Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11](B3OC(C)(C)C(C)(C)O3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:24]1[C:32]2[C:27](=[N:28][CH:29]=[N:30][C:31]=2[NH2:33])[N:26]([C@H:34]2[CH2:39][CH2:38][C@@H:37]([N:40]3[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]3)[CH2:36][CH2:35]2)[N:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:7]([C:8]1[CH:9]=[CH:10][C:11]([C:24]2[C:32]3[C:27](=[N:28][CH:29]=[N:30][C:31]=3[NH2:33])[N:26]([CH:34]3[CH2:35][CH2:36][CH:37]([N:40]4[CH2:41][CH2:42][N:43]([CH3:46])[CH2:44][CH2:45]4)[CH2:38][CH2:39]3)[N:25]=2)=[CH:12][CH:13]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: CC1(C)OB(c2ccc(Nc3ccccc3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN1CCN(C2CCC(n3nc(-c4ccc(Nc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Yield: 76.3 %

Procedure:
A mixture of N-phenyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (Intermediate AE) (0.33 g, 0.0011 mol), cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate AC) (0.43 g, 0.00097 mol), tetrakis(triphenylphosphine)palladium (0.0067 g, 0.000058 mol) and sodium carbonate (0.26 g, 0.0024 mol) was heated in a mixture of ethylene glycol dimethyl ether (16 mL) and water (8 mL) at 80° C. for 16 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (50 mL), the organic layer separated and the aqueous layer further extracted with ethyl acetate twice. The combined organic extracts were dried over magnesium sulfate and evaporated under reduced pressure to give a tan solid which was purified by flash column chromatography on silica using dichloromethane/triethylamine/methanol (92:7:1) as a mobile phase to give 3-(4-anilinophenyl)-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a white solid (0.400 g, 0.00074 mol). It was dissolved at reflux in ethanol (17 mL) and a preheated solution of maleic acid (0.342 g, 0.003 mol) in ethanol (8 mL) was added. The mixture was refluxed for 10 min, cooled to ambient temperature and the precipitate collected by filtration, washed with ethyl acetate and dried to give cis-3-(4-anilinophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine trimaleate (0.44 g, 0.00053 mol) 1H NMR (DMSO-d6, 400 MHz) 8.45 (s, 1H), 8.23 (s, 1H) 7.52 (d, 2H), 7.28 (m, 2H), 7.20 (m, 4H), 6.89 (t, 1H), 6.19 (s, 6H), 4.83 (m, 1H), 3.1 (br, 9H), 2.72 (s, 3H), 2.28 (m, 2H), 2.07 (m, 2H), 1.74 (m, 4H);
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7](C(O)C#C)[CH:8]=[CH:9][C:10]=1[N:11]([CH2:16][CH3:17])[CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].I[C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1>[Cu](I)I.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>[C:1]([C:5]1[C:10]([N:11]([CH2:16][CH3:17])[CH2:12][CH:13]([CH3:15])[CH3:14])=[C:9]([CH:27]([OH:28])[C:26]#[C:25][C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C#CC(O)c1ccc(N(CC)CC(C)C)c(C(C)(C)C)c1
Reactant: O=C(O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Product: CCN(CC(C)C)c1c(C(O)C#Cc2ccc(C(=O)O)cc2)cccc1C(C)(C)C
Yield: 107.2 %

Procedure:
In a manner analogous to example 1 e, the process is carried out by a reaction of 300 mg (1 mmol) of 1-[3-tert-butyl-4-(ethylisobutylamino)phenyl]prop-2-yn-1-ol with 216 mg (0.87 mmol) of 4-iodobenzoic acid, 12 mg (0.04 mmol) of copper iodide and 15 mg (0.02 mmol) of bis(triphenylphosphine)palladium chloride. 190 mg of 4-{[tert-butyl(ethylisobutylamino)phenyl]hydroxyprop-1-ynyl}benzoic acid are obtained in the form of a beige solid (Mp=117° C., yield=53%).
Reaction SMILES: [CH:1]([P:4]1(=[O:12])[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[CH2:6][O:5]1)=[C:2]=[CH2:3].CC1(C)COP(C#CC)(=O)[O:16]C1.O.NN.Cl>>[CH2:1]([P:4]1(=[O:12])[O:5][CH2:6][C:7]([CH3:10])([CH3:11])[CH2:8][O:9]1)[C:2]([CH3:3])=[O:16]
Reactant: C=C=CP1(=O)OCC(C)(C)CO1
Reactant: CC#CP1(=O)OCC(C)(C)CO1
Agent: Cl
Agent: NN
Solvent: O
Product: CC(=O)CP1(=O)OCC(C)(C)CO1
Yield: 57.5 %

Procedure:
A solution mixture of II and III obtained in Reference Example 1 was stirred under cooling with ice and 510 g (10.2 mol) of hydrazine monohydrate was dropwise added thereto. After the completion of dropwise addition, the solution mixture was stirred for 30 minutes (the reaction was completed in ten minutes), and 11.2 kg of 10% by weight hydrochloric acid was added thereto. The solution mixture was stirred for one hour at room temperature and 5.0 kg of the solvent was distilled off. The solution was subjected to salting-out by addition of 1.38 kg of sodium chloride and extracted 2 times with 15.8 kg of chloroform. The chloroform layers were combined and dried over anhydrous sodium sulfate, followed by filtration. The solvent was distilled off, and the residue was dissolved in 3.5 kg of toluene and cooled with ice. The crystal thus precipitated was collected by filtration by means of suction and washed with 1.0 kg of toluene cooled and dried to obtain 1,000 g (yield: 57.5% through 4 steps) of the desired product of 2-acetonyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane as colorless crystal.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][C@H:4]([C:7]([OH:10])([CH3:9])[CH3:8])[CH2:3]1.Cl[C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)=[CH:19][N:20]=2)[N:17]=1.[F-].[K+].O>CS(C)=O>[Cl:27][C:23]1[CH:22]=[C:21]([C:18]2[N:16]3[N:17]=[C:12]([NH:1][C@H:2]4[CH2:6][CH2:5][C@H:4]([C:7]([OH:10])([CH3:9])[CH3:8])[CH2:3]4)[CH:13]=[CH:14][C:15]3=[N:20][CH:19]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: Clc1cccc(-c2cnc3ccc(Cl)nn23)c1
Reactant: CC(C)(O)[C@H]1CC[C@H](N)C1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(O)[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)C1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(trans-3-aminocyclopentyl)propan-2-ol (82 mg, 0.57 mmol), 6-chloro-3-(3-chlorophenyl)imidazo[1,2-b]pyridazine (100 mg, 0.38 mmol) and KF (66.2 mg, 1.14 mmol) in DMSO (1 mL) was stirred at 130° C. overnight. LCMS showed the reaction was complete. The mixture was poured into water (100 mL) and extracted with EtOAc (50 mL*3). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC to give EX. 8-82 (45 mg, 32%) as an off-white solid.
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([OH:23])=O)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:39]([O:46][C:47]([NH:49][CH2:50][CH2:51][CH2:52][CH2:53][C@@H:54]([C:56]([OH:58])=[O:57])[NH2:55])=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C)C=O.[OH-].[Na+]>[C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([NH:55][C@H:54]([C:56]([OH:58])=[O:57])[CH2:53][CH2:52][CH2:51][CH2:50][NH:49][C:47]([O:46][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:48])=[O:23])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)O
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.2 %

Procedure:
To a solution of N-hydroxysuccinimide ester of 3-hexadecanoyloxyoctadecanoic acid (7.5 g) prepared by the method of Example 8 (1) in dimethylformamide (200 ml) was added a solution of Nε -benzyloxycarbonyl-L-lysine (6.6 g) in 1N sodium hydroxide (23.6 ml) at room temperature. The mixture was stirred at ambient temperature for 3 hours. The precipitated solid was collected by filtration and the filtrate was concentrated under reduced pressure. The solid and the residue was combined. Then, the mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water. The ethyl acetate solution was dried over magnesium sulfate, and then concentrated to give a residue which was dried up by high vacuum pump to afford powder of Nα -(3-hexadecanoyloxyoctadecanoyl)-Nε -benzyloxycarbonyl-L-lysine (8.5 g).
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].Br[C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=1>C1COCC1.[Cl-].[NH4+].[Br-].[Zn+2].[Br-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=1)=[CH2:2]
Reactant: C=C[Mg]Br
Reactant: FC(F)(F)c1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=Cc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of vinylmagnesium bromide in THF (1M, 7.38 mL, 7.38 mmol) in THF (29 mL) was added anhydrous zinc bromide (1.66 g, 7.38 mmol) at −78° C. After one hour at this temperature, the mixture was warmed to room temperature. After one hour, tetrakis(triphenylphosphine)palladium(0) (147 mg) and 2-bromo-5-trifluoromethylpyridine (1 g, 4.42 mmol) were added and the mixture heated at 50° C. for 5.25 hours. The mixture was diluted with ammonium chloride solution (10%, 29 mL) and extracted with ethyl acetate (70 mL×2). The combined organic extracts were dried over magnesium sulphate, evaporated and purified by column chromatography (SPE column, silica), eluting with cyclohexane, followed by cyclohexane/ethyl acetate (95:5 v/v), then (9:1 v/v). This afforded the title compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]([O:16][C@@H:17]([C@@H:19]2[CH2:23][C:22](=[O:24])[NH:21][CH2:20]2)[CH3:18])[C:10]2[S:14][CH:13]=[N:12][C:11]=2[CH:15]=1)(=O)=O.[CH3:27][O:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[CH:31][C:30]=1[N:44]1[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2].O>[CH3:27][O:28][C:29]1[CH:34]=[C:33]([C:7]2[CH:8]=[C:9]([O:16][C@@H:17]([C@@H:19]3[CH2:23][C:22](=[O:24])[NH:21][CH2:20]3)[CH3:18])[C:10]3[S:14][CH:13]=[N:12][C:11]=3[CH:15]=2)[CH:32]=[CH:31][C:30]=1[N:44]1[CH2:45][CH2:46][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:48][CH2:49]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C[C@@H](Oc1cc(OS(=O)(=O)C(F)(F)F)cc2ncsc12)[C@H]1CNC(=O)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(-c2cc(O[C@H](C)[C@H]3CNC(=O)C3)c3scnc3c2)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 65 °C
Reaction time: 1.25 h

Procedure:
7-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)benzo[d]thiazol-5-yl trifluoromethanesulfonate (4.04) (100.7 mg, 0.245 mmol), tert-butyl 4-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate 7.08 (144 mg, 0.344 mmol), Pd(OAc)2 (2.8 mg, 0.012 mmol), 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (12 mg 0.025 mmol), and K3PO4 (155 mg, 0.73 mmol) were taken up in THF (3.6 mL) under Ar. Water (0.36 mL) was added and the resulting stirred mixture was heated to 65° C. After 1.25 h, the reaction mixture was cooled and was partitioned between EtOAc, water, and brine. The phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic phase was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography to afford tert-butyl 4-(2-methoxy-4-(7-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)benzo[d]thiazol-5-yl)phenyl)piperazine-1-carboxylate. LCMS-ESI+ (m/z): [M+H]+ calcd for C29H37N4O5S: 553.3; found: 552.8.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.[OH-].[Na+]>O1CCCC1.CCOCC>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][NH:9][C:5]2[CH:4]=[C:3]([CH2:2][OH:1])[CH:8]=[CH:7][CH:6]=2)=[CH:12][CH:13]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)Nc2cccc(CO)c2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCOc1ccc(CNc2cccc(CO)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the N-[3-(hydroxymethyl)phenyl]-4-(tetradecyloxy)benzamide in 80 ml of tetrahydrofuran at 0° C. under argon is added 36.39 ml of 1M lithium aluminum hydride. Stirred at room temperature for 1 hour and refluxed for 7 hours. After stirring overnight and cooling to 0° C., ethyl acetate is added followed by sodium hydroxide solution until a solid forms. The mixture is diluted with ether, filtered and evaporated to a residue which is crystallized from hexane to give 6.7 g of the desired product as a white solid, m.p. 72°-75° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:10]1(=[O:16])[O:15][C:13](=[O:14])[CH2:12][CH2:11]1.Cl>N1C=CC=CC=1>[N:1]1([C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)O1
Reactant: c1ccc2c(c1)CCN2
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)CCC(=O)N1CCc2ccccc21
Yield: 84.3 %

Procedure:
The procedure was modified from the reported one. In a 20 mL microwave reaction tube equipped with a magnetic stirring bar, indoline (1.196 g, 10 mmol), succinic anhydride (1.004 g, 10 mmol) and pyridine (8 mL) was mixed at room temperature. The tube was capped and irradiated in the microwave reactor (Biotage Initiator I) at 90° C. for 20 minutes. The reaction mixture was acidified to pH=1 using 2 M HCl. The resulting precipitate was filtered, washed with water and dried under high vacuum to afford light pink solid product (1.849 g, 92%). 1H NMR (400 MHz, CDCl3) d 8.19 (d, 1H, J=8.5 Hz), 7.18 (m, 2H), 7.03 (t, 1H, J=7.4 Hz), 4.08 (t, 2H, J=8.4 Hz), 3.22 (t, 2H, J=8.4 Hz), 2.78 (m, 4H).
Reaction SMILES: Cl.[CH3:2][C:3]1[N:8]=[C:7]([C:9]2[C:10](=[O:16])[NH:11][C:12](=[O:15])[NH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:24]([Cl:28])[CH2:25][CH2:26][CH3:27].CC1N=C(C2C(=O)NC(=O)NC=2)C=CC=1>CN(C=O)C.O>[Cl:28][CH2:24][CH2:25][CH2:26][CH2:27][N:13]1[CH:14]=[C:9]([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH3:2])[N:8]=2)[C:10](=[O:16])[NH:11][C:12]1=[O:15]
Reactant: CCCC(Cl)Br
Reactant: Cc1cccc(-c2c[nH]c(=O)[nH]c2=O)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(-c2cn(CCCCCl)c(=O)[nH]c2=O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 157.1 %

Procedure:
5-(6-Methyl-pyridin-2-yl)-1H-pyrimidine-2,4-dione hydrochloride (Prep 50, 50 mg, 0.208 mmol) and K2CO3 (43 mg, 0.312 mmol) were suspended in dry DMF (2 mL) and stirred for 1 h at room temperature. Then a solution of bromo-chloro-butane (71.3 mg, 0.416 mmol) in dry DMF (0.5 mL) was added dropwise and the mixture stirred for 48 hrs at room temperature. A second run of reaction was performed using 5-(6-Methyl-pyridin-2-yl)-1H-pyrimidine-2,4-dione (135 mg, 0.563 mmol), K2CO3 (116 mg, 0.8445 mmol) and bromo-chloro-butane (193 mg, 1.126 mmol). After stirring the reactions at room temperature for 48 hours, the two mixtures were mixed. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered and evaporated; the crude was purified by flash chromatography with DCM-MeOH—NH4OH (98-2-0.2) to give the title compound as a pale yellow solid (96 mg, 43% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8]([B:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]2)=[CH:7][C:5]=1[NH2:6])([O-])=O.C1N=CN([C:25](N2C=NC=C2)=[O:26])C=1>C(OCC)(=O)C.C(Cl)Cl.[Pt](=O)=O>[CH3:18][C:13]1([CH3:19])[C:14]([CH3:17])([CH3:16])[O:15][B:11]([C:8]2[CH:9]=[CH:10][C:4]3[NH:1][C:25](=[O:26])[NH:6][C:5]=3[CH:7]=2)[O:12]1
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])c(N)c2)OC1(C)C
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=[Pt]=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2ccc3[nH]c(=O)[nH]c3c2)OC1(C)C
Reaction time: 0.5 h

Procedure:
A solution of 2-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.35 g, 8.9 mmol) in ethyl acetate (100 mL) was treated with platinum(IV) oxide (0.2 g) and stirred vigorously under a hydrogen atmosphere for 30 minutes. The reaction mixture was degassed with nitrogen and filtered through celite washing with ethyl acetate. This solution was then treated with CDI (1.8 g, 11.1 mmol) and stirred overnight at ambient temperature. The solution was diluted with methylene chloride (100 mL) and the precipate was filtered and washed with cold methanol. The solids were dried in vacuo to yield 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-benzimidazol-2-one as a white solid.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:37])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[N:34]=[C:33]([C:35]#[N:36])[CH:32]=[CH:31][CH:30]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[OH:8][CH2:9][C:10]1([CH3:37])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[N:34]=[C:33]([C:35]#[N:36])[CH:32]=[CH:31][CH:30]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5cccc(C#N)n5)cc4)CC3)n2CCS1
Agent: Cl
Solvent: CO
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5cccc(C#N)n5)cc4)CC3)n2CCS1
Yield: 90.9 %

Procedure:
A solution of the compound (466 mg, 0.88 mmol) obtained in Example 41-1) and 4 M hydrochloric acid (1,4-dioxane solution, 1 mL) in methanol (4 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (334 mg, 91%) as a colorless solid.
Reaction SMILES: C([O:4][C:5](=[O:7])[CH3:6])(=O)C.O[N:9]=[C:10]1[C:24]2[C:25]3[C:20]([CH:21]=[CH:22][N:23]=2)=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]2[C:11]1=[CH:12][CH:13]=[CH:14]2>N1C=CC=CC=1>[C:5]([O:4][N:9]=[C:10]1[C:24]2[C:25]3[C:20]([CH:21]=[CH:22][N:23]=2)=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]2[C:11]1=[CH:12][CH:13]=[CH:14]2)(=[O:7])[CH3:6]
Reactant: ON=c1c2nccc3cccc(c32)n2cccc12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)ON=c1c2nccc3cccc(c32)n2cccc12
Temperature: 10 °C
Reaction time: 0.08 h

Procedure:
Acetic anhydride (20 cc.) is added, over the course of 5 minutes, to a stirred suspension of 7-hydroxyimino-7H-indolizino[5,6,7-ij]isoquinoline (10 g.) in pyridine (100 cc.) kept at between 8° and 10° C. A brown solution is thus obtained. After stirring for 5 minutes at 10° C., the acetic acid ester crystallises. The mixture is kept at ambient temperature for a further 2 hours and then water (600 cc.) is added. The ochre-yellow crystals thus obtained are filtered off and washed copiously with water. After drying, 7-acetyloxyimino-7H-indolizino[5,6,7-ij]isoquinoline (11.0 g.), melting at 177°-179° C. with decomposition, is obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C>CN(C)C=O.[OH-].[Pd+2].[OH-]>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[CH3:14])[N:5]=[CH:4][N:3]=[CH:2]2
Reactant: COc1cc2c(Cl)ncnc2cc1C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc2cncnc2cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
4-Chloro-6-methoxy-7-methyl-quinazoline (99 mg) was dissolved in N,N-dimethylformamide (6 ml) to prepare a solution. Triethylamine (0.6 ml) and 20% palladium hydroxide (4 mg) were added to the solution, and the mixture was stirred under hydrogen pressure at room temperature overnight. The reaction solution was filtered through Celite and was then washed with chloroform and methanol, and the solvent was removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give 6-methoxy-7-methyl-quinazoline (76 mg, yield 93%).
Reaction SMILES: [CH2:1]([O:3][P:4]([O:23][CH2:24][CH3:25])([CH:6]=[CH:7][CH2:8][C:9]1[N:14]2[CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=[C:13]2[CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2]>[Pd]>[CH2:1]([O:3][P:4]([O:23][CH2:24][CH3:25])([CH2:6][CH2:7][CH2:8][C:9]1[N:14]2[CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=[C:13]2[CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn2c(CC=CP(=O)(OCC)OCC)cccc2n1
Agent: [Pd]
Product: CCOC(=O)c1cn2c(CCCP(=O)(OCC)OCC)cccc2n1

Procedure:
The title material is prepared by catalytic (Pd/C hydrogenation of the title product of Example 102 under standard Parr conditions.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][C:10]3[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=3[C:6]=2[N:5]2[N:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:4]2[N:3]=1.[CH2:25]([NH2:29])[CH2:26][CH2:27][CH3:28]>>[CH2:25]([NH:29][C:2]1[C:7]2[CH:8]=[N:9][C:10]3[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=3[C:6]=2[N:5]2[N:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:4]2[N:3]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCOC(=O)c1cnn2c1nc(Cl)c1cnc3c(cnn3CC)c12
Reactant: CCCCN
Product: CCCCNc1nc2c(C(=O)OCC)cnn2c2c1cnc1c2cnn1CC
Reaction time: 8 h
Yield: 83.9 %

Procedure:
3.5 g of 5-chloro-8-ethyl-8H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidine-3-carboxylic acid, ethyl ester (0.01 mol) and 7.3 g of n-butylamine are refluxed together with 30 ml of alcohol with stirring for 8 hours. The solution is evaporated to dryness and the residue treated with water and filtered off. Recrystallization from ethyl acetate yields 3.2 g (84%) of 5-(n-butylamino)-8-ethyl-8H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidine-3-carboxylic acid, ethyl ester; m.p. 275°-277°.