Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16](O)=[O:17])=[O:13])=[C:4]1[CH3:23])[CH3:2].[CH3:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]2[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[CH:41][CH:40]=2)=[CH:34][CH:33]=1>>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2([N:38]([C:39]3[CH:40]=[CH:41][C:42]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[CH:43][CH:44]=3)[C:35]3[CH:34]=[CH:33][C:32]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH3:24])=[CH:37][CH:36]=3)[C:14]3[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:16](=[O:17])[O:13]2)=[C:4]1[CH3:23])[CH3:2]
Reactant: CCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Reactant: CCCCCCCCc1ccc(Nc2ccc(CCCCCCCC)cc2)cc1
Product: CCCCCCCCc1ccc(N(c2ccc(CCCCCCCC)cc2)C2(c3c(C)n(CC)c4ccccc34)OC(=O)c3ccccc32)cc1

Procedure:
Following a procedure similar to that described in Example 2B but employing 10.0 g of 2-(1-ethyl-2-methyl-3-indolylcarbonyl)benzoic acid and 13.0 g of 4,4'-dioctyldiphenylamine there was obtained a quantitive yield of 3-(1-ethyl-2-methyl-3-indolyl)-3-[N,N-bis-(4-octylphenyl)amino]phthalide, m.p. 106°-108° C. A toluene solution of the product contacted with acidic clay or phenolic resin developed a yellow-colored image.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Cl[C:9]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12].O>CN(C=O)C>[N:3]1([C:9]2[CH:16]=[C:15]([C:17]([F:18])([F:20])[F:19])[CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: c1c[nH]cn1
Reactant: N#Cc1ccc(C(F)(F)F)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(F)(F)F)cc1-n1ccnc1
Temperature: 100 °C
Yield: 73 %

Procedure:
To a suspension of NaH 60% (0.09 g, 3.97 mmol) in DMF (20 mL) at 0° C. was added in one portion 1H-imidazole (2.5 mol eq, 0.61 g). After 10 min 2-chloro-4-(trifluoromethyl)-benzonitrile (0.5 mL, 3.61 mmol) was added and the reaction mixture was heated at 100° C. for 2 h. The reaction was cooled at room temperature, water was added and the aqueous solution was extracted with EtOAc (3×25 mL). The recombined organic phases were dried over sodium sulfate and evaporated to dryness to give the 2-imidazol-1-yl-4-(trifluoromethyl)benzonitrile as pale yellow oil (0.63 g, 73% Yield) used for the reduction without further purification.
Reaction SMILES: [OH:1][N:2]1[CH:6]=[C:5]([I:7])[CH:4]=[N:3]1.[N:8]1([C:14](Cl)=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>>[I:7][C:5]1[CH:4]=[N:3][N:2]([O:1][C:14]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[O:15])[CH:6]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: On1cc(I)cn1
Product: O=C(On1cc(I)cn1)N1CCOCC1

Procedure:
The title compound was prepared from 1-hydroxy-4-iodopyrazole and 4-morpholine carbonyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (99%, crystals).
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:13]1[N:18]([CH3:19])[C:17](=[O:20])[CH:16]=[C:15]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:14]=1.C(N(CC)CC)C>>[CH3:19][N:18]1[C:17](=[O:20])[CH:16]=[C:15]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:14]=[C:13]1[N:9]1[CH2:10][CH2:11][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8]1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Reactant: c1ccc(C2CCNC2)cc1
Solvent: CCN(CC)CC
Product: Cn1c(N2CCC(c3ccccc3)C2)nc(-c2ccncc2)cc1=O
Yield: 88 %

Procedure:
A solution of 3-phenyl-pyrrolidine (449 mg, 3.05 mmol), 2-chloro-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (436 mg, 1.97 mmol) and triethylamine (412 mg, 4.07 mmol) was refluxed for one hour. After removal of the solvent, the residue was partitioned between water and ethyl acetate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate/ethanol=10/1) to afford 3-methyl-2-(3-phenyl-pyrrolidin-1-yl)-6-pyridin-4-yl-3H-pyrimidin-4-one (576 mg, 88%).
Reaction SMILES: C([NH:9][C:10]([NH:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:16][CH2:15]1)=[S:11])(=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CO.O>[CH2:23]([O:22][C:21](=[O:30])[NH:20][CH:17]1[CH2:16][CH2:15][CH:14]([CH2:13][NH:12][C:10]([NH2:9])=[S:11])[CH2:19][CH2:18]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(NC1CCC(CNC(=S)NC(=O)c2ccccc2)CC1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: NC(=S)NCC1CCC(NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.7 %

Procedure:
To a solution of benzyl N-[4-({[(benzoylamino)carbothioyl]amino}methyl)cyclohexyl]carba mate (5.02 g, 11.4 mmol) in MeOH (110 ml) was added a solution of K2CO3 (3.5 g, 25.3 mmol) in water (30 ml). The solution was stirred for 24 hours at room temperature. The solvent was removed in vacuo with repeated additions of MeOH to azeotropically remove water. The resulting solid was treated with acetone (60 ml) and filtered. The filtrate was evaporated to yield 95% (3.47 g) of a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH3:13][C:14]([CH3:18])=[CH:15][CH:16]=O.C1(B(O)O)C=CC=CC=1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:6]=[C:7]2[C:8](=[CH:9][CH:10]=1)[O:11][C:14]([CH3:18])([CH3:13])[CH:15]=[CH:16]2
Reactant: CC(C)=CC=O
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: OB(O)c1ccccc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)Cc1ccc2c(c1)C=CC(C)(C)O2
Temperature: 25 °C
Reaction time: 7 h

Procedure:
25 g methyl-4-hydroxyphenylacetate, 14.5 ml 3-methylbut-2-enal and 18.3 g phenylboronic acid were placed together under nitrogen atmosphere in 1 l dry toluene and heated to boiling for 7 hours under reflux cooling. Then 60 ml glacial acetic acid was added to this receiving solution at room temperature (=RT) and the mixture was again heated to boiling for 7 hours under reflux cooling. It was allowed to cool to room temperature, the solvent was largely evaporated at reduced pressure and the remaining residue was poured into 300 ml of a 1:1 (v/v) mixture of ethyl acetate (═EA) and water. The pH value was adjusted to 5 by addition of solid sodium bicarbonate, the organic phase was separated off and largely evaporated at reduced pressure. Chromatography of the remaining residue on silica gel (mobile phase: petroleum ether/EA 10:1 v/v) yielded 16 g methyl-(2,2-dimethyl-2H-chromen-6-yl)acetate as pale yellow oil.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[CH2:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH:16]=[CH:15][N:14]=1.[OH-].[Na+]>C(O)C>[CH3:25][O:24][CH2:23][CH2:22][CH2:21][CH2:20][O:19][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([CH2:12][S:1][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=2)[CH:18]=1
Reactant: COCCCCOc1ccnc(CCl)c1
Reactant: Sc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1
Yield: 70.7 %

Procedure:
A mixture comprising 2.55 g (0.017 mol) of 2-mercaptobenzimidazole, 5.09 g (0.022 mol) of 2-chloromethyl-4-(4-methoxybutoxy)pyridine, 0.84 g (0.020 mol) of 95% sodium hydroxide and 60 ml of ethanol was stirred at 40° C. for 1.5 hours. After the completion of the reaction, the reaction mixture was distilled to remove the solvent. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) to obtain 4.13 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:3][CH:4]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.9 %

Procedure:
To a solution of 4-aminophenol (30.00 g, 275 mmol) in DMF (120 ml) at 0° C. under an atmosphere of nitrogen was added triethylamine (42.5 ml, 302 mmol, 1.2 eq). The reaction mixture was stirred for 10 minutes before dropwise addition of benzoyl chloride (31.9 ml, 275 mmol, 1.0 eq) over a period of 20 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was poured in ice cold water (800 ml) with vigorous stirring. A precipitate was collected by filtration and washed with water (2×500 ml). The precipitate was slurried in diethyl ether (1.5 L) and vigorously stirred for 30 minutes. The precipitate was collected by filtration and allowed to dry under reduced pressure to afford the title compound as an off-white solid (41.56 g, 71% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24]CC)=[O:23])=[CH:16][CH:15]=1)=[C:8]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:7]([CH2:33][CH2:34][C:35]([F:38])([F:37])[F:36])=[CH:6]2.[OH-].[Na+]>C1COCC1.CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:15]=[CH:16][C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])=[CH:18][CH:19]=1)=[C:8]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:7]([CH2:33][CH2:34][C:35]([F:36])([F:38])[F:37])=[CH:6]2
Reactant: CCOC(=O)/C=C/c1ccc(Oc2c(-c3ccccc3)c(CCC(F)(F)F)cc3cc(OC)ccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2c(Oc3ccc(/C=C/C(=O)O)cc3)c(-c3ccccc3)c(CCC(F)(F)F)cc2c1
Yield: 87.5 %

Procedure:
Ethyl ester (127) (0.34 g, 0.65 mmol) was saponified with 1 N NaOH in THF and EtOH to give 0.28 g (88%) of the title compound (128) as a white solid. 1H NMR (400 MHz, CDCl3): δ 2.10-2.25 (m, 2H), 2.80-2.90 (m, 2H), 3.94 (s, 3H), 6.22 (d, J=15.9 Hz, 1H), 6.57 (d, J=8.6 Hz, 2H), 7.06-7.14 (m, 3H), 7.17 (d, J=2.4 Hz, 1H), 7.22-7.30 (m, 5H), 7.59 (s, 1H), 7.62 (d, J=15.9 Hz, 1H), 7.72 (d, J=9.1 Hz, 1H). LCMS (ESI): m/z 493 (M+H)+, m/z 491 (M−H)−.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:36](=[O:37])[N:6]2[C:7]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)=[O:24])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([S:19][CH2:20][CH2:21][OH:22])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].C(N(CC)C(C)C)(C)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>ClCCl>[OH:1][C@@H:2]([C@H:4]1[C:36](=[O:37])[N:6]2[C:7]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)=[O:24])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([S:19][CH2:20][CH2:21][O:22][S:48]([CH3:47])(=[O:50])=[O:49])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(SCCO)c4s3)[C@H](C)[C@H]12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(SCCOS(C)(=O)=O)c4s3)[C@H](C)[C@H]12
Reaction time: 0.67 h

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(2-hydroxyethyl)thioimidazo[5,1-b]thiazol-2-yl]-1-methyl-1-carbapen-2-em-3-carboxylate (62.8 mg) was dissolved in 2 ml of dichloromethane. N,N-Diisopropylethylamine (0.040 ml) and 0.011 ml of methanesulfonyl chloride were added to the solution at −50° C. The mixture was stirred at that temperature for 40 min. The reaction solution was then diluted with dichloromethane, and the diluted solution was washed with water. The organic layer was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=20:1) to prepare 40.9 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(2-methanesulfonyloxyethyl)thioimidazo[5,1-b]thiazol-2-yl]-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:3]=1[CH3:20].[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[C:32]([NH2:33])=[CH:31][C:30]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:29][N:28]=2)[CH2:23][CH2:22]1.Cl.O1CCOCC1>CO>[N:24]1([C:27]2[C:32]([NH:33][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=4)[N:5]=[C:4]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[F:19])[C:3]=3[CH3:20])=[CH:31][C:30]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:29][N:28]=2)[CH2:23][CH2:22][O:21][CH2:26][CH2:25]1
Reactant: Cc1c(-c2ccccc2F)nc2cc(F)ccc2c1Cl
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1c(-c2ccccc2F)nc2cc(F)ccc2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
Prepared according to general Procedure K using 4-chloro-7-fluoro-2-(2-fluorophenyl)-3-methylquinoline (100 mg, 0.34 mmol), 2,5-dimorpholinopyridin-3-amine (91 mg, 0.34 mmol) and a 4.0M solution of HCl in dioxane (0.017 mL, 0.069 mmol) in MeOH (1.0 mL) and heating in the microwave for 2 h at 150° C. After purification N-(2,5-di-4-morpholinyl-3-pyridinyl)-7-fluoro-2-(2-fluorophenyl)-3-methyl-4-quinolinamine was obtained as a yellow film. 1H NMR (500 MHz, chloroform-d) δ ppm δ ppm 7.85 (1H, br. s.), 7.81 (1H, dd, J=9.9, 2.6 Hz), 7.58-7.65 (2H, m), 7.44-7.51 (1H, m), 7.30-7.37 (2H, m), 7.20 (1H, t, J=9.2 Hz), 6.85 (1H, br. s.), 6.27 (1H, br. s.), 3.94 (4H, t, J=4.6 Hz), 3.71-3.80 (4H, m), 3.22 (4H, br. s.), 2.98 (4H, br. s.), 2.18 (3H, s). Mass Spectrum (ESI) m/e=518.2 (M+1).
Reaction SMILES: [CH2:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)[CH:2]=[CH2:3].[I:9]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>C1COCC1>[I:9][CH2:3][CH2:2][CH2:1][C:4]1[S:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CCC(=O)N1I
Reactant: C=CCc1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: ICCCc1cccs1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 61.4 %

Procedure:
Cp2ZrHCl (9.141 g, 35.4 mmol) was added to a solution of 33 (3.668 g, 29.5 mmol) in THF (50 mL). The mixture was stirred for 1.5 h at 40° C., cooled to 0° C. and was then treated with N-iodosuccinimide (NIS, 7.972 g, 35.4 mmol). The reaction was allowed to warm to room temperature and after 75 min., 100 mL of saturated NaHCO3 solution was added. The mixture was extracted with ether (2×100 mL) and the combined ether solution was dried (Na2SO4), filtered and evaporated. The residue was purified on a Teledyne Isco Combiflash unit (330 g silica gel column, 0%→20% ethyl acetate/hexanes) which gave the title compound (4.558 g, 18.1 mmol, 61%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[N:3]=1.Cl.[NH2:21][C:22]1[C:27]([C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])=[CH:26][CH:25]=[C:24]([NH:34][CH:35]2[CH2:40][CH2:39][CH2:38][NH:37][CH2:36]2)[N:23]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[ClH:1].[NH2:21][C:22]1[N:23]=[C:24]([NH:34][CH:35]2[CH2:40][CH2:39][CH2:38][N:37]([C:2]3[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[C:4]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=4[Cl:19])[N:3]=3)[CH2:36]2)[CH:25]=[CH:26][C:27]=1[C:28](=[O:33])[C:29]([F:32])([F:31])[F:30]
Reactant: COC(=O)c1ccc(-c2ccc(Cl)cc2Cl)nc1Cl
Reactant: Nc1nc(NC2CCCNC2)ccc1C(=O)C(F)(F)F
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(-c2ccc(Cl)cc2Cl)nc1N1CCCC(Nc2ccc(C(=O)C(F)(F)F)c(N)n2)C1
Temperature: 140 °C

Procedure:
255 mg (0.533 mmol) of methyl 2-chloro-6-(2,4-dichlorophenyl)pyridine-3-carboxylate (Example 16A), 259 mg (0.799 mmol) of 1-[2-amino-6-(piperidin-3-ylamino)pyridin-3-yl]-2,2,2-trifluoroethanone hydrochloride (Example 13A) and 0.56 ml (3.2 mmol) of N,N-diisopropylethylamine were initially charged in 4.5 ml of DMSO. The mixture was heated at 140° C. in a microwave for 45 min. The crude product was purified by means of preparative HPLC (method 10). 28 mg (8% of theory) of the product were obtained in solid form.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH3:5][N:6]1[C:14]2[C:13](=[O:15])[NH:12][C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])=[N:10][C:9]=2[C:8]([CH2:26][CH2:27][CH3:28])=[N:7]1.[Br:29][CH2:30][C:31](Cl)=[O:32].O>ClCCl>[Br:29][CH2:30][C:31]([C:20]1[CH:19]=[CH:18][C:17]([O:22][CH2:23][CH2:24][CH3:25])=[C:16]([C:11]2[NH:12][C:13](=[O:15])[C:14]3[N:6]([CH3:5])[N:7]=[C:8]([CH2:26][CH2:27][CH3:28])[C:9]=3[N:10]=2)[CH:21]=1)=[O:32]
Reactant: CCCOc1ccccc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Reactant: O=C(Cl)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCCOc1ccc(C(=O)CBr)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.9 %

Procedure:
Aluminum trichloride (6.0 g, 0.045 mol) was added portionwise to a stirred solution of -1-methyl-5-(2-n-propoxyphenyl)-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one (5.0 g, 0.0153 mol) and 2-bromoacetyl chloride (2.5 ml, 0.0303 mol) in dichloromethane (100 ml) at 0° C. The reaction mixture was allowed to warm to room temperature, stirred for 18 hours, heated under reflux for 3 hours and then added cautiously to ice and water (100 g). The resulting mixture was stirred for 1 hour and extracted with dichloromethane (2×50 ml). The combined organic extracts were washed with brine (2×50 ml), dried (Na2SO4), then evaporated under vacuum to give an off-white solid, which was triturated with ether to give the title compound as a white solid (4.1 g, 60%). A small sample was crystallised from ethyl acetate-hexane to give the pure product, m.p. 136°-137° C. Found: C,53.82; H,5.24; N,12.57. C20H23BrN4O3 requires C,53.70;H,5.18; N,12.52%
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:27](=[N:29][OH:30])[NH2:28])[CH:5]=[C:6]([Cl:26])[C:7]=1[NH:8][C:9]1[C:18]2[CH:19]=[CH:20][N:21]=[C:22]([O:23][CH2:24][CH3:25])[C:17]=2[C:16]2[C:11](=[CH:12][CH:13]=[N:14][CH:15]=2)[N:10]=1.N1C=CC=CC=1.[C:37]([O:40][C:41]([CH3:46])([CH3:45])[C:42](Cl)=O)(=[O:39])[CH3:38]>O1CCOCC1>[C:37]([O:40][C:41]([C:46]1[O:30][N:29]=[C:27]([C:4]2[CH:5]=[C:6]([Cl:26])[C:7]([NH:8][C:9]3[C:18]4[CH:19]=[CH:20][N:21]=[C:22]([O:23][CH2:24][CH3:25])[C:17]=4[C:16]4[C:11](=[CH:12][CH:13]=[N:14][CH:15]=4)[N:10]=3)=[C:2]([Cl:1])[CH:3]=2)[N:28]=1)([CH3:45])[CH3:42])(=[O:39])[CH3:38]
Reactant: CCOc1nccc2c(Nc3c(Cl)cc(C(N)=NO)cc3Cl)nc3ccncc3c12
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CCOc1nccc2c(Nc3c(Cl)cc(-c4noc(C(C)(C)OC(C)=O)n4)cc3Cl)nc3ccncc3c12
Temperature: 110 °C

Procedure:
To a solution of 3,5-dichloro-4-[(10-ethoxypyrido[4,3-c]-1,6-naphthyridin-6-yl)amino]-N′-hydroxybenzenecarboximidamide (50 mg, 0.11 mmol) in 1,4-dioxane (1 mL) was added pyridine (0.1 mL) and 2-chloro-1,1-dimethyl-2-oxoethyl acetate (0.016 mL, 0.11 mmol). The reaction was heated to 110° C. for 4 h in a sealed tube. After cooling to room temperature, the solvents were evaporated and the residue was dissolved in THF/MeOH, filtered and purified by reverse phase HPLC to afford the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:35]=[CH:36][CH:37]=1)[CH2:6][N:7]([C@@H:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1)[C:8]([C:10]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C:13]([C:19]([OH:21])=[O:20])=[CH:12][C:11]=1[C:22]([OH:24])=[O:23])=[O:9])=O.[CH2:38]([O:45][NH2:46])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH2:38]([O:45][N:46]=[CH:1][C:3]1[CH:4]=[C:5]([CH:35]=[CH:36][CH:37]=1)[CH2:6][N:7]([C@@H:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1)[C:8]([C:10]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C:13]([C:19]([OH:21])=[O:20])=[CH:12][C:11]=1[C:22]([OH:24])=[O:23])=[O:9])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: NOCc1ccccc1
Reactant: O=Cc1cccc(CN(C(=O)c2cc(C(=O)O)c(C(=O)O)cc2C(=O)O)[C@H]2CCCc3ccccc32)c1
Product: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(C=NOCc3ccccc3)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O

Procedure:
The product from Example 76E and O-benzylhydroxylamine were processed as described in Example 76F to provide the title compound.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[CH:15][N:16]=[CH:17][C:18]([Br:19])=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:20]([N-]C(C)C)(C)[CH3:21].[Li+].C(I)C>C1COCC1>[C:1]1([S:7]([N:10]2[C:14]3=[CH:15][N:16]=[CH:17][C:18]([Br:19])=[C:13]3[CH:12]=[C:11]2[CH2:20][CH3:21])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)[N-]C(C)C
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)cncc21
Agent: [Li+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCc1cc2c(Br)cncc2n1S(=O)(=O)c1ccccc1
Temperature: -35 °C
Reaction time: 0.5 h
Yield: 39.7 %

Procedure:
To a solution of 1-benzenesulfonyl-4-bromo-1H-pyrrolo[2,3-c]pyridine (0.63 g, 1.86 mmol) in anhydrous THF (10 mL), at −35° C., was added a solution of lithium diisopropylamide (2.0M in heptane/THF/ethyl benzene, 1.86 mL, 3.77 mmol) dropwise. The reaction mixture was stirred at −35° C. for 30 min and then ethyl iodide (0.90 mL, 11.18 mmol) was added dropwise. The resulting solution was allowed to reach room temperature and was stirred for 4 h. The reaction mixture was quenched by addition of a solution of 1N HCl (5 mL); the solution was diluted with water (15 mL) and extracted with EtOAc (2×75 mL). The organic extracts were combined, washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, EtOAc:cyclohexane 0:100 to 70:30). The residue was triturated in EtOAc (2 mL) and collected by filtration to give the title compound as a white solid (0.27 g, 40%). LCMS (Method H): RT=4.65 min, [M+H]+ 367 (79Br), 369 (81Br)
Reaction SMILES: C([O:3][CH2:4][C:5]1[N:6]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)C.CC(C)CN.NCC(C)(O)C.B(Br)(Br)Br>ClCCl>[NH2:17][C:9]1[C:8]2[N:18]=[C:5]([CH2:4][OH:3])[N:6]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:7]=2[C:16]2[N:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCOCc1nc2c(N)nc3cccnc3c2n1CC(C)C
Agent: BrB(Br)Br
Agent: CC(C)(O)CN
Solvent: ClCCl
Solvent: CC(C)CN
Product: CC(C)Cn1c(CO)nc2c(N)nc3cccnc3c21
Temperature: 25 °C
Reaction time: 44 h

Procedure:
To a chilled solution (ice bath) of 2-(ethoxymethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (2.0 g, 6.69 mmol, prepared according to the general methods of Example 148 using 2-methylpropan-1-amine in lieu of 1-amino-2-methylpropan-2-ol) in dichloromethane (50 mL) was added boron tribromide (20 mL, 1M solution in dichloromethane). The mixture turned light purple and was stirred at ambient temperature for 44 hours. The reaction was quenched with methanol (20 mL) and aqueous hydrochloric acid (6N, 10 mL). After stirring for 4 hours, the pH was adjusted to 10 by the addition of aqueous sodium hydroxide (50%). Dichloromethane (50 mL) was added with stirring and the layers were separated. The aqueous fraction was extracted with chloroform (2×250 mL). The combined organic fractions were concentrated to provide 1.4 g of [4-amino-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-2-yl]methanol as a white powder, mp 226-228° C.
Reaction SMILES: [CH2:1]([N:3]1[CH2:12][CH2:11][CH:10]2[C:5](=[C:6]([N+:14]([O-])=O)[CH:7]=[CH:8][CH:9]2[Br:13])[CH2:4]1)[CH3:2].[H][H]>[Ni].CC(C)=O.C1COCC1>[CH2:1]([N:3]1[CH2:12][CH2:11][CH:10]2[C:5](=[C:6]([NH2:14])[CH:7]=[CH:8][CH:9]2[Br:13])[CH2:4]1)[CH3:2]
Reactant: CCN1CCC2C(=C([N+](=O)[O-])C=CC2Br)C1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CCN1CCC2C(=C(N)C=CC2Br)C1
Reaction time: 1 h

Procedure:
Raney nickel was refluxed in acetone for 2 hours prior to use to deactivate the metal. The product from Example 26 (0.1 g, 0.35 mmol) was dissolved in THF (10 mL), the Raney nickel added, and the reaction vessel charged with hydrogen gas. After stirring for 1 hour, the Raney nickel was removed by filtration and the solvent removed by filtration to give N-ethyl-5-bromo-8-aminotetrahydroisoquinoline (used without further purification).