Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]([S:8][C:9](=O)[CH3:10])([CH3:7])[CH3:6])[CH3:2].C[O-].[Na+].BrCC[CH2:19][C:20]([F:23])([F:22])[F:21]>C(O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]([CH3:7])([S:8][CH2:9][CH2:10][CH2:19][C:20]([F:23])([F:22])[F:21])[CH3:6])[CH3:2]
Reactant: FC(F)(F)CCCBr
Reactant: CCOC(=O)C(C)(C)SC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)SCCCC(F)(F)F
Temperature: 85 °C
Yield: 84.3 %

Procedure:
To a solution of 149 g (785.4 mmol) of 2-acetylsulfanyl-2-methyl-propionic acid ethyl ester (prepared as described in Method C, step 1) in ethanol (1.2 L, degassed under nitrogen for 1 h) are added 169.7 g (105 mmol) of sodium methoxide, followed by a solution of 150 g (785.4 mmol) of 4-bromo-1,1,1-trifluoro-butane. The reaction is heated to 85° C. for 3 d. The solvent is removed under reduced pressure. The residue is dissolved in DCM (1 L) and washed with saturated aqueous NaHCO3 solution (2×1 L). The organic layer is dried over Na2SO4, filtered and the filtrate is concentrated under reduced pressure to afford 171 g of 2-methyl-2-(4,4,4-trifluoro-butylsulfanyl)-propionic acid ethyl ester as a brown oil. Yield: 84%; ES-MS: m/z 259 [M+H]; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.29 (3H, t, J=7.17 Hz), 1.51 (6H, s), 1.76-1.86 (2H, m), 2.12-2.27 (2H, m), 2.69 (2H, t, J=7.17 Hz), 4.18 (2H, q, J=7.17 Hz)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([Br:15])[CH:9]=2)=[O:5])[CH3:2].[C:16]([O:20][C:21]([N:23]1[CH2:27][C@H:26]([CH3:28])OS1(=O)=O)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C@H:26]([CH3:28])[CH2:27][NH:23][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([Br:15])[CH:9]=2)=[O:5])[CH3:2]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reactant: CCOC(=O)c1cc2ccc(Br)cc2[nH]1
Product: CCOC(=O)c1cc2ccc(Br)cc2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
The title compound, ISP-MS: m/e=425.3, 427.3 (M+H+), was prepared in accordance with the general method of example 12b) from 6-bromo-1H-indole-2-carboxylic acid ethyl ester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][C:2]#[N:3].C([Li])CCC.C([O:11][C:12]([C@@H:14]1[CH2:16][C@@H:15]1[F:17])=O)C>C1COCC1>[F:17][C@H:15]1[CH2:16][C@H:14]1[C:12](=[O:11])[CH2:1][C:2]#[N:3]
Reactant: CC#N
Reactant: CCOC(=O)[C@@H]1C[C@@H]1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CCC(=O)[C@@H]1C[C@@H]1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
To a solution of MeCN (7.28 mL, 139 mmol) in anhydrous THF (130 mL) at −78° C. under N2 was added n-butyllithium (2.4 mol/L) in hexanes (58 mL, 139 mmol) dropwise. The mixture was stirred at −78° C. for 30 min then cis-ethyl-2-fluorocyclo-propanecarboxylate (1.5 g; 87.0 mmol) was added dropwise with stirring while maintaining the temperature at −78° C. The resulting solution was stirred at 25° C. for 2 h, quenched by the addition of 50% satd. aq. NH4Cl solution and extracted with EtOAc (3×50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum to afford 7.7 g of crude cis-3-(2-fluorocyclopropyl)-3-oxopropanenitrile as a red oil. Crude cis-3-(2-fluoro-cyclopropyl)-3-oxopropanenitrile was dissolved in EtOH (130 mL) and hydrazine (8.45 mL, 261 mmol) was added. The reaction mixture was heated at reflux for 16 h then concentrated in vacuo. The resultant orange solid was triturated with DCM (ca. 50 mL). The precipitate was filtered, rinsed with DCM, and dried in vacuo to obtain 7.48 g (60.9%) of cis-5-(2-fluorocyclopropyl)-1H-pyrazol-3-amine as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 11.18 (br s, 1H), 5.16 (s, 1H), 4.81 (ddd, J=66.3, 9.5, 5.2 Hz, 1H), 4.46 (br s, 2H), 1.99-1.81 (m, 1H), 1.23-1.02 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([CH2:10]C=C)[N:6]1[C:13](=[O:26])[CH:14]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH:16]=[CH2:17])=[O:4].CS(C)=O>ClCCl.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[CH3:1][O:2][C:3]([C@H:5]1[N:6]2[C:13](=[O:26])[C@@H:14]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH2:15][CH:16]=[CH:17][CH2:10][C@@H:7]2[CH2:8][CH2:9]1)=[O:4]
Reactant: C=CCC(NC(=O)OC(C)(C)C)C(=O)N1C(CC=C)CCC1C(=O)OC
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Solvent: CS(C)=O
Product: COC(=O)[C@@H]1CC[C@H]2CC=CC[C@H](NC(=O)OC(C)(C)C)C(=O)N21
Reaction time: 2 h
Yield: 60 %

Procedure:
5-Allyl-1-(2-tert-butoxycarbonylamino-pent-4-enoyl)-pyrrolidine-2-carboxylic acid methyl ester, 6, (3.2 g, 8.7 mmol) is dissolved in dichloromethane (40 mL). Grubbs catalyst (0.7 g, 0.85 mmol) is added and the mixture heated to reflux for 4 hours. The reaction is allowed to cool and methylsulfoxide (2 mL) is added. After 2 hours the solution is reduced to a oil, which is purified over silica (50% ethyl acetate hexane) to afford 1.76 g (60% yield) of the desired product as a dark yellow oil. 1H-NMR (300 MHz, CDCl3): δ 5.79 (m, 2H), 5.61 (d, J=6.9, 1H), 4.89 (dd, J=15, 7.2, 5.79 (m, 2H), 5.61 (d, J=6.9, 1H), 4.89 (dd, J=15, 7.2, 5.79 (m, 2H), 5.61 (d, J=6.9, 1H), 4.89 (dd, J=15, 7.2, 1H), 4.54 (m, 1H), 4.15 (m, 1H), 3.75 (s, 3H), 2.81 (m, 2H) 2.49–1.98 (m, 6H), 1.47 (s, 9H). 13C NMR (CDCl3): □ 172.6, 171.3, 155.4, 129.4, 126.0, 79.9, 60.3, 58.9, 52.2, 52.1, 35.5, 33.2, 33.1, 28.6, 27.4. ESI MS: 339.18 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C1COCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][S:14]([CH3:13])(=[O:16])=[O:15])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1)#[N:7]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(N)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc(C#N)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 16 %

Procedure:
KH (700 mg, 6.1 mmol) was dissolved in THF (15 mL) at −78° C. and to the solution was added dropwise the solution of 4-amino-3-nitro-benzonitrile (500 mg, 3.1 mmol) in THF (10 mL). After the reaction solution was stirred for 30 minutes, to the solution was added dropwisely methanesulfonyl chloride (0.35 mL, 4.6 mmol) and stirred for 3 hours. The reaction solution was quenched with water and the resulting solution was diluted with ethylacetate. The organic phase was washed with water and brine, dried over anhydride MgSO4 and concentrated under reduced pressure. The residue was purified with column chromatography (n-hexane/ethyl acetate=5/1) to yield the nitrile (120 mg, 16%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]2[C@@H:3]1[S:4][C@@:5]([N:23]1[CH2:27][CH2:26][N:25]([N:28]=[CH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]1=[O:36])([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:11])[CH2:6]2.[C:37]([C:41]1[CH:42]=[C:43]([CH:46]=[C:47]([C:50]([CH3:53])([CH3:52])[CH3:51])[C:48]=1[OH:49])[CH:44]=O)([CH3:40])([CH3:39])[CH3:38]>C1C=CC=CC=1>[CH:29](=[N:28][N:25]1[CH2:26][CH2:27][N:23]([C@@:5]2([C:10]([O:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=3)=[O:11])[S:4][C@H:3]3[N:7]([C:8](=[O:9])[C@H:2]3[N:1]=[CH:44][C:43]3[CH:42]=[C:41]([C:37]([CH3:38])([CH3:40])[CH3:39])[C:48]([OH:49])=[C:47]([C:50]([CH3:53])([CH3:52])[CH3:51])[CH:46]=3)[CH2:6]2)[C:24]1=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: N[C@@H]1C(=O)N2C[C@@](C(=O)OCc3ccc([N+](=O)[O-])cc3)(N3CCN(N=Cc4ccccc4)C3=O)S[C@H]12
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Solvent: c1ccccc1
Product: CC(C)(C)c1cc(C=N[C@@H]2C(=O)N3C[C@@](C(=O)OCc4ccc([N+](=O)[O-])cc4)(N4CCN(N=Cc5ccccc5)C4=O)S[C@H]23)cc(C(C)(C)C)c1O
Yield: 98.3 %

Procedure:
30 ml of benzene was added to 1.00 g of (3R,5R,6R)-6-amino-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane and 0.46 g of 3,5-di-tert-butyl-4-hydroxybenzaldehyde. The mixture was subjected to azeotropy and dehydration under reflux for 1 hour using a Dean-Stark aparatus. The reaction mixture was cooled, and the solvent was removed by distillation under reduced pressure to obtain 1.40 g (yield: 98.6%) of (3R,5R,6R)-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-6-(3,5-di-tert-butyl-4-hydroxybenzylideneamino)-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].O.[CH3:8]B1OB(C)OB(C)O1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([F:29])([F:28])([F:27])([F:26])[F:25])=[CH:20][C:19]=1Br>C(COC)OC.CCOCC.Cl[Pd]Cl.C(Cl)Cl>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([F:29])([F:28])([F:27])([F:26])[F:25])=[CH:20][C:19]=1[CH3:8]
Reactant: Nc1ccc(S(F)(F)(F)(F)F)cc1Br
Reactant: CB1OB(C)OB(C)O1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: Cc1cc(S(F)(F)(F)(F)F)ccc1N
Temperature: 70 °C
Yield: 86.2 %

Procedure:
A mixture Of Cs2CO3 (794 g, 2.7 mol), dimethoxyethane (2 l), water (300 ml) and trimethylboroxine (50 percent solution in THF, 225 g. 0.9 mol) was heated to 70° C., PdCl2 (dppf)×CH2Cl2 (37 g. 45 μmmol) was added, and a solution of 4-amino-3-bromophenylsulfur pentafluoride (270 g., 0.9 mol) in dimethoxyethane (400 ml) was added dropwise over the course of 2 h while the reaction mixture was heated to reflux. It was subsequently heated under reflux for a further 3 h and then cooled to room temperature, diluted with MTB ether (500 ml), filtered through a silica gel column (14×7 cm, 70-200 μm) and washed with MTB ether (2500 ml). The filtrate was evaporated in vacuo. 490 g of a black, semicrystalline mass was obtained and was subjected to a steam distillation. A total of 5.5 l of condensate was collected, from which the crystals of the product separated out. The condensate was extracted 3× with MTB ether, and the combined organic phases were dried over Na2SO4 and evaporated in vacuo. 4-Amino-3-methylphenylsulfur pentafluoride (181 g. 76%) was obtained as colorless crystals, m.p. 65-66° C.
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:30][CH:29]=2)[C:9]=1[Br:39].C(O)(C(F)(F)F)=O.O>>[NH2:7][C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:30][CH:29]=2)[C:9]=1[Br:39]
Reactant: COC(=O)Cc1ccc(Cc2nc3c(-c4cnc5ccccc5c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COC(=O)Cc1ccc(Cc2nc3c(-c4cnc5ccccc5c4)cnn3c(N)c2Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The crude methyl 2-(4-((7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)methyl)phenyl)acetate from above step E was treated with 50% TFA/H2O (3 mL) and stirred at room temperature for 1 h. Solvent was removed to yield thick oil, Methyl 2-(4-((7-amino-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)methyl)phenyl)acetate which was used in the next step directly without further purification. HPLC-MS tR=1.72 min (UV254 nm); mass calculated for formula C25H20BrN5O2 501.1, observed LCMS m/z 502.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.N.O>C(Cl)Cl.[Cl-].[Na+].O.[Zn]>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(Cl)nc(Cl)c2c1
Agent: N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc2nc(Cl)ncc2c1
Yield: 68.1 %

Procedure:
To a solution of 2,4-dichloro-6-methoxyquinazoline (400 mg, 1.75 mmol) in CH2Cl2 (10 mL) was added brine (10 mL) containing 9% NH3.H2O. Then zinc powder (336 mg, 5.25 mmol) was added and the mixture was refluxed for 2 hours. The mixture was diluted with CH2Cl2 (50 mL) and filtered off, the filtrate was neutralized by 2M HCl to pH 7. The aqueous layer extracted with CH2Cl2 (20 mL×2), the combined organic layer washed with brine (30 mL), dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by silica gel column (PE/EtOAc=5/1) to give Intermediate 8 (232 mg, yield 68%). 1H NMR (CDCl3 300 MHz): δ 9.20 (s, 1H), 7.90 (d, J=9.3 Hz, 1H), 7.40 (dd, J=9.3, 2.7 Hz, 1H), 7.15 (d, J=3.0 Hz, 1H), 3.95 (s, 3H).
Reaction SMILES: [C:1]([O:24]CC)(=[O:23])/[CH:2]=[CH:3]\[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[OH-].[Na+].O.Cl>CO>[C:1]([OH:24])(=[O:23])/[CH:2]=[CH:3]\[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCC=CC=CC=CC=CC=C/C=C\C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCCCCC=CC=CC=CC=CC=C/C=C\C(=O)O
Reaction time: 1.5 h
Yield: 91.3 %

Procedure:
To a solution of ethyl cis-docosahexaenoate (5 g, 14.0 mmol) in methanol (100 mL) was added an aqueous solution of NaOH (6 g, 150 mmol, in 20 mL of water) at rt and stirred for 1.5 h. The reaction mixture was poured into ice cooled water and acidified with dil. HCl. The solution was extracted with DCM (3×50 mL) and the combined layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and the solvent evaporated to give the acid (4.2 g, 91%) as an oil; LCMS (ESI, negative ion mode): m/z 327 (M-H)−.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:40][CH2:41][C:42]([O:44]CC)=[O:43])[C:8]([C:10]1[CH:39]=[CH:38][C:13]2[N:14]([CH3:37])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[NH:36])[NH:26][C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:28])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[OH-].[Na+]>ClCCl.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:40][CH2:41][C:42]([OH:44])=[O:43])[C:8]([C:10]1[CH:39]=[CH:38][C:13]2[N:14]([CH3:37])[C:15]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:25](=[NH:36])[NH:26][C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:28])=[CH:23][CH:24]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: CCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)O)c4ccccn4)ccc3n2C)cc1
Yield: 97 %

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and sodium hydroxide solution. Yield: 97% of theory, C32H37N7O5 (599.7) Rf value: 0.22 (silica gel; dichloromethane/methanol=9:1) ##EQU123##
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[C:15]([Cl:18])[CH:16]=[CH:17][N:11]2[N:10]=[C:9]1[CH:19]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O:25][C:26](=[O:32])[NH:27][CH2:28][CH2:29][CH2:30][NH2:31])([CH3:24])([CH3:23])[CH3:22].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CCO>[C:21]([O:25][C:26](=[O:32])[NH:27][CH2:28][CH2:29][CH2:30][NH:31][CH2:19][C:9]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:13](=[O:14])[C:12]2=[C:15]([Cl:18])[CH:16]=[CH:17][N:11]2[N:10]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: O=Cc1nn2ccc(Cl)c2c(=O)n1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCNCc1nn2ccc(Cl)c2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-benzyl-5-chloro-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-2-carbaldehyde (Example 22 E, 50 mg, 0.17 mmol) in EtOH (1 mL) was added 4 A molecular sieves (50 mg), (3-amino-propyl)-carbamic acid tert-butyl ester (Fluka, 33 mg, 0.19 mmol) and NaBH(OAc)3 (55 mg, 0.26 mmol) under Ar. The reaction mixture was stirred at rt for 2 h, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 1–2% MeOH/CHCl3) to afford the desired compound, as a colorless oil (12 mg, 16%): MS (ESI+) 446 (M++H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=[O:18])[CH2:13]1)=[N:7][N:6]=[CH:5]2.[CH:19]1([NH:22][C:23](=[O:40])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:25]=2)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CCO.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:19]1([NH:22][C:23](=[O:40])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8]([N:12]3[CH2:17][CH2:16][NH:15][C:14](=[O:18])[CH2:13]3)=[N:7][N:6]=[CH:5]4)[CH:25]=2)[CH2:20][CH2:21]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C1CN(c2nncc3cc(Br)ccc23)CCN1
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: [K+]
Solvent: CCO
Solvent: COCCOC
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CCNC(=O)C3)nncc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A mixture of 4-(6-bromophthalazin-1-yl)piperazin-2-one (0.10 g, 326 μmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (98mg, 326 μmol), and tetrakis(triphenylphosphine)palladium (19 mg, 16 μmol) in 5 mL DME/EtOH (4:1) was treated with 2M potassium carbonate (488 μl, 977 μmol). The resulting mixture was warmed up to 90° C. and stirred for 1 h under nitrogen. The mixture was cooled to room temperature, and the crude product was purified via flash chromatography (silica gel) eluting with a gradient of 4% 2 M ammonia in MeOH/DCM to 6% 2 M ammonia in MeOH/DCM to give the title compound (0.11 g) as a pale yellow solid. Found MS(ES+): 402(M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][O:10][C:11]2[CH:19]=[C:18]3[C:14]([C:15](=[O:29])[C:16](=[CH:20][CH:21]=[CH:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[O:17]3)=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])O.[Na+].[F:35][C:36]1[CH:50]=[CH:49][C:39]([C:40]([NH:42][CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[O:41])=[CH:38][CH:37]=1>CN(C)C=O>[F:35][C:36]1[CH:50]=[CH:49][C:39]([C:40]([NH:42][CH:43]2[CH2:48][CH2:47][N:46]([CH2:2][C:3]3[CH:4]=[C:5]([CH2:9][O:10][C:11]4[CH:19]=[C:18]5[C:14]([C:15](=[O:29])[C:16](=[CH:20][CH:21]=[CH:22][C:23]6[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=6)[O:17]5)=[CH:13][CH:12]=4)[CH:6]=[CH:7][CH:8]=3)[CH2:45][CH2:44]2)=[O:41])=[CH:38][CH:37]=1
Reactant: O=C(NC1CCNCC1)c1ccc(F)cc1
Reactant: O=C1C(=CC=Cc2ccccc2)Oc2cc(OCc3cccc(CCl)c3)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NC1CCN(Cc2cccc(COc3ccc4c(c3)OC(=CC=Cc3ccccc3)C4=O)c2)CC1)c1ccc(F)cc1
Temperature: 60 °C
Yield: 65.8 %

Procedure:
A mixture of 520 mg 6-(3-chloromethyl-phenylmethoxy)-2-cinnamylidenecoumaran-3-one (preparation 6), 150 mg sodium hydrogencarbonate, 330 mg 4-(4-fluorobenzamido)piperidine and 15 ml dimethylformamide is warmed to 60° C. for 3 hours, then evaporated, mixed with water and extracted with ethyl acetate. After evaporation of the extract, the residue is purified by silica gel chromatography (eluent ethyl acetate) to give 500 mg (65%) of the desired compound, m.p. 126-128° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH:11]=[CH:12][C:13](=[O:19])[NH:14]3)=[CH:5][CH:4]=1>Br>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH:11]=[CH:12][C:13](=[O:19])[NH:14]3)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nccc3[nH]c(=O)ccc23)cc1
Agent: Br
Product: O=c1ccc2c(-c3ccc(O)cc3)nccc2[nH]1
Yield: 94.1 %

Procedure:
A mixture containing 12.6 g of 5-(4-methoxyphenyl)-1,6-naphthyridin-2(1H)-one and 100 ml of 40% aqueous hydrogen bromide was refluxed for 14 hours, cooled and evaporated on a rotary evaporator. The remaining solution was neutralized by adding aqueous ammonium hydroxide solution. The resulting yellow solid was collected, washed with water, dried, recrystallized from dimethylformamide and dried in a vacuum oven at 90°-95° C. to yield 11.2 g of 5-(4-hydroxyphenyl)-1,6-naphthyridin-2(1H)-one, m.p. >300° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[C:17]([NH:19][C:20]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([N:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)[CH:23]=4)=[O:21])[CH:16]=[CH:15][C:14]=3[CH3:34])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:35][CH3:36].C1(C)C=CC(S(O[CH2:47][CH2:48][CH2:49][S:50]([CH3:53])(=[O:52])=[O:51])(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C(=O)C>O>[CH3:36][O:35][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:47][CH2:48][CH2:49][S:50]([CH3:53])(=[O:52])=[O:51])[N:9]=[CH:8][N:7]=[C:6]2[NH:12][C:13]1[CH:18]=[C:17]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=2)=[O:21])[CH:16]=[CH:15][C:14]=1[CH3:34]
Reactant: COc1cc2c(Nc3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3C)ncnc2cc1O
Reactant: Cc1ccc(S(=O)(=O)OCCCS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc2c(Nc3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3C)ncnc2cc1OCCCS(C)(=O)=O
Temperature: 100 °C
Yield: 12.2 %

Procedure:
A mixture of 7-hydroxy-6-methoxy-4-[2-methyl-5-(2-morpholinopyridine-4-carboxamido)anilino]quinazoline (250 mg), 3-methylsulphonylpropyl 4-toluenesulphonate (150 mg), cesium carbonate (501 mg) and N,N-dimethylacetamide (5 ml) was stirred and heated to 100° C. for 1 hour. After cooling the reaction mixture to ambient temperature, water was added and the precipitated solid was isolated and dried under vacuum. The material so obtained was purified by column chromatography on silica using a 10:1 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound as a solid (38 mg); NMR: 2.14 (s, 3H), 2.13 (m, 2H), 3.02 (s, 3H), 3.24 (m, 2H), 3.49 (m, 4H), 3.68 (m, 4H), 3.93 (s, 3H), 4.29 (t, 2H), 7.08 (d, 1H), 7.16 (s, 1H), 7.21 (s, 1H), 7.27 (d, 1H), 7.58 (d, 1H), 7.76 (s, 1H), 7.83 (s, 1H), 8.25 (d, 1H), 8.27 (s, 1H), 9.4 (s, 1H), 10.28 (s, 1H); m/s: M+H+ 607.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([O:13]C)=[O:12])[CH2:4][CH2:3][NH:2]1.Cl.[Br:16][C:17]1[C:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N:19][C:20](Cl)=[CH:21][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.O>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][CH:6]=3)[CH2:1]2)=[N:19][C:18]=1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]
Reactant: CC(C)(C)OC(=O)c1nc(Cl)ccc1Br
Reactant: COC(=O)c1cccc2c1CNCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)O)c3C2)ccc1Br
Temperature: 120 °C

Procedure:
A solution of methyl 1,2,3,4-tetrahydroisoquinoline-8-carboxylate, hydrochloric acid (13.6 g), tert-butyl 3-bromo-6-chloropicolinate (17.4 g) and cesium carbonate (39 g) were stirred together in N,N-dimethylacetamide (110 mL) and heated at 120° C. under nitrogen overnight. The reaction mixture was cooled, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and the combined aqueous layers were back-extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Silica gel chromatography using 20-100% ethyl acetate in hexanes provided the title compound.