][C:24](=[O:33])[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([C:18]#[C:17][C:9]2[CH:8]=[C:7]([O:19][CH3:20])[C:6]3[CH:5]([N:4]([CH:1]4[CH2:3][CH2:2]4)[CH3:21])[CH2:14][CH2:13][C:12]([CH3:15])([CH3:16])[C:11]=3[CH:10]=2)=[CH:30][CH:31]=1
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: C#Cc1cc(OC)c2c(c1)C(C)(C)CCC2N(C)C1CC1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2cc(OC)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1

Procedure:
Following General Procedure B and using 5-(cyclopropyl-methyl-amino)-2-ethynyl-8,8-dimethyl-4-methoxy-5,6,7,8-tetrahydro-naphthalene (Intermediate 81, 0.065 g, 0.23 mmol), methyl-4-iodophenylacetate (0.063 g, 0.23 mmol), triethyl amine (8 mL), copper(I)iodide (0.018 g, 0.093 mmol) and dichlorobis(triphenylphosphine)palladium(I) (0.065 g, 0.093 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 5-20% ethyl acetate in hexane as the eluent, the title compound was obtained as a yellow solid (0.09 g, 90%).
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[C:10]([C:18]2[O:19][N:20]=[C:21]3[C:26]=2[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])=[N:24][N:23]=[CH:22]3)[N:9]=[N:8]1.C(#N)C>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo].O>[NH2:20][C:21]1[C:26]([C:18]([C:10]2[N:9]=[N:8][N:7]([CH2:6][C:5]3[CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=[C:3]([C:2]([F:42])([F:41])[F:1])[CH:4]=3)[C:11]=2[C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)=[O:19])=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[N:24]=[N:23][CH:22]=1
Reactant: FC(F)(F)c1cc(Cn2nnc(-c3onc4cnnc(-c5ccccc5Cl)c34)c2-c2ccncc2)cc(C(F)(F)F)c1
Agent: [Mo]
Agent: [C-]#[O+]
Solvent: O
Solvent: CC#N
Product: Nc1cnnc(-c2ccccc2Cl)c1C(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccncc1
Temperature: 80 °C
Yield: 41.9 %

Procedure:
To 3-[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-4-(2-chloro-phenyl)-isoxazolo[3,4-d]pyridazine (100 mg, 0.166 mmol), add 8.0 ml of acetonitrile, and 170 μL of water, followed by molybdenum hexacarbonyl (22 mg, 0.083 mmol). Heat the mixture to 80° C. for 4 h., then cool to RT. Pour the mixture through a plug of Celite® (1 cm) and silica gel (2 cm). Concentrate and purify the residue by chromatography (silica gel, hexanes/EtOAc gradient) to provide 42 mg of a yellow solid. Exact Mass 603.1: MS (aspci): m/z=603.9 (M+1), m/z=601.9 (M−1); 1H NMR (300 MHz, CDCl3) δ 8.65–8.80 (m, 3H), 7.79 (s, 1H), 7.65 (br d, J=7.4 Hz, 1H), 7.31 (s, 2H), 7.15–7.00 (m, 2H), 6.96 (d, J=7.4 Hz, 1H), 6.87 (br t, J=7.4 Hz, 1H), 6.12 (br s, 2H), 5.21 (ABq, J=22.5, 7.5 Hz, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH:8][C:9]2[C:10]3[CH:11]=[CH:12][N:13]=[CH:14][C:15]=3[CH:16]=[CH:17][CH:18]=2)=[CH:4][C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)(Cl)Cl.O>O1CCOCC1>[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][C:34]([C:4]2[C:3]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[CH:2][N:7]=[N:6][C:5]=2[NH:8][C:9]2[C:10]3[CH:11]=[CH:12][N:13]=[CH:14][C:15]=3[CH:16]=[CH:17][CH:18]=2)=[CH:33][CH:32]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: FC(F)(F)c1ccc(-c2cc(Nc3cccc4cnccc34)nnc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1ccc(-c2cnnc(Nc3cccc4cnccc34)c2-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Yield: 34.3 %

Procedure:
To a mixture of Example 30 (0.08 g, 0.2 mmol) and 4-trifluoromethylphenylboronic acid (0.057 g, 0.3 mmol) in anhydrous dioxane (2 ml) was added (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (0.007 g, 0.009 mmol) and saturated aqueous sodium carbonate solution (0.3 ml). The mixture was irradiated in a microwave reactor at 170° C. for 10 minutes, allowed to cool to room temperature and poured onto a mixture of chloroform/water (30 ml/10 ml). The phases were separated and the aqueous phase was extracted two times more with chloroform. The combined organic layers were washed with brine, dried over sodium sulfate and adsorbed onto silica gel. Purification by flash column chromatography (ethyl acetate) yielded the title compound (35 mg, 34%) as a yellow solid. m/z (ES+) 511 (M+H+).
Reaction SMILES: C[O-].[Na+].[C:4]([CH2:6][C:7]([O:9][CH3:10])=[O:8])#[N:5].Cl[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].Cl>O.C(OC(=O)C)C.CS(C)=O>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]([N+:19]([O-:21])=[O:20])=[C:12]([CH:6]([C:4]#[N:5])[C:7]([O:9][CH3:10])=[O:8])[CH:17]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Reactant: COC(=O)CC#N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C(C#N)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 93 %

Procedure:
In a flask made of glass equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel and having an inner volume of 200 ml were charged 2.79 g (51.6 mmol) of sodium methoxide and 15 ml of dimethyl sulfoxide under argon atmosphere, and then, while stirring at room temperature, 5.16 g (51.6 mmol) of methyl cyanoacetate with a purity of 99% was gradually added dropwise over 5 minutes. Moreover, at room temperature, to the mixture was gradually added dropwise 5.00 g (25.8 mmol) of 2,4-dichloronitrobenzene with a purity of 98%, and the resulting mixture was reacted at 40 to 48° C. for 10 minutes and at 65° C. for 2 hours. After completion of the reaction, the mixture was cooled to room temperature, 100 ml of ethylacetate was added to the mixture, and 4.30 ml (25.7 mmol) of 6 mol/l hydrochloric acid and 20 ml water were gradually added dropwise while stirring. Then, the organic layer was separated, washed with 50 ml of a saturated saline solution, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting concentrate was purified by silica gel column chromatography (filler: Daisogel 1002W, eluent: hexane:ethyl acetate=9:1 (volume ratio)) to obtain 6.11 g (isolation yield: 92%) of methyl 2-(5-chloro-2-nitrophenyl)-2-cyanoacetate as yellowish crystals with a purity of 99% (areal percentage by high performance liquid chromatography).
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([C:17]([F:20])([F:19])[F:18])[CH:4]=[C:5]([NH:7][C:8]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([OH:16])=[O:15])[CH:6]=1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1)([O-:23])=[O:22].CCN=C=NCCCN(C)C>C(Cl)Cl>[F:20][C:17]([F:18])([F:19])[C:3]1[CH:4]=[C:5]([NH:7][C:8]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([O:16][C:27]2[CH:28]=[CH:29][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=2)=[O:15])[CH:6]=[CH:1][CH:2]=1
Reactant: O=C(O)c1cccnc1Nc1cccc(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)c1cccnc1Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.5 %

Procedure:
To a warmed (40° C. ) suspension of niflumic acid (10.0 g, 35.4 mmol) and 4-nitrophenol (4.9 g, 35.4 mmol) in CH2Cl2 (80 mL) was added a suspension of EDCI (6.8 g, 35.4 mmol) in CH2Cl2 (20 mL). The reaction was stirred for 16 h, and then cooled to room temperature. The solution was quenched with water (50 mL), and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were washed with water and dried over Na2SO4. The solvent was removed in vacuo, and the residue was purified by trituration with Hex:CH2Cl2 to afford 4-Nitrophenyl 2-{[3-(trifluoromethyl)phenyl]amino}nicotinate (4.5 g, 31%): LCMS RT: 4.03 min, MH+: 404.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][N:18]([C:21](Cl)=[O:22])[CH2:17][CH2:16]1.[N:24]1([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.CCN(C(C)C)C(C)C>O1CCOCC1>[N:24]1([C:31]2[CH:32]=[CH:33][C:34]([NH:37][C:21]([N:18]3[CH2:19][CH2:20][CH:15]([C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[CH:8][N:7]=4)[CH2:16][CH2:17]3)=[O:22])=[CH:35][CH:36]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Nc1ccc(N2CCCCCC2)cc1
Reactant: COc1cc2ncnc(C3CCN(C(=O)Cl)CC3)c2cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(N5CCCCCC5)cc4)CC3)c2cc1OC
Temperature: 100 °C
Reaction time: 3 h
Yield: 6.1 %

Procedure:
4-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-1-carbonyl chloride (37 mg, 0.11 mmol), prepared as described in Example 3a, was dissolved in anhydrous dioxane (2 mL) and to it was added 4-azepan-1-yl-phenylamine (19 mg, 0.1 mmol) followed by DIEA (20 uL, 0.11 mmol) and the mixture was stirred at 100° C. for 3 h. It was then concentrated in vacuo and the residue was purified by Preparative TLC (silica gel, 5% MeOH/DCM) to obtain 3 mg (6%) of pure 4-(6,7-dimethoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-azepan-1-yl-phenyl)-amide. 1H-NMR (300 MHz, CDCl3) 9.08 (s, 1H), 7.55-7.23 (m, 4H), 7.18 (d, 1H), 6.77 (d, 1H), 6.37 (s, 1H), 4.27 (m, 2H), 4.07 (s, 6H), 3.68-3.32 (m, 3H), 3.30-2.90 (m, 2H), 2.24-1.88 (m, 4H), 1.86-1.38 (m, 10H). LC/MS (ESI): 490.3 (MH)+.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24]C)=[O:23])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[OH-].[Li+]>O1CCCC1.CO.O>[F:27][C:2]([F:1])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: COC(=O)Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
In a 100 mL flask, methyl 2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acetate (3.45 g, 9.14 mmol) and lithium hydroxide.hydrate (1.15 g, 27.4 mmol) were diluted with tetrahydrofuran (24.4 mL), methanol (24.4 mL), water (12.2 mL). The reaction was stirred at room temperature for 2 hours. The solvent was evaporated and the resulting solid was diluted with water and adjusted to pH 3 with hydrogen chloride (1 N). The resulting precipitate was extracted with ethyl acetate (5×100 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated to give the title compound as a white solid (3.27 g, 96%): 1H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 9.40 (s, 1H), 8.15-8.03 (m, 4H), 7.63 (dq, J=7.9, 1.0 Hz, 2H), 7.49-7.36 (m, 2H), 3.66 (s, 2H), 3.35 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ −56.98; ESIMS m/z 364 ([M+H]+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.FC1C(F)=CC=CC=1CSC1N=C(NS(N2CCC2)(=O)=O)C=C([O:43][CH:44](CO)[CH2:45][OH:46])N=1.C(O)CO.[H-].[Na+]>C1COCC1>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=[C:2]([O:43][CH2:44][CH2:45][OH:46])[CH:7]=1
Reactant: O=S(=O)(Nc1cc(OC(CO)CO)nc(SCc2cccc(F)c2F)n1)N1CCC1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: OCCO
Solvent: C1CCOC1
Product: OCCOc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4,6-dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine ((the product of example 1 step 5 g) and ethylene glycol (1.517 g) in THF (100 ml) was added NaH (1.3 g) slowly and the reaction was then allowed to stir overnight at RT. The reaction mixture was then partitioned between EtOAc (200 ml) and H2O (200 ml). The organics were separated and the aqueous layer was re-extracted with EtOAc (2×200 ml). Organics were combined, dried (MgSO4) and reduced in vacuo and the resulting residue was purified by column chromatography on silica gel 10% EtOAc/90% iso-Hex to give the subtitle compound as a clear oil. Yield: 2.4 g
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[Br:23]N1C(=O)CCC1=O.O>O1CCCC1>[Br:23][C:12]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:10][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CS(=O)(=O)c1ccc(-c2cccn2-c2ccc(F)cc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2ccc(Br)n2-c2ccc(F)cc2)cc1
Reaction time: 1 h
Yield: 71 %

Procedure:
0.32 g (1.0 mmol) of 1-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)pyrrole (prepared as described in Example 33) was dissolved in 10 ml of anhydrous tetrahydrofuran, and 0.18 g (1.0 mmol) of N-bromosuccinimide was added to the resulting solution, whilst ice-cooling. The mixture was then stirred, whilst ice-cooling for 1 hour and then at room temperature for a further 1 hour. At the end of this time, water was added to the mixture, and the resulting mixture was extracted with methylene chloride. The organic extract was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation under reduced pressure. The resulting residue was applied to a silica gel chromatography column and eluted with a 1:3 by volume mixture of ethyl acetate and hexane, to give 0.28 g of the title compound as a white powder (yield 70%), melting at 174-176° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:23]3[CH2:26][CH2:25][CH2:24]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH2:20][CH2:21][Cl:22])[CH:11]=3)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[CH:34]1([C@H:37]([OH:39])[CH3:38])[CH2:36][CH2:35]1.[C:40](Cl)(Cl)=[O:41]>ClCCCl.CN(C1C=CN=CC=1)C.Cl>[CH:34]1([CH:37]([O:39][C:40](=[O:41])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:9]([CH:23]4[CH2:26][CH2:25][CH2:24]4)[C:10]4[C:15]([C:16]=3[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH2:20][CH2:21][Cl:22])[CH:11]=4)=[CH:4][CH:3]=2)[CH3:38])[CH2:36][CH2:35]1
Reactant: O=C(Cl)Cl
Reactant: N#Cc1c(-c2ccc(N)cc2)n(C2CCC2)c2cc(OCCCl)ccc12
Reactant: C[C@@H](O)C1CC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCCl
Product: CC(OC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCCCl)cc3n2C2CCC2)cc1)C1CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
2-(4-Amino-phenyl)-6-(2-chloro-ethoxy)-1-cyclobutyl-1H-indole-3-carbonitrile (800 mg, 2.19 mmol) was dissolved in phosgene in toluene (2M, 10 mL, 5.00 mmol) and stirred for 2 h at 80° C. in a sealed tube. Solvent was removed and the white solid obtained was suspended in 1 ml of DCE. To this solution was added (R)-1-cyclopropylethanol (400 uL, 5.28 mmol) and DMAP (268 mg, 2.19 mmol). Solution was stirred in a sealed tube for 16 h at room temperature. An aqueous workup was performed in 0.5M HCl (200 mL) and extracted with EtOAc (2×100 mL). The organic layers were combined, dried over MgSO4 and concentrated. Solid product was triturated with ether to generate 800 mg (77% yield) of {4-[6-(2-Chloro-ethoxy)-3-cyano-1-cyclobutyl-1H-indol-2-yl]-phenyl}-carbamic acid 1-cyclopropyl-ethyl ester, as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:33])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:34][O:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][N:41]([CH2:44][CH2:45][OH:46])[CH2:40][CH2:39]1.O1CCN(CCO)CC1>>[CH:30]1([C:26]2[N:25]=[C:24]([CH2:23][N:18]3[C:19]4[C:15](=[C:14]([NH:13][C:11]([C:8]5[N:5]6[CH:6]=[CH:7][C:2]([O:46][CH2:45][CH2:44][N:41]7[CH2:42][CH2:43][N:38]([CH2:37][CH2:36][O:35][CH3:34])[CH2:39][CH2:40]7)=[CH:3][C:4]6=[N:10][CH:9]=5)=[O:12])[CH:22]=[CH:21][CH:20]=4)[C:16]([CH3:33])=[N:17]3)[CH:29]=[CH:28][CH:27]=2)[CH2:31][CH2:32]1
Reactant: COCCN1CCN(CCO)CC1
Reactant: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(F)ccn34)c12
Agent: OCCN1CCOCC1
Product: COCCN1CCN(CCOc2ccn3c(C(=O)Nc4cccc5c4c(C)nn5Cc4cccc(C5CC5)n4)cnc3c2)CC1
Yield: 41 %

Procedure:
Prepared according Example 1, Step B, substituting N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide (Example 16, Steps A-G) for 7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide and 2-(4-(2-methoxyethyl)piperazin-1-yl)ethanol for 2-morpholinoethanol to give the title compound (41%). MS (APCI), positive scan, m/z=609.1 (M+H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:21][C@@H:22]([C:26]1[CH:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1)[CH2:23][CH2:24][OH:25].C(N(CC)C(C)C)(C)C>C(#N)C>[OH:25][CH2:24][CH2:23][C@@H:22]([NH:21][C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1)[C:26]1[CH:27]=[N:28][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:31]=1
Reactant: N[C@H](CCO)c1ccc(C(F)(F)F)nc1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(N2CCc3ncnc(N[C@H](CCO)c4ccc(C(F)(F)F)nc4)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (200 mg, 0.70 mmol) and (R)-3-amino-3-(6-(trifluoromethyl)pyridin-3-yl)propan-1-ol (180 mg, 0.82 mmol) in acetonitrile (2 mL) and N,N-diisopropylethylamine (0.7 mL, 4 mmol) was subjected to microwave irradiation at 185° C. for 2.5 h. The reaction mixture was concentrated and the residue was purified by semi-preparative HPLC (100×20.2 mm, C18 column; 40-60% acetonitrile-water [10 mM Et2NH]) to yield an off-white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][N:5]([CH3:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13].[S:17]([O:22]C)([O:20][CH3:21])(=[O:19])=[O:18]>C(#N)C>[CH3:21][O:20][S:17]([O-:22])(=[O:19])=[O:18].[CH3:1][N+:2]([CH3:21])([CH3:16])[CH2:3][CH2:4][N:5]([CH3:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13]
Reactant: COS(=O)(=O)OC
Reactant: CN(C)CCN(C)c1ccccc1[N+](=O)[O-]
Solvent: CC#N
Product: CN(CC[N+](C)(C)C)c1ccccc1[N+](=O)[O-]
Product: COS(=O)(=O)[O-]

Procedure:
5.0 g (22.4 mmol) of the free amine from Step 10.2 was dissolved in 50 ml of acetonitrile and to this solution was added dropwise with agitation over a period of 10 min 2.83 g (22.4 mmol) of dimethyl sulfate. The reaction temperature gradually rose to 45° C. and a precipitate formed. After an agitation period of 3 hours, the mixture was filtered and the filter cake was washed with a small amount of acetonitrile and then dried at 40° C. under vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:41])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:11]=2[NH:17][C:18](=[O:40])[C:19]2[CH:24]=[CH:23][C:22]([C:25]3[C:26](=[O:39])[N:27]([CH2:31][CH2:32][N:33]4[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]4)[CH:28]=[CH:29][CH:30]=3)=[CH:21][CH:20]=2)=[N:6][CH:7]=1.[C:42](OC(=O)C)(=[O:44])[CH3:43]>N1C=CC=CC=1>[ClH:1].[C:42]([N:36]1[CH2:35][CH2:34][N:33]([CH2:32][CH2:31][N:27]2[CH:28]=[CH:29][CH:30]=[C:25]([C:22]3[CH:23]=[CH:24][C:19]([C:18]([NH:17][C:11]4[C:12]([OH:16])=[CH:13][CH:14]=[CH:15][C:10]=4[C:9]([NH:8][C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=4)=[O:41])=[O:40])=[CH:20][CH:21]=3)[C:26]2=[O:39])[CH2:38][CH2:37]1)(=[O:44])[CH3:43]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Nc1c(O)cccc1C(=O)Nc1ccc(Cl)cn1)c1ccc(-c2cccn(CCN3CCNCC3)c2=O)cc1
Solvent: c1ccncc1
Product: CC(=O)N1CCN(CCn2cccc(-c3ccc(C(=O)Nc4c(O)cccc4C(=O)Nc4ccc(Cl)cn4)cc3)c2=O)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(5-chloropyridin-2-yl)-3-hydroxy-2-({4-[2-oxo-1-(2-piperazin-1-ylethyl)-1,2-dihydropyridin-3-yl]benzoyl}amino)benzamide (128 mg) was dissolved in pyridine (5 mL), and acetic anhydride (21 μL) was added, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, then azeotroped twice with toluene. Water was added to the residue, followed by extraction with chloroform and drying over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by NH-silica gel column chromatography (methanol/chloroform=0% to 5%). The resulting compound was dissolved in ethyl acetate and 4 N hydrochloric acid/ethyl acetate was added. The precipitate formed was collected by filtration and dried under reduced pressure to obtain 2-[(4-{1-[2-(4-acetylpiperazin-1-yl)ethyl]-2-oxo-1,2-dihydropyridin-3-yl}benzoyl)amino]-N-(5-chloropyridin-2-yl)-3-hydroxybenzamide hydrochloride (109 mg) as a yellow white solid.