Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[F:25][C:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[CH:28][C:27]=1[NH:41][C:42]1[O:43][C:44]2[C:50]([CH3:51])=[CH:49][C:48]([CH3:52])=[CH:47][C:45]=2[N:46]=1.NC1N=CN=C2N([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)N=C(C3C=CC(NC4OC5C=CC=CC=5N=4)=C(F)C=3)C=12>>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:30]3[CH:29]=[CH:28][C:27]([NH:41][C:42]4[O:43][C:44]5[C:50]([CH3:51])=[CH:49][C:48]([CH3:52])=[CH:47][C:45]=5[N:46]=4)=[C:26]([F:25])[CH:31]=3)[C:10]=12
Reactant: Cc1cc(C)c2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3F)nc2c1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6ccccc6o5)c(F)c4)c4c(N)ncnc43)CC2)CC1
Product: Cc1cc(C)c2oc(Nc3ccc(-c4nn([C@H]5CC[C@@H](N6CCN(C)CC6)CC5)c5ncnc(N)c45)cc3F)nc2c1

Procedure:
Cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-5,7-dimethyl-1,3-benzoxazol-2-amine was prepared from cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo [3,4-d]pyrimidin-4-amine (0.200 g, 0.453 mmol) and N2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5,7-dimethyl-1,3-benzoxazol-2-amine (0.216 g, 0.566 mmol) in a manner similar to that used for the preparation of cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-1,3-benzoxazol-2-amine. The compound was formed as a pale yellow powder (0.111 g, 43%). 1H NMR (DMSO-d6, 400 MHz) 1.56-1.83 (m, 4H), 2.15 (s, 3H), 2.22-2.55 (m, 12H), 2.34 (s, 3H), 2.41 (s, 3H), 3.22-3.53 (m, 1H), 4.78-4.83 (m, 1H), 6.81 (s, 1H), 7.10 (s, 1H), 7.45-7.53 (m, 2H), 8.23 (s, 1H), 8.49 (t, 1H), 10.59 (s, 1H); RP-HPLC Rt 11.873 min, 95% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 570 (MH+).
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[CH3:6][N:7]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3](=[O:4])[CH2:2][Br:1]
Reactant: CNCCc1ccccc1
Reactant: O=C(Cl)CBr
Solvent: ClCCl
Product: CN(CCc1ccccc1)C(=O)CBr
Temperature: -25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 27.07 g (171.95 mmol) of bromoacetyl chloride in 100 ml of methylene chloride, cooled to -25° C. by means of an external cooling bath, is added dropwise a solution of 46.5 g (343.9 mmol) of N-methyl-N-phenethyl amine in 50 ml of methylene chloride over a period of 11/2 hours. The reaction mixture is stirred at -25° C. for additional 15 minutes and then allowed to equilibrate to room temperature. The reaction mixture is then partitioned between methylene chloride and water. The organic layer is washed with 1N aqueous HCl solution and water, dried over magnesium sulfate and concentrated in vacuo to give N-methyl-N-phenethyl-2-bromoacetamide which is used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:11]=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[CH3:14][N:15](C)[CH2:16]CCN=C=NCC.ClCCl.CNC>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:11]=[O:12])=[C:6]([CH:10]=1)[C:7]([N:15]([CH3:16])[CH3:14])=[O:8]
Reactant: O=Cc1ccc(Br)cc1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CN(C)C(=O)c1cc(Br)ccc1C=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 21.9 %

Procedure:
A 100 mL round-bottom flask was charged with 5-bromo-2-formylbenzoic acid (350 mg, 1.53 mmol, 1.00 equiv), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (355 mg, 1.85 mmol, 1.20 equiv), 1-hydroxybenzotrizole (315 mg, 2.33 mmol, 1.50 equiv), dichloromethane (10 mL). The resulting solution was stirred for 15 min at room temperature. Dimethylamine (208 mg, 4.61 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature, diluted with water (20 mL), extracted with dichloromethane (3×20 mL) and the organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (50/50) to provide 86.0 mg (22% yield) of 5-bromo-2-formyl-N,N-dimethylbenzamide as light yellow oil. LCMS (ESI, m/z): 256 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([F:16])=[C:13]([OH:15])[CH:14]=2)=[N:6][CH:7]=1.Br[CH2:18][CH2:19][OH:20].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Br:1][C:2]1[CH:7]=[N:6][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([F:16])=[C:13]([CH:14]=2)[O:15][CH2:18][CH2:19][OH:20])=[N:4][CH:3]=1
Reactant: Oc1cc(Nc2ncc(Br)cn2)ccc1F
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: OCCOc1cc(Nc2ncc(Br)cn2)ccc1F

Procedure:
A solution of 5-(5-bromopyrimidin-2-ylamino)-2-fluorophenol 45 (0.25 mmol), 2-bromoethanol (0.28 mmol) and cesium carbonate (0.36 mmol) in acetonitrile (3 mL) is heated to 100° C. for 12 h. The reaction is evaporated to dryness then re-dissolved in DCM. The organic mixture is washed with water and brine then dried over magnesium sulfate, filtered and reduced to dryness to yield 2-(5-(5-bromopyrimidin-2-ylamino)-2-fluorophenoxy)ethanol 46a as a brown solid which is used without further purification. MS (m/z) (M+1)+: 329.2.
Reaction SMILES: [H-].[Na+].[C:3]([NH:7][C:8]1[CH:20]=[CH:19][C:11]([CH:12]=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=1)(=[O:6])[CH2:4][CH3:5].I[CH3:22].O>CN(C)C=O>[CH3:22][N:7]([C:8]1[CH:20]=[CH:19][C:11]([CH:12]=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=1)[C:3](=[O:6])[CH2:4][CH3:5]
Reactant: CI
Reactant: CCOC(=O)C=Cc1ccc(NC(=O)CC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C=Cc1ccc(N(C)C(=O)CC)cc1
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a suspension of sodium hydride (60% active, 31 mg) in dimethylformamide (1 ml) was added a solution of ethyl 4-propionamidocinnamate (160 mg) in dimethylformamide (2 ml) at ambient temperature under nitrogen atmosphere. The mixture was stirred for 1 hour at same temperature, and a solution of iodomethane (111 mg) in dimethylformamide (2 ml) was added thereto. The reaction mixture was stirred at same temperature for 2 hours, poured into water, and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo to give ethyl 4-(N-methylpropionamido)cinnamate (168 mg) as an oil.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:6]=[C:7]([CH:11]2[NH:23][C:21]3[C:22]4[C:13](=[N:14][NH:15][C:16](=[O:24])[C:17]=4[CH:18]=[CH:19][CH:20]=3)[CH:12]2C2C=CC=C(C(OCC)OCC)C=2)[CH:8]=[CH:9][CH:10]=1)C.[C:41](=[O:44])([O-])[O-].[K+].[K+]>Cl>[O:24]=[C:16]1[C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[NH:23][C:11]([C:7]4[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=4)[CH:4]=[O:3])([C:5]4[CH:10]=[C:9]([CH:8]=[CH:7][CH:6]=4)[CH:41]=[O:44])[CH2:12][C:13]([C:22]=23)=[N:14][NH:15]1
Reactant: CCOC(OCC)c1cccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2cccc(C(OCC)OCC)c2)c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Product: O=Cc1cccc(C2(c3cccc(C=O)c3)Cc3n[nH]c(=O)c4cccc(c34)N2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A mixture of 8,9-bis(3-(diethoxymethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (120 mg, 0.46 mmol) in 3N hydrochloric acid (5 mL) was stirred at room temperature for 2 hr. Then the mixture was adjusted to pH=8 with potassium carbonate. The resulting suspension was filtered to give 3,3′-(3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8,8-diyl)dibenzaldehyde (160 mg, yield 88%) as a light yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 4.57-4.59 (d, J=9.6 Hz, 1H), 4.98-5.00 (d, J=9.2 Hz, 1H), 7.20-7.22 (d, J=7.6 Hz, 1H), 7.42-7.52 (m, 5H), 7.60-7.77 (m, 5H), 7.89 (s, 1H), 9.90 (s, 1H), 9.93 (s, 1H), 12.08 (s, 1H); LC-MS (ESI) m/z: 396 (M+1)+.
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([CH3:14])=[C:7]([CH3:13])[C:8]=1[C:9]([O:11]C)=O)=[C:2]=[S:3].[CH3:15][C:16]1[N:20]([CH2:21][CH2:22][CH2:23][NH2:24])[CH:19]=[N:18][CH:17]=1>>[CH3:13][C:7]1[C:8]2[C:9](=[O:11])[N:24]([CH2:23][CH2:22][CH2:21][N:20]3[C:16]([CH3:15])=[CH:17][N:18]=[CH:19]3)[C:2](=[S:3])[NH:1][C:4]=2[S:5][C:6]=1[CH3:14]
Reactant: COC(=O)c1c(N=C=S)sc(C)c1C
Reactant: Cc1cncn1CCCN
Product: Cc1sc2[nH]c(=S)n(CCCn3cncc3C)c(=O)c2c1C

Procedure:
The compound was synthesized starting from methyl 2-isothiocyanato-4,5-dimethylthiophene-3-carboxylate (0.1 g, 0.44 mmol) and 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (5) (0.06 g, 0.44 mmol) as described above.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Si:25]([N:32]1[C@H:35]([CH:36]=O)[CH2:34][C:33]1=[O:38])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].C([O-])(O)=O.[Na+]>ClCCl>[Si:25]([N:32]1[C@H:35]([CH:36]=[C:1]([Br:5])[Br:2])[CH2:34][C:33]1=[O:38])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C[C@H]1C=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)N1C(=O)C[C@H]1C=C(Br)Br
Reaction time: 0.33 h
Yield: 48 %

Procedure:
To a solution of CBr4 (3.11 g) in dichloromethane (15 ml) was added dropwise a solution of triphenylphosphine (4.92 g) in dichloromethane (15 ml) at 0° C. After stirring for 10 minutes a solution of (S)-N-tert-butyldimethylsilyl-4-formyl-2-azetidinone (1.0 g) in dichloromethane (10 ml) was added dropwise at 0° C. and stirred for 20 minutes. The mixture was poured into saturated aqueous NaHCO3 solution and extracted with dichloromethane. The extract was washed with water, dried over MgSO4 and evaporated in vacuo. The residue was purified by chromatography on silica gel eluting with (diethyl ether:n-hexane=1:5) to give (S)-N-tert-butyldimethylsilyl-4-(2,2dibromoethenyl)-2-azetidinone (0.83 g) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[NH:5][C:6](=[O:14])[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9].C(N(CC)CC)C.[C:25](Cl)(Cl)=[O:26]>O1CCCC1>[F:13][C:7]([F:12])([C:8]([F:9])([F:10])[F:11])[C:6]([NH:5][C:4]1[CH:3]=[C:2]([N:1]=[C:25]=[O:26])[CH:17]=[CH:16][CH:15]=1)=[O:14]
Reactant: Nc1cccc(NC(=O)C(F)(F)C(F)(F)F)c1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C=Nc1cccc(NC(=O)C(F)(F)C(F)(F)F)c1
Temperature: -5 °C

Procedure:
Sixty-three and one half grams of m-amino pentafluoropropionanilide is dissolved in 150 ml of tetrahydrofuran containing 65 g. of triethylamine. This mixture is added dropwise with coolng to 37 g. of phosgene dissolved in 150 ml of tetrahydrofuran cooled to -5° C. When addition is complete the mixture is allowed to warm up to room temperature. The triethylamine hydrochloride is filtered off and the solvent is removed under vacuum. The product, 70 g., was not isolated but diluted to 140 ml with tetrahydrofuran and used in subsequent reactions.
Reaction SMILES: [CH2:1]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([O:25][CH2:26][C:27]#[N:28])[CH:19]=[CH:18]2)[CH2:2][CH2:3][CH2:4][CH3:5].[C:29]([C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1)([CH3:32])([CH3:31])[CH3:30]>>[C:29]([C:33]1[CH:34]=[CH:35][C:36]([CH2:37][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[C:7]2[C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[C:20]([O:25][CH2:26][C:27]#[N:28])[CH:19]=[CH:18]3)=[CH:39][CH:40]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CCCCCc1c(-c2ccc3cc(OCC#N)ccc3c2)[nH]c2ccccc12
Reactant: CC(C)(C)c1ccc(CBr)cc1
Product: CCCCCc1c(-c2ccc3cc(OCC#N)ccc3c2)n(Cc2ccc(C(C)(C)C)cc2)c2ccccc12

Procedure:
The title compound was prepared as a solid (0.191 g, 46%) from {[6-(3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetonitrile using 4-tert-butylbenzyl bromide and the procedure from step 4 of Example 2; 1H NMR (DMSO-d6) δ 0.73 (t, J=7.4 Hz, 3H), 1.08-1.27 (m, 4H), 1.17 (s, 9H), 1.48-1.65 (m, 2H), 2.69 (t, J=8.1 Hz, 2H), 5.29 (s, 2H), 5.52 (s, 2H), 6.78 (d, J=8.1 Hz, 2H), 7.05-7.14 (m, 2H), 7.18 (d, J=8.1 Hz, 2H), 7.32 (dd, J=1.4, 9.9 Hz, 1H), 7.38 (d, J=7.4, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.58-7.67 (m, 2H), 7.90-8.00 (m, 3H); mass spectrum [(+) ESI], m/z 515 (M+H)+, 537 (M+Na)+ and [(−) ESI], m/z 513 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH2:27][CH:28]2[CH2:32][CH2:31][CH2:30][O:29]2)[N:17]=[CH:16][N:15]=1>CN(C=O)C>[O:29]1[CH2:30][CH2:31][CH2:32][CH:28]1[CH2:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:18]1[N:17]=[CH:16][N:15]=[C:14]([NH:1][C:2]2[CH:3]=[C:4]([CH2:8][S:9]([NH2:12])(=[O:10])=[O:11])[CH:5]=[CH:6][CH:7]=2)[CH:19]=1
Reactant: Clc1cc(-c2ccccc2OCC2CCCO2)ncn1
Reactant: Nc1cccc(CS(N)(=O)=O)c1
Solvent: CN(C)C=O
Product: NS(=O)(=O)Cc1cccc(Nc2cc(-c3ccccc3OCC3CCCO3)ncn2)c1
Temperature: 85 °C

Procedure:
A mixture of (3-amino-phenyl)-methanesulfonamide (0.18 g, 0.62 mmol) and 4-chloro-6-[2-(tetrahydro-furan-2-ylmethoxy)-phenyl]-pyrimidine (0.115 g, 0.62 mmol) in DMF (3 mL) was stirred at 80-90° C. till the reaction completion (TLC control), then evaporated in vacuo. The resulting residue was purified by column chromatography on silica gel yielding (3-{6-[2-(tetrahydro-furan-2-ylmethoxy)-phenyl]-pyrimidin-4-ylamino}-phenyl)-methanesulfonamide (Compound 82) as white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:36]([O:38][C:39]1[CH:45]=[C:44]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH2:48][CH2:47]2)[CH:43]=[CH:42][C:40]=1[NH2:41])[CH3:37].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:41][C:40]3[CH:42]=[CH:43][C:44]([N:46]4[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH2:48][CH2:47]4)=[CH:45][C:39]=3[O:38][CH2:36][CH3:37])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1N
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 130 °C
Yield: 44 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (300 mg, 0.61 mmol), a different batch of 2-(ethyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}aniline (180 mg, 0.55 mmol), and p-toluenesulfonic acid (278 mg, 1.46 mmol) were weighed into a 40 mL vial. 25 mL of iPrOH was added and the mixture was heated to 130° C. for 48 h. The mixture was transferred to a 50 mL round bottom and neutralized with 5 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 30 mL of DCM. 3 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (190 mg, 0.242 mmol, 44%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.77 (s, 1H), 9.31 (s, 1H), 8.35 (s, 1H), 8.21 (d, J=5.31 Hz, 1H), 8.09 (d, J=2.20 Hz, 1H), 7.76 (dd, J=8.61, 2.20 Hz, 1H), 7.68 (d, J=8.97 Hz, 1H), 7.35-7.46 (m, 3H), 7.26 (d, J=8.79 Hz, 1H), 7.17 (t, J=8.06 Hz, 2H), 6.92 (t, J=6.68 Hz, 1H), 6.66 (d, J=2.38 Hz, 1H), 6.53 (d, J=5.13 Hz, 1H), 6.47 (dd, J=8.61, 2.38 Hz, 1H), 4.05 (q, J=7.08 Hz, 2H), 3.97 (s, 3H), 3.31-3.34 (m, 2H), 3.08-3.15 (m, 4H), 3.02 (s, 3H), 2.74 (t, J=6.78 Hz, 2H), 2.51-2.60 (m, 4H), 1.22 (t, J=6.96 Hz, 3H). MS (ESI): 783 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13](=O)[CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([NH2:18])=O.[OH-].[Na+]>O>[NH2:18][CH:13]([CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:14]
Reactant: COc1ccc(CCC(C)=O)cc1OC
Reactant: NC=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(CCC(C)N)cc1OC
Temperature: 210 °C

Procedure:
A mixture of 41.4 g of 4-(3,4-dimethoxy-phenyl)-2-butanone and 41.9 ml of formamide is heated at 210° C. for 20 hours, cooled to ambient, 104 ml of 10N sodium hydroxide is added and the reaction mixture heated at reflux temperature for 24 hours. The reaction is cooled, added to 200 ml of water and extracted with diethyl ether. The diethyl ether solution is washed with 10% hydrochloric acid. The aqueous layer is made basic and extracted with diethyl ether. The organic layer is dried, filtered and evaporated in vacuo. The residue is purified by chromatography (silica gel: chloroform/hexane/ethyl acetate to 5% methyl alcohol/chrloroform) to give 5.72 g of racemic 2 -amino-4 -(3,4-dimethoxyphenyl)butane.
Reaction SMILES: [Na].[C:2]([O:6][C:7]([N:9]([C:17]1[C:22]([CH3:23])=[CH:21][C:20]([CH2:24][C:25]2([CH3:35])[C:30](=[O:31])[O:29][C:28](C)([CH3:32])[O:27][C:26]2=[O:34])=[CH:19][N:18]=1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:8])([CH3:5])([CH3:4])[CH3:3].C(Cl)Cl>C(O)C>[CH2:28]([O:27][C:26](=[O:34])[C:25]([CH2:24][C:20]1[CH:19]=[N:18][C:17]([N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:7]([O:6][C:2]([CH3:5])([CH3:3])[CH3:4])=[O:8])=[C:22]([CH3:23])[CH:21]=1)([CH3:35])[C:30]([OH:31])=[O:29])[CH3:32]
Reactant: Cc1cc(CC2(C)C(=O)OC(C)(C)OC2=O)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Na]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(C)(Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C)c1)C(=O)O
Reaction time: 1 h
Yield: 101.8 %

Procedure:
A solution of sodium metal (184 mg, 8.0 mmol) in ethanol (20 mL) was added to a solution of crude 2-[N,N-bis(tert-butoxycarbonyl)amino]-3-methyl-5-(2,2,5-trimethyl-4,6-dioxo-[1,3]dioxan-5-ylmethyl)-pyridin (2.06 g, ˜4.0 mmol) in ethanol (20 mL) under argon. The reaction was stirred for 60 min. and methylene chloride was then added. The mixture was washed with 0.5 M HCl and brine, dried and concented under reduced pressure to give crude 2-(6-[N,N-bis(tert-butoxycarbonyl)amino]-5-methyl-pyridin-3-ylmethyl)-2-methyl-malonic acid monoethyl ester (1.9 g)
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH2:7]1[CH:11]2[CH2:12][CH2:13][CH2:14][CH:10]2[CH2:9][N:8]1[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.[OH-:28].[K+]>C(O)C.O>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH2:9]1[CH:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[CH2:7][N:8]1[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]([NH2:25])=[O:28])=[CH:22][CH:21]=1
Reactant: [OH-]
Reactant: N#Cc1ccc(NCCCCN2CC3CCCC3C2)cc1
Agent: O=C(O)C(=O)O
Agent: [K+]
Solvent: CCO
Solvent: O
Product: NC(=O)c1ccc(NCCCCN2CC3CCCC3C2)cc1

Procedure:
436 mg of the compound of Example 18 are dissolved in 4 ml of ethanol. 86 mg of potassium hydroxide (1 eq.) are dissolved in 1.5 ml of water before being added to the alcohol solution. The mixture is heated at reflux for 1.5 hours and then evaporated to dryness. The residue is taken up in dichloromethane. The resulting solution is washed with water, dried over magnesium sulphate and then concentrated in vacuo. The product is crystallised in oxalate form.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[C:6]([OH:17])[C:3]=1[CH:4]=[O:5].N1C=CC=CC=1.[O:24](S(C(F)(F)F)(=O)=O)[S:25]([C:28]([F:31])([F:30])[F:29])(=O)=[O:26]>ClCCl>[F:29][C:28]([F:31])([F:30])[S:25]([O:17][C:6]1[CH:7]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:9]=[C:2]([F:1])[C:3]=1[CH:4]=[O:5])(=[O:26])=[O:24]
Reactant: O=Cc1c(O)cc(OC2CCCCO2)cc1F
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=Cc1c(F)cc(OC2CCCCO2)cc1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.5 %

Procedure:
To a mixture of 2-fluoro-6-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)benzaldehyde (3.60 g, 15.0 mmol) and pyridine (5.93 g, 75.0 mmol) in dichloromethane (50 mL) was added dropwise Tf2O (6.35 g, 22.5 mmol) at −15° C. After stirring at room temperature for 3 h, the reaction was quenched by addition of iced-brine (50 mL) and extracted with dichloromethane (2×50 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (EtOAc/PE=1/8) on silica gel to give the title compound as a white solid (3.77 g, Yield: 67.5%). 1H NMR (400 MHz, DMSO-d) δ 10.12 (s, 1H), 7.26-7.30 (m, 1H), 7.04 (s, 1H), 5.78 (s, 1H), 3.62-3.71 (m, 2H), 1.80-1.87 (m, 3H), 1.56-1.64 (m, 3H). MS (ESI) m/z=373 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]([N:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.B.CO>O1CCCC1>[C:7]1([N:6]([CH2:4][CH2:3][CH2:2][Br:1])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(CCBr)N(c1ccccc1)c1ccccc1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: BrCCCN(c1ccccc1)c1ccccc1
Temperature: 21 °C

Procedure:
A solution of 304 g. (1.00 moles) of 3-bromo-N,N-diphenyl propionamide in 800 ml. of tetrahydrofuran is stirred and maintained at -3° C. to -1° C. while adding 1.1 l. of a 1 molar solution of borane in tetrahydrofuran over a period of 15 minutes. The reaction is allowed to gradually warm to 21° C. over a period of about 1.75 hours and refluxed for a period of about 10 minutes. The reaction mixture is then treated dropwise with 50 ml. of methanol. After gas evolution ceases, solvent is removed under vacuum. The oily residue is dissolved in cyclohexane, washed with 20% caustic solution and then with water, dried and passed through a column of about 400 g. of silica gel, eluting with cyclohexane, to give 3-[N,N-diphenylamino]-1-bromopropane.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([S:14]([CH3:16])=[O:15])[S:13][C:6]=12.C1C=C(Cl)C=C(C(OO)=[O:32])C=1.O>C(Cl)Cl>[F:1][C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([S:14]([CH3:16])(=[O:32])=[O:15])[S:13][C:6]=12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CS(=O)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a solution of 233 (50 mg, 0.142 mmol) in DCM (2 mL), was added mCPBA (77%, 33 mg, 0.142 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour, water was added and the phases were separated. The organic layer was collected, washed with a 1% sodium hydroxide solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford title compound 236 (46 mg, 88% yield, crude) as a yellow solid which was used in the next step without additional purification. MS (m/z): 369.0 (M+1).