Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)=[CH:10][CH:9]=[C:8]([CH2:19][CH3:20])[N:7]=1)=[O:5])C.[OH-].[Li+]>C1COCC1.C(O)C>[CH2:19]([C:8]1[N:7]=[C:6]([C:4]([OH:5])=[O:3])[C:11]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)=[CH:10][CH:9]=1)[CH3:20]
Reactant: CCOC(=O)c1nc(CC)ccc1Nc1cncnc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1ccc(Nc2cncnc2)c(C(=O)O)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
6-Ethyl-3-(pyrimidin-5-ylamino)-pyridine-2-carboxylic acid ethyl ester (prepared according to US 2006/199960; 200 mg, 0.73 mmol) was dissolved in a THF/ethanol (12 ml/3 ml) mixture, cooled to 0° C. and treated with lithium hydroxide (2.2 ml, 1N aqueous solution). The reaction mixture was allowed to warm-up to ambient temperature and stirring was continued at that temperature for 2 hours. The pH value was subsequently adjusted to acidic and the reaction mixture was extracted with dichloromethane (3×40 ml). The combined organic phases were dried and evaporated to yield the product as light yellow solid (175 mg, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH2:14][O:15][CH3:16])[C:8]=1[O:9][C:10](=[O:13])[NH:11][CH3:12])[NH2:5].C(N(CC)C1C=CC=CC=1)C.Cl[C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:29](=[O:30])[O:31][CH:32]([CH3:34])[CH3:33])[CH:6]=[C:7]([CH2:14][O:15][CH3:16])[C:8]=1[O:9][C:10](=[O:13])[NH:11][CH3:12]
Reactant: CC(C)OC(=O)Cl
Reactant: CNC(=O)Oc1c(Cl)cc(N)cc1COC
Solvent: CCN(CC)c1ccccc1
Solvent: Cc1ccccc1
Product: CNC(=O)Oc1c(Cl)cc(NC(=O)OC(C)C)cc1COC
Temperature: 0 °C
Reaction time: 12 h
Yield: 90.2 %

Procedure:
3-Chloro-4-methylcarbamoyloxy-5-methoxymethylaniline (1.0 g) and N,N-diethylaniline (0.90 g) were dissolved in toluene (15 ml). To the resultant solution was dropwise added isopropyl chloroformate (0.75 g) in 5 minutes under ice-cooling. The resultant mixture was allowed to stand at room temperature for 12 hours, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of benzene and tetrahydrofuran as the eluent to give isopropyl N-(3-chloro- 4-methylcarbamoyloxy-5-methoxymethylphenyl)carbamate (1.22 g) in a yield of 90.5%. M.P., 113°-114° C.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5](=[O:14])[NH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.CCN(C(C)C)C(C)C>C(O)CO>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5]([OH:14])=[N:4][CH:3]=[C:2]2[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: C1COCCN1
Reactant: COc1ccc2c(=O)[nH]cc(Br)c2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: OCCO
Product: COc1ccc2c(O)ncc(N3CCOCC3)c2c1
Yield: 56.6 %

Procedure:
To a solution of 4-bromo-6-methoxyisoquinolin-1(2H)-one (0.5 g, 1.968 mmol) and morpholine (0.429 g, 4.92 mmol) in ethylene glycol (2.5 ml) was added DIPEA (1.031 ml, 5.90 mmol). The reaction was irradiated in a microwave at 145° C. for 1.5 h. The reaction mixture was adsorbed on silica was purified by silica gel chromatography (30% ethyl acetate in pet ether) to get desired compound (0.29 g, 53.8%) as solid. 1H NMR (400 MHz, CDCl3): δ ppm 10.98(s, 1H), 8.11 (s, 1H), 7.24-7.11 (m, 3H), 3.88 (s, 3H), 3.56-3.55 (m, 4H), 2.52-2.51 (m, 4H); MS: MS m/z 261 (M++1).
Reaction SMILES: [C:1]1([C:7]2[N:11]3[C:12](=[O:20])[C:13]([CH2:17][CH2:18]Cl)=[C:14]([CH3:16])[N:15]=[C:10]3[S:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:21][C:22]1[CH:36]=[CH:35][C:25]2[C:26]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:27][O:28][C:24]=2[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CN(C)C=O>[F:21][C:22]1[CH:36]=[CH:35][C:25]2[C:26]([CH:29]3[CH2:30][CH2:31][N:32]([CH2:18][CH2:17][C:13]4[C:12](=[O:20])[N:11]5[C:7]([C:1]6[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=6)=[CH:8][S:9][C:10]5=[N:15][C:14]=4[CH3:16])[CH2:33][CH2:34]3)=[N:27][O:28][C:24]=2[CH:23]=1
Reactant: Cc1nc2scc(-c3ccccc3)n2c(=O)c1CCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2scc(-c3ccccc3)n2c(=O)c1CCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 20 °C

Procedure:
In 50 ml de N,N-dimethylformamide, 3.12 g (10.2 mmoles) of 3-phenyl-6-(2-chloroethyl)-7-methyl-thiazolo[3,2-a]pyrimidin-5-one, 2.23 g (10.2 mmoles) of 6-fluoro-3-(4-piperidinyl)-benzisoxazol, 4.50 g (32.5 mmoles) of potassium carbonate and a catalytic amount of potassium iodide were suspended. The reaction mixture was heated for 18 hours at a temperature ranging between 85° and 90° C., cooled to 20° C. and poured into 100 ml of water. The solid formed was purified on silica gel column, using acetonitrile/methanol as eluent. 2.1 g of 6-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-3-phenyl-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one, mp 76°-91° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][NH2:9])=O.Cl[C:11]1[N:16]=[N:15][C:14]([S:17][CH:18](C)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=1>CCCCO>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:16]2[N:15]=[C:14]([S:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:13]=[CH:12][C:11]2=[N:9][N:8]=1
Reactant: NNC(=O)c1cccs1
Reactant: CCOC(=O)C(C)Sc1ccc(Cl)nn1
Solvent: CCCCO
Product: CCOC(=O)CSc1ccc2nnc(-c3cccs3)n2n1
Temperature: 142.5 °C

Procedure:
To 2-thiophenecarbohydrazide (215 mg, 1.5 mmol) dissolved in n-BuOH (3 mL) was added ethyl 2-((6-chloropyridazin-3-yl)thio)propanoate (232 mg, 1 mmol), and the whole was heated for 5 h in a 140-145° C. oil bath. The reaction mixture was then cooled to room temperature (˜25° C.), and the solid residue removed by filtration. The filtrate was then diluted with methylene chloride (50 mL), and washed with saturated with NaHCO3 (˜15 mL). The combined aqueous layers were washed twice with methylene chloride, and the organic layers were then combined, washed with brine, dried over MgSO4, filtered, and evaporated. The resulting solid was then recrystallized from EtOH to give ethyl 2-((3-(thiophen-2-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thio)acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][N:16]4C(=O)C5=CC=CC=C5C4=O)=[CH:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])[C:6]=2[CH:34]=1.O.NN>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][NH2:16])=[CH:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])[C:6]=2[CH:34]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1cnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
A suspension of 8-chloro-1-(phthalimidomethyl)-6-(o-chlorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine (2.14g, 4.4 mmole) and hydrazine hydrate (1 g, 22 mmole) in 75ml. of absolute ethanol is stirred at room temperature under nitrogen for 20 hours. The white solid which precipitates is removed by filtration. Theethanol solution is evaporated to dryness in vacuo and the residue is dissolved in chloroform. The chloroform solution is washed with water, then with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated in vacuo to give 1.56 g. (100%) of yellow oil. This oil is alkylated without any purification [example 37].
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7](=[O:18])[CH2:8][N:9]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[N:10]1)C>O.C1COCC1>[F:17][C:14]([F:15])([F:16])[C:11]1[CH:12]=[CH:13][N:9]([CH2:8][C:7]([OH:18])=[O:6])[N:10]=1
Reactant: CCOC(=O)Cn1ccc(C(F)(F)F)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cn1ccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 19.2 %

Procedure:
Lithium hydroxide monohydrate (127 mg, 3.03 mmol) in water (0.5 mL) was added to (3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid ethyl ester (250 mg, 1.125 mmol) in THF (5 mL). The mixture was stirred at room temperature for 5 hours then the reaction mixture volume was reduced to one third by evaporation in vacuo. The aqueous residue was acidified using aqueous HCl (2M) to pH=5. The resulting off white solid was filtered, collected and dried, washed with ether to afford the title compound as a white solid (42 mg, 19%).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:27]([O:31][C:32](=[O:43])[NH:33][CH2:34][CH:35]([NH2:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:43])[NH:33][CH2:34][CH:35]([NH:42][C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CN1CCN(c2nccn3c(-c4ccnc(S(C)(=O)=O)n4)cnc23)CC1
Reactant: CC(C)(C)OC(=O)NCC(N)c1ccccc1
Product: CN1CCN(c2nccn3c(-c4ccnc(NC(CNC(=O)OC(C)(C)C)c5ccccc5)n4)cnc23)CC1
Temperature: 140 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
The mixture of 3-(2-methanesulfonyl-pyrimidin-4-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine (from Example 46 supra) (120 mg, 0.32 mmol) and (2-amino-2-phenyl-ethyl)-carbamic acid tert-butyl ester (from Example 51 supra) (305 mg, 1.29 mmol) was heated at 140° C. with stirring for 2 hours. The oil was purified by chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to 20:1) to afford crude (2-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamino}-2-phenyl-ethyl)-carbamic acid tert-butyl ester (Yield 44 mg).
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[F:17][C:18]1[CH:19]=[C:20]([C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([CH:33]=O)[CH:31]=3)[N:26]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[N:25]=2)[CH:21]=[CH:22][CH:23]=1.O>CN(C)C=O>[CH2:13]([O:12][C:10](=[O:11])/[CH:9]=[CH:33]/[C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[N:26]([C:35]([O:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:36])[N:25]=[C:24]2[C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([F:17])[CH:19]=1)[CH3:14]
Reactant: CC(C)(C)OC(=O)n1nc(-c2cccc(F)c2)c2cc(C=O)ccc21
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc2c(c1)c(-c1cccc(F)c1)nn2C(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
To a solution of 0.11 ml ethyl diethylphosphonoacetate in 5 ml N,N-dimethylformamide was added 20 mg of sodium hydride (60% oily) under ice-cooling, and the mixture was stirred for 15 minutes. To the reaction mixture was added a solution of 150 mg of tert-butyl 3-(3-fluorophenyl)-5-formyl-1H-1-indazolecarboxylate in 1 ml N,N-dimethylformamide, followed by stirring at room temperature for 30 minutes. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:10), to give 0.16 g of tert-butyl 5-[(E)-3-ethoxy-3-oxo-1-propenyl]-3-(3-fluorophenyl)-1H-1-indazolecarboxylate as a colorless oil. This product was dissolved in 2 ml of tetrahydrofuran, 0.1 ml of 5 N hydrochloric acid was added and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate for two times. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 0.14 g of the title compound as a colorless powder.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:47])[NH:10][C:11]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[CH2:14][N:13]1[C:20](=[O:46])[C:21]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[C:22]([C:24](=O)[NH:25][CH2:26][C:27](=O)[CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[N:23]=[C:12]21)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:57])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9](=[O:47])[NH:10][C:11]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[CH2:14][N:13]1[C:20](=[O:46])[C:21]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[C:22]([C:24]3[S:57][C:27]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)=[CH:26][N:25]=3)[N:23]=[C:12]21)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC1CCC2(NC(=O)OCc2ccccc2)CC1)Cc1ccc(F)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: O=C(NC12CCC(CC1)Cn1c2nc(-c2ncc(Cc3ccc(F)cc3)s2)c(OCc2ccccc2)c1=O)OCc1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 50.2 %

Procedure:
To a solution of benzyl(3-(benzyloxy)-2-((3-(4-fluorophenyl)-2-oxopropyl)carbamoyl)-4-oxo-6,7,8,9-tetrahydro-7,10-ethanopyrimido[1,2-a]azepin-10(4H)-yl)carbamate, Intermediate 7 (120 mg, 0.188 mmol) in toluene was added Lawesson's Reagent (76 mg, 0.188 mmol) and stirred for 15 min at room temperature, 30 min at 60° C. and 2 h at 100° C. The resulting clear yellow mixture was then cooled, concentrated and purified by preparative HPLC to provide the title compound (60 mg, 0.094 mmol, 50.2% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.79 (1H, s), 7.47-7.52 (2H, m), 7.29-7.39 (8H, m), 7.17 (2H, dd, J=8.28, 5.27 Hz), 6.94-7.07 (3H, m), 5.38 (2H, s), 5.09 (2H, s), 4.09-4.19 (4H, m), 2.69-2.84 (2H, m), 2.49 (1H, br. s.), 1.94-2.04 (4H, m), 1.65-1.76 (2H, m). LCMS (M+H)=637.27.
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[C:10]2[C:5](=[CH:6][C:7](B3OC(C)(C)C(C)(C)O3)=[CH:8][CH:9]=2)[N:4]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=3)[N:23]=[C:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[C:21]=2[CH3:37])[CH2:3]1.[CH:39]1[C:44](Cl)=[N:43][C:42]([NH2:46])=[N:41][CH:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:30][C:26]1[CH:25]=[C:24]2[C:29]([C:20]([N:4]3[C:5]4[C:10](=[CH:9][CH:8]=[C:7]([C:40]5[CH:39]=[CH:44][N:43]=[C:42]([NH2:46])[N:41]=5)[CH:6]=4)[C:2]([CH3:1])([CH3:38])[CH2:3]3)=[C:21]([CH3:37])[C:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)=[N:23]2)=[CH:28][CH:27]=1
Reactant: Nc1nccc(Cl)n1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ccc(-c3ccnc(N)n3)cc21
Temperature: 120 °C

Procedure:
Prepared according to procedure P using 4-(3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-1-yl)-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (75 mg, 0.147 mmol), PdCl2(PPh3)2 (10.33 mg, 0.015 mmol), 2-amine-4-chloropyrimidine (21.0 mg, 0.162 mmol) and sodium carbonate (26.5 mg, 0.442 mmol) in 1,4-dioxane (2.0 mL) and water (0.7 mL) and heating in the microwave for 1 h at 120° C. After purification 4-(1-(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-pyrimidinamine was obtained as a yellow film. 1H NMR (400 MHz, chloroform-d) δ ppm 8.66-8.83 (1H, m), 8.17 (1H, d, J=5.5 Hz), 7.79-7.99 (4H, m), 7.36-7.48 (2H, m), 7.26-7.29 (2H, m), 6.87 (1H, d, J=5.5 Hz), 6.62 (1H, d, J=1.6 Hz), 5.43 (2H, br. s.), 3.82 (2H, s), 2.29-2.44 (3H, m), 1.58 (3H, s), 1.52 (3H, s). Mass Spectrum (ESI) m/e=477 (M+1).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[N:48]([CH:51]([CH3:53])[CH3:52])=[C:49]=[O:50]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:49]([NH:48][CH:51]([CH3:53])[CH3:52])=[O:50])[CH2:42][CH2:41]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: CC(C)N=C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 41 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and 2-isocyanatopropane as starting materials in 41% yield. 1H NMR (300 MHz, DMSO-d6): δ 9.43 (s, 1H), 9.33 (s, 1H), 9.31 (s, 1H), 8.12 (s, 1H), 7.98 (s, 1H), 7.73 (s, 1H), 7.21 (d, 1H), 7.04 (m, 2H), 6.87 (d, 1H), 6.78 (d, 1H), 6.09 (m, 1H), 3.95 (m, 2H), 3.72 (m, 1H), 2.83 (m, 4H), 2.62 (m, 2H), 2.27 (m, 2H), 1.91 (m, 1H), 1.62 (m, 2H), 1.12 (m, 2H), 1.00 (d, 6H). LCMS for C29H35ClN7O3 (M+H)+: m/z=548.2.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:11][C:12](=[O:23])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[CH3:10].I[CH2:25][CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O.CN(C)P(N(C)C)(N(C)C)=O>[CH2:9]([O:11][C:12](=[O:23])[CH:13]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[CH2:25][CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[CH3:10]
Reactant: ICC1CCCC1
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 77.2 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (430.55 mL of a 0.3M stock solution, 129.16 mmol) was cooled to −78° C. and then treated with a solution of (4-nitro-phenyl)-acetic acid ethyl ester (26.32 g, 125.83 mmol) in tetrahydrofuran/hexamethylphosphoramide (312.5 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction mixture was treated with a solution of iodomethylcyclopentane (27.75 g, 132.1 mmol) in hexamethylphosphoramide (27.75 mL). The mixture was stirred at −78° C. for 4 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 16 h. At this time, the reaction mixture was quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (250 mL). This mixture was concentrated in vacuo, diluted with water (250 mL), and extracted with ethyl acetate (3×300 mL). The combined organic extracts were washed with a saturated aqueous lithium chloride solution (2×250 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 98/2 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid ethyl ester (28.30 g, 77.2%) as a yellow oil: EI-HRMS m/e calcd for C16H21NO4 (M+) 291.1470, found 291.1470.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([OH:20])=[O:19])[CH:8]=[C:7]2[NH:21][CH3:22])(=[O:3])[CH3:2].Cl.N.[CH2:25](O)[CH3:26]>>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([O:20][CH2:25][CH3:26])=[O:19])[CH:8]=[C:7]2[NH:21][CH3:22])(=[O:3])[CH3:2]
Reactant: CCO
Reactant: CCCc1c(O)c(C(C)=O)cc2c(NC)cc(C(=O)O)nc12
Agent: Cl
Agent: N
Product: CCCc1c(O)c(C(C)=O)cc2c(NC)cc(C(=O)OCC)nc12

Procedure:
The crude product of step (d) (6.4 g) in ethanol (500 mls) which had been previously saturated with hydrogen chloride gas was heated under reflux for 1 hour. The reaction mixture was cooled, made basic with 880 ammonia and extracted with ethyl acetate, which was then washed with water and dried over magnesium sulphate. The solvent was removed by evaporation to leave 8.0 g of residual yellow solid. This solid was recrystallised from ethanol to give 3.8 g of yellow needles mp 219°-220°.
Reaction SMILES: [ClH:1].CCO.[CH2:5]([N:12]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[N:23]=[C:22]([CH3:24])[C:21](/[CH:25]=[CH:26]/[C:27]([NH:29][O:30]C3CCCCO3)=[O:28])=[CH:20][N:19]=2)[CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CCO>[ClH:1].[ClH:1].[CH2:5]([N:12]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[N:23]=[C:22]([CH3:24])[C:21](/[CH:25]=[CH:26]/[C:27]([NH:29][OH:30])=[O:28])=[CH:20][N:19]=2)[CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1nc(NC2CCN(Cc3ccccc3)C2)ncc1/C=C/C(=O)NOC1CCCCO1
Agent: Cl
Solvent: CCO
Product: Cc1nc(NC2CCN(Cc3ccccc3)C2)ncc1/C=C/C(=O)NO
Temperature: 22.5 °C
Reaction time: 2 h

Procedure:
A solution of 2N HCl-EtOH solution (1.2 ml) was added to a mixture of (2E)-3-{2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (200 mg) in EtOH (5 ml) and stirred at 20-25° C. for 2 hours. IPE (30 ml) was added to a reaction mixture and the resultant mixture was stirred at ambient temperature for 20 minutes. The precipitate was collected by filtration to give (2E)-3-(2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinyl)-N-hydroxyacrylamide dihydrochloride (90 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([N:15]([CH3:17])[CH3:16])=[N:13][N:14]=[C:7]1[NH:6][C:5]2=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]=[CH:33][CH2:34]Cl)[CH:27]=1>COCCOC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([N:15]([CH3:16])[CH3:17])=[N:13][N:14]=[C:7]1[N:6]([CH2:34][CH:33]=[CH:32][C:28]1[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=1)[C:5]2=[O:18]
Reactant: CN(C)c1nnc2[nH]c(=O)c3cc(Br)ccc3n12
Reactant: ClCC=Cc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CN(C)c1nnc2n(CC=Cc3cccnc3)c(=O)c3cc(Br)ccc3n12
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
In a reactor equipped with magnetic shaker and refrigeration, we resuspend 7.4 g (0.024 mol) of 7-bromo-1-(N,N-dimethylamino)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one in 200 ml de 1,2-dimethoxyethane then we shake. We add 17.0 g (0.052 mol) of cesium carbonate then shake at ambient temperature for 15 minutes. 4.5 g (0.024 mol) of 3-(3-pyridyl)-allyl chloride hydrochloride are then added by fraction, then the mixture is heated to 70° C., under shaking, for 3 hours. The solvent is evaporated under vacuum then the residue is then put in suspension in 300 ml of iced water. After repeated extractions with ethyl acetate, the joined organic phases are washed with aqueous solution saturated with sodium chloride, dried on sodium sulfate then the solvent is evaporated under vacuum.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:34]([O:41][CH2:42][CH2:43]O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH2:34]([O:41][CH2:42][CH2:43][O:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)c1cc(O)ccc1[N+](=O)[O-]
Reactant: OCCOCc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCCOCc2ccccc2)ccc1[N+](=O)[O-]
Reaction time: 18 h
Yield: 93.1 %

Procedure:
To a solution of methyl 5-hydroxy-2-nitro-benzoate (7.97 g, 40.43 mmol), triphenylphosphine (12.73 g, 48.53 mmol), and 2-benzyloxyethanol (5.86 ml, 41.24 mmol) in tetrahydofuran (100 ml) was added DEAD (8.04 ml, 95%, 48.51 mmol) dropwise. After addition of the DEAD, the reaction was stirred under nitrogen for 18 h. The solvent was evaporated, benzene was added, and the triphenylphosphine oxide was filtered off. The solid was washed with some benzene, and the filtrate evaporated. The yellow oil was dissolved in minimal benzene, and chromatographed on silica gel eluting with 25% ethyl acetate/hexanes to give methyl 5-(2-benzyloxy-ethoxy)-2-nitro-benzoate (12.47 g, 93%) as a light yellow oil. Analysis calculated for C17H17NO6 : C, 61.63; H, 5.17; N, 4.23. Found: C, 61.46; H, 5.02; N, 4.28.