Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:19]([NH2:21])=[N:18][CH:17]=[N:16][C:15]=4[N:14]([CH3:22])[CH:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[CH3:23][C:24]1[CH:28]=[C:27]([CH3:29])[N:26]([CH2:30][C:31](O)=[O:32])[N:25]=1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.C(OC(=O)C)C>CN(C)C=O>[CH3:23][C:24]1[CH:28]=[C:27]([CH3:29])[N:26]([CH2:30][C:31]([N:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]4[C:20]5[C:19]([NH2:21])=[N:18][CH:17]=[N:16][C:15]=5[N:14]([CH3:22])[CH:13]=4)=[CH:9][CH:10]=3)[CH2:5][CH2:4]2)=[O:32])[N:25]=1
Reactant: Cn1cc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Reactant: Cc1cc(C)n(CC(=O)O)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C)n(CC(=O)N2CCc3cc(-c4cn(C)c5ncnc(N)c45)ccc32)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
To a mixture of 5-(2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine dihydrochloride (175 mg, 0.517 mmol) and (3,5-dimethyl-1H-pyrazol-1-yl)acetic acid (80 mg, 0.517 mmol) in N,N-Dimethylformamide (DMF) (3 mL) was added DIPEA (0.271 mL, 1.552 mmol) dropwise. The mixture was cooled in an ice bath, and T3P (1-propanephosphonic acid cyclic anhydride), 50% in ethylacetate (˜1.68M) (0.370 mL, 0.621 mmol) was then added dropwise. After stirring 30 minutes, the ice bath was removed and the mixture was allowed to warm to room temperature and stir 2 hours. The mixture was diluted with water (˜5 mL) and basified to pH 7-8 with 0.5M NaOH. Methanol was added to give a clear solution. This solution was loaded onto a reversed phase C18 SF25-55g Analogix cartridge and the product purified by eluting with a gradient of 30-95% methanol-water. The combined pure fractions containing the product was evaporated and azeotroped with acetonitrile and then benzene to give a solid that was triturated with acetonitrile (˜4 mL), filtered and washed with acetonitrile to afford 5-{1-[(3,5-dimethyl-1H-pyrazol-1-yl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (90 mg, 41.2% yield) as a white solid after drying under vacuum. LCMS (ES) m/z=402.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.15 (s, 1H) 8.07 (d, J=8.1 Hz, 1H) 7.34 (s, 1H) 7.20-7.29 (m, 2H) 6.08 (br. s, 2H) 5.86 (s, 1H) 5.09 (s, 2H) 4.26 (t, J=8.3 Hz, 2H) 3.74 (s, 3H) 3.27 (t, J=8.3 Hz, 2H) 2.17 (s, 3H) 2.10 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[C:3]([CH3:8])[CH:2]=1.[OH:9]O.CCCCCC>C(O)(=O)C>[N+:1]1([O-:9])[CH:6]=[CH:5][C:4]([CH3:7])=[C:3]([CH3:8])[CH:2]=1
Reactant: OO
Reactant: Cc1ccncc1C
Solvent: CCCCCC
Solvent: CC(=O)O
Product: Cc1cc[n+]([O-])cc1C
Temperature: 75 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
The general procedure of Boekelheide1 for the preparation of hydroxymethylpyridines was used. Thus, a solution of freshly distilled 3,4-lutidine (46.0 g, 0.43 mol) in 120 mL of glacial acetic acid was cooled at 0° C. and then 64 mL of 30% H2O2 was added dropwise. The resulting solution was heated at 75° C. (oil-bath temperature) for 3 h. Another 20 mL of 30% H2O2 was then added and heating was continued for 18 h. Finally, 20 mL of 30% H2O2 was again added and the reaction was kept at 75° C. for another 3 h. The solution was then concentrated to about 100 mL under water-aspirator pressure, 50 mL of H2O was added and the mixture was concentrated to about one half volume. The resulting mixture was cooled (0°-5° C.) and basified to about pH 10 using cold 40% aqueous NaOH. The mixture was then extracted with CH2Cl2 (5x) and the extract was dried (Na2CO3 +Na2SO4) and concentrated on the roto-vap to give a yellow solution. Dilution of this solution with hexane afforded a solid which was collected by filtration and then dried in vacuo to give 3,4-lutidine-N-oxide (48.0 g, 83%) as an off-white solid.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.[CH2:11]([N:14]1[C@H:19]([CH3:20])[CH2:18][N:17]([C@H:21]([C:36]2[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=2)[C:39](Cl)=[O:40])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][Si](C(C)(C)C)(C)C)[CH:23]=2)[C@@H:16]([CH3:45])[CH2:15]1)[CH:12]=[CH2:13]>>[CH2:11]([N:14]1[C@H:19]([CH3:20])[CH2:18][N:17]([C@H:21]([C:36]2[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=2)[C:39]([N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:40])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=2)[C@@H:16]([CH3:45])[CH2:15]1)[CH:12]=[CH2:13]
Reactant: C=CCN1C[C@H](C)N([C@@H](c2cccc(O[Si](C)(C)C(C)(C)C)c2)c2cccc(C(=O)Cl)c2)C[C@H]1C
Reactant: c1ccc(NC2CC2)cc1
Product: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C(=O)N(c3ccccc3)C3CC3)c2)C[C@H]1C

Procedure:
N-Cyclopropylaniline was then be coupled with 3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)-benzyl)benzoyl chloride, deprotected and purified by the methods described in Example 10 to give 3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-cyclopropyl-N-phenylbenzamide as a yellow powder. NMR (200 MHz, DMSO-d6): δ 0.44 (m, 2H); 0.70 (m, 2H); 0.93 (d, J=6.1 Hz, 3H); 1.01 (d, J=5.7 Hz, 3H); 1.74 (dd, J1 =7.7 Hz, J2 =11.8 Hz, 1H); 2.05 (dd, J1 =6.8 Hz, J2 =11.1 Hz, 1H); 2.39 (br d, J=10.5 Hz, 1H); 2.41-2.54 (m, 2H); 2.69 (br d, J=11.8 Hz, 1H); 2.83 (dd, J1 =6.6 Hz, J2 =13.6 Hz, 1H); 3.05-3.36 (m, 2H); 4.83 (s, 1H); 5.10 (d, J=9.8 Hz, 1H); 5.17 (d, J=17.4 Hz, 1H); 5.70-5.86 (m, 1H); 6.57 (d, J=7.1 Hz, 1H); 6.63 (s, 1H); 6.65 (d, J=8.2 Hz, 1H); 7.03-7.38 (m, 10H); 9.34 (s, 1H). Mass spectrum (CI--CH4) m/e: 496 (M+1, 100%), 342 (45%), 153 (90%). [α]D20 =+7.1° (abs. ethanol, c=1.1). The free amine was dissolved in ethanol and titrated with ethanolic hydrogen chloride to pH 3.95 followed by precipitation with diethyl ether from dichloromethane to give the monohydrochloride salt as a hygroscopic orange powder. Calc. for C32H37N3O2HCl 1.50H2O: C, 68.74; H, 7.39; N, 7.51; Cl, 6.34. Found: C, 68.56; H, 7.49; N, 7.26; Cl, 6.37.
Reaction SMILES: C([O:5][C:6](=[O:31])[CH2:7][N:8]1[C:12]2([CH2:17][CH2:16][C:15](=[CH:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:14][CH2:13]2)[S:11][CH:10]([CH2:23][C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[C:9]1=[O:30])(C)(C)C.Cl>C(OCC)C.O1CCOCC1>[CH:27]([O:26][C:24](=[O:25])[CH2:23][CH:10]1[C:9](=[O:30])[N:8]([CH2:7][C:6]([OH:31])=[O:5])[C:12]2([CH2:13][CH2:14][C:15](=[CH:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:16][CH2:17]2)[S:11]1)([CH3:29])[CH3:28]
Reactant: CC(C)CC=C1CCC2(CC1)SC(CC(=O)OC(C)C)C(=O)N2CC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)CC=C1CCC2(CC1)SC(CC(=O)OC(C)C)C(=O)N2CC(=O)O
Reaction time: 2 h
Yield: 27.7 %

Procedure:
In 3 ml of diethyl ether was dissolved 0.33 g of isopropyl 2-[4-[2-(tert-butoxy)-2-oxoethyl]-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-2-yl]-acetate. Then, 1 ml of a 5.39 mol/L solution of dry hydrogen chloride in dioxane was added and the resulting mixture was stirred at the same temperature as above for 2 hours. Further, 1 ml of 5.39 mol/L solution of dry hydrogen chloride in dioxane was added and the resulting mixture was stirred for one hour, after which 3 ml of 5.39 mol/L solution of dry hydrogen chloride in dioxane was added and the resulting mixture was stirred for one hour. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography [eluent: chloroform]. Then, hexane was added, and the deposited crystal was collected by filtration. Thus, 0.08 g of 2-[2-(2-isopropoxy-2-oxoethyl)-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl]-acetic acid was obtained as a colorless crystalline product.
Reaction SMILES: S(Cl)(C)(=O)=O.[CH3:6][C:7]1[O:11][N:10]=[C:9]([C:12]2[N:16]3[N:17]=[C:18]([O:25][CH2:26][C:27]4[N:28]=[N:29][N:30]([CH2:32][CH2:33]O)[CH:31]=4)[C:19]4[C:24]([C:15]3=[N:14][N:13]=2)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:8]=1.C[CH2:36][N:37](CC)[CH2:38]C.N(C)C>C(Cl)Cl.C1COCC1.O>[CH3:36][N:37]([CH3:38])[CH2:33][CH2:32][N:30]1[CH:31]=[C:27]([CH2:26][O:25][C:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15]3=[N:14][N:13]=[C:12]([C:9]4[CH:8]=[C:7]([CH3:6])[O:11][N:10]=4)[N:16]3[N:17]=2)[N:28]=[N:29]1
Reactant: CCN(CC)CC
Reactant: Cc1cc(-c2nnc3c4ccccc4c(OCc4cn(CCO)nn4)nn23)no1
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4cn(CCN(C)C)nn4)nn23)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.9 %

Procedure:
Mesyl chloride (349 μl, 4.5 mmol) was added to a stirred suspension of 2-{4-[3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[3,4-α]phthalazin-6-yloxymethyl]-[1,2,3]triazol-1-yl}ethanol (354 mg, 0.9 mmol) in Et3N (629 μl, 4.5 mmol) and CH2Cl2 (50 ml) at 0° C. under N2. The reaction was stirred overnight slowly warming to room temperature. H2O (20 ml) was added and the organics separated, dried and concentrated under reduced pressure. The crude residue was taken up in DMF (5 ml) in a sealed tube and a solution of Me2NH (8 mmol) in THF (2.0 M, 4 ml) was added. The reaction was heated at 80° C. for 4 h. The reaction mixture was concentrated under reduced pressure and then taken up in MeOH/CH2Cl2 and dry loaded onto silica. The mixture was purified by column chromatography on silica using 1.5% MeOH/CH2Cl2 containing 1% NH3 as eluent to yield the desired phthalazine (30 mg, 8%). 1H NMR (360 MHz, CDCl3) δ 8:85 (1H, s), 8.64 (1H, d, J=7.4 Hz), 8.24 (1H, d, J=7.4 Hz), 7.93 (1H, t, J=7.4 Hz), 7.80 (1H, t, J=7.4 Hz), 6.90 (1H, s), 5.77 (2H, s), 4.46 (2H, t, J=6.5 Hz), 2.92 (2H, t, J=6.5 Hz), 2.60 (3H, s), 2.24 (6H, s). m/z (ES+) 420 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[C@H:7]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[NH:8][C:9](=[O:26])[C@H:10]([CH:23]([CH3:25])[CH3:24])[N:11](C(OCC1C=CC=CC=1)=O)[CH3:12])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:35])[C@H:7]([CH2:27][C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[NH:8][C:9](=[O:26])[C@H:10]([CH:23]([CH3:25])[CH3:24])[NH:11][CH3:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)[C@@H](C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)N(C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CN[C@H](C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(C)C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of the compound (0.91 g, 1.8 mmol) obtained in step 1 in ethanol (40 ml) was added a catalytic amount of 10% palladium/carbon, and the mixture was stirred for 3 hours under a hydrogen atmosphere. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (0.66 g, 1.8 mmol, 99%).
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH2:13][N:12](CC2C=CC=CC=2)[CH2:11][CH:10]1[CH2:22][NH:23][C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])C1C=CC=CC=1>C(O)(=O)C.[Pd]>[ClH:1].[CH:27]([O:26][C:24]([NH:23][CH2:22][CH:10]1[CH2:11][NH:12][CH2:13][CH2:14][NH:9]1)=[O:25])([CH3:29])[CH3:28]
Reactant: CC(C)OC(=O)NCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)OC(=O)NCC1CNCCN1
Temperature: 60 °C
Yield: 100.7 %

Procedure:
32.3 g (71 mmol) of 1,4-dibenzyl-2-isopropyloxycarbonylaminomethylpiperazine hydrochloride are dissolved in 100 ml of acetic acid and 200 mg of palladium (10%) on charcoal are added. Using PARR apparatus, the suspension is stirred and heated at 60° C. under hydrogen pressure (2.7 bar) overnight. The catalyst is filtered off and the solvent is evaporated to give a compound which is crystallized from an ethanol/ether mixture (5/95 v/v) to give 17 g of 2-isopropyloxycarbonylaminomethylpiperazine hydrochloride in the form of white crystals. Yield: 87%. Melting point: 237.1° C. Rf=0.6 (80/20/2 v/v/v CHCl3/MeOH/NH4OH).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].I[C:14]1[CH:15]=[N:16][C:17]([NH2:20])=[N:18][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+].N#N.[OH-].[Na+]>O.CCO.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:15]=[N:16][C:17]([NH2:20])=[N:18][CH:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(B(O)O)cc1F
Reactant: Nc1ncc(I)cn1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-c2cnc(N)nc2)cc1F
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
In a 500 mL round bottom flask under N2, 3-fluoro-4-methoxyphenylboronic acid (5.0 g, 29.4 mmol) and 5-iodopyrimidin-2-amine (5.5 g, 24.9 mmol) were mixed. Toluene (100 mL), EtOH (40 mL) and H2O (20 mL) were added, followed by the addition of Na2CO3 (3.0 g, 24.2 mmol). A stream of N2 was bubbled through the mixture for 5 min before the catalyst Pd(PPh)4 (0.30 g, 0.26 mmol) was added. The mixture was heated at 80° C. under N2 for 20 h whereby it was cooled to RT. A solution of NaOH (5 N, 10 mL) was added to the mixture and stirring was continued for 10 min. The mixture was filtered and the solid was washed with H2O (3×10 mL), followed by a mixture of hexanes—EtOAc (1:1, 30 mL). The solid was dried in the air to give the title compound. MS (ESI pos. ion) m/z: 220. Calc'd for C11H10FN3O: 219.08.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[C:12]([O:18][CH2:19][CH2:20][Cl:21])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].N1CCCCC1.C(O)(=O)C>C1C=CC=CC=1>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[C:13]([C:14]([CH3:16])=[O:15])[C:12]([O:18][CH2:19][CH2:20][Cl:21])=[O:17])([O-:3])=[O:2]
Reactant: CC(=O)CC(=O)OCCCl
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Solvent: c1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CC(=O)C(=Cc1ccccc1[N+](=O)[O-])C(=O)OCCCl

Procedure:
A mixture of 2-nitrobenzaldehyde (4.536 g), 2-chloroethyl acetoacetate (4.94 g) and piperidine (110 mg) in benzene (18 ml) and acetic acid (360 mg) was refluxed for an hour under azeotropic dehydration. The reaction mixture was washed with water and dried. The solvent was distilled off to give an reddish oil of B 2-chloroethyl 2-(2-nitrobenzylidene)acetoacetate, and thus obtained oil was treated with ethyl 3-amino-4,4-diethoxycrotonate (7.1 g) to give yellow granules of 2-chloroethyl 2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate, m.p. 82° to 84° C. (recrystallized from diisopropyl ether).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23]>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:22]([NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][C:13]([F:12])([F:24])[F:25])=[O:23]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: O=C=Nc1ccccc1OC(F)(F)F
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1ccccc1OC(F)(F)F

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N′-(2-trifluoromethyloxyphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-trifluoromethoxy phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (0.69 g, 60%). EI-MS m/z 358 (M+H)+
Reaction SMILES: Br[C:2]1[CH:20]=[C:19]([Cl:21])[C:5]([O:6][C@H:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([O:10][CH3:11])=[O:9])=[C:4]([Cl:22])[CH:3]=1.[CH:23]1[C:31]2[C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[O:28][C:27]=2[C:26](B(O)O)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[Cl:21][C:19]1[CH:20]=[C:2]([C:35]2[C:29]3[O:28][C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:31]=4[C:30]=3[CH:32]=[CH:33][CH:34]=2)[CH:3]=[C:4]([Cl:22])[C:5]=1[O:6][C@H:7]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: OB(O)c1cccc2c1oc1ccccc12
Reactant: COC(=O)[C@@H](Cc1ccccc1)Oc1c(Cl)cc(Br)cc1Cl
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: Cc1ccccc1
Product: COC(=O)[C@@H](Cc1ccccc1)Oc1c(Cl)cc(-c2cccc3c2oc2ccccc23)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.3 %

Procedure:
A mixture of Example 1A (944 mg, 2.34 mmol), dibenzo(b,d)furan-4-ylboronic acid (619 mg, 2.92 mmol), Pd(PPh3)4 (216 mg, 0.187 mmol), and 2M Na2CO3 (5 mL, 10 mmol) in toluene (10 mL) was heated to 78° C., stirred for 18 hours, cooled to room temperature, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10% ethyl acetate/hexanes to provide 1.05 g (91%) of the desired product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:12]([O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[C:11]2[C:7]([CH2:8][O:9][C:10]2=[O:20])=[C:6]([CH3:21])[C:5]=1[O:22][CH3:23].[CH:24]([O:27][P:28]([CH2:34]Br)(=[O:33])[O:29][CH:30]([CH3:32])[CH3:31])([CH3:26])[CH3:25].CC(C)([O-])C.[Li+]>CN(C=O)C>[CH:30]([O:29][P:28]([CH2:34][O:1][CH2:2][CH2:3][C:4]1[C:12]([O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[C:11]2[C:7](=[C:6]([CH3:21])[C:5]=1[O:22][CH3:23])[CH2:8][O:9][C:10]2=[O:20])(=[O:33])[O:27][CH:24]([CH3:26])[CH3:25])([CH3:32])[CH3:31]
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CCO)C(=O)OC2
Reactant: CC(C)OP(=O)(CBr)OC(C)C
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CCOCP(=O)(OC(C)C)OC(C)C)C(=O)OC2

Procedure:
A mixture of 6-(2-hydroxy-ethyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one (79 mg, 0.23 mmol) was heated with bromomethylphosphonic acid diisopropyl ester (120 mg, 0.46 mmol) in the presence of lithium t-butoxide (22 mg, 0.27 mmol) in DMF (2 mL) at 70° C. overnight. The reaction mixture was purified by RP HPLC (acetonitrile and 0.1% aqueous CF3COOH) to provide the desired product. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 1.13-1.25 (m, 2H), 1.26 (t, 12H, J=6 Hz), 2.12 (s, 3H), 2.98 (t, 2H, J=7 Hz), 3.60-3.73 (m, 4H), 3.77 (s, 3H), 4.05-4.16 (m, 2H), 4.62-4.74 (m, 2H), 5.07 (s, 2H) ppm; MS (m/z) 539 [M+Na]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[NH2:7][CH:8]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]([F:39])([F:38])[F:37])[CH2:9][NH:10][C:11](=[O:29])[CH2:12][N:13]1[C:17](=[O:18])[N:16]([CH:19]2[CH2:21][CH2:20]2)[C:15]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[N:14]1>N1C=CC=CC=1>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:15]2[N:16]([CH:19]3[CH2:21][CH2:20]3)[C:17](=[O:18])[N:13]([CH2:12][C:11]([NH:10][CH2:9][CH:8]([NH:7][S:2]([CH3:1])(=[O:4])=[O:3])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]([F:38])([F:39])[F:37])=[O:29])[N:14]=2)=[CH:23][CH:24]=1
Reactant: CS(=O)(=O)Cl
Reactant: NC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O)c1ccccc1C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)NC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At RT, 4.1 μl of methanesulphonyl chloride were added to a solution of 29 mg (48 μmol) of the compound of Example 59A in 0.5 ml of pyridine. The mixture was stirred at RT for 1 h, and another 4.1 ml of methanesulphonyl chloride were added. The mixture was stirred at RT for another 18 h, and another 12.3 μl of methanesulphonyl chloride were added over a period of 3 h (265 μmol, 5.5 eq., in total). After 1 h, the volatile components were removed on a rotary evaporator. The residue was dissolved in a little DMSO and purified by preparative HPLC [Method 9]. This gave 17 mg (65% of theory) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:33])[N:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:31])[CH:18]=2)[C:13]1=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:53]1[CH:58]=[CH:57][C:56]([CH2:59]O)=[CH:55][CH:54]=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[N:53]1[CH:58]=[CH:57][C:56]([CH2:59][O:23][C:22]([C:21]2[N:12]([N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH3:33])[C:13](=[O:32])[C:14]3[C:19]([C:20]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:18][C:17]([Cl:31])=[CH:16][CH:15]=3)=[O:24])=[CH:55][CH:54]=1
Reactant: OCc1ccncc1
Reactant: CN(C(=O)OCc1ccccc1)n1c(C(=O)O)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CN(C(=O)OCc1ccccc1)n1c(C(=O)OCc2ccncc2)c(-c2ccccc2)c2cc(Cl)ccc2c1=O

Procedure:
To a mixture of 2-[(benzyloxycarbonyl)(methyl)amino]-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (150 mg), triphenylphosphine (120 mg), 4-pyridinemethanol (51 mg) and THF (3.0 ml) was added diethyl azodicarboxylate toluene solution (40%, 210 μl) at 0° C. with stirring and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure and the residue was purified by medium pressure preparative LC (hexane/ethyl acetate=1/1-1/3) to give 2-[(benzyloxycarbonyl)(methyl)amino]-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid pyridin-4-ylmethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH:12]([NH2:15])[CH2:13][NH2:14])=[CH:5][CH:4]=1.[CH3:16]OC1C=CC(C(C)CCCO)=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH3:16])[CH2:10][CH2:11][CH:12]([NH2:15])[CH2:13][NH2:14])=[CH:7][CH:8]=1
Reactant: COc1ccc(CCCC(N)CN)cc1
Reactant: COc1ccc(C(C)CCCO)cc1
Product: COc1ccc(C(C)CCC(N)CN)cc1

Procedure:
This compound is prepared analogously to Intermediate I by replacing 4-(4-methoxyphenyl)-1-butanol with 4-(4-methoxyphenyl)-1-pentanol.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1([CH3:20])[O:19][C:7]2=[C:8]3[C:13](=[C:14]([CH3:16])[CH:15]=[C:6]2[CH2:5]1)[NH:12][C:11](=[O:17])[C:10]([CH3:18])=[CH:9]3.[H][H]>O.CO.[Pd]>[NH2:2][CH2:3][C:4]1([CH3:20])[O:19][C:7]2=[C:8]3[C:13](=[C:14]([CH3:16])[CH:15]=[C:6]2[CH2:5]1)[NH:12][C:11](=[O:17])[CH:10]([CH3:18])[CH2:9]3.[ClH:1]
Reactant: Cc1cc2c3c(cc(C)c2[nH]c1=O)CC(C)(CN)O3
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1cc2c(c3c1NC(=O)C(C)C3)OC(C)(CN)C2
Yield: 80.6 %

Procedure:
A hydrochloric acid salt of 2-Aminomethyl-2,5,8-trimethyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (1.18 g, 4.0 mmol) was suspended in a mixture of water (200 ml) and methanol (40 ml), to which 10% palladium-on-carbon (1.2 g) was added. The mixture was then stirred in a bath at 80° C. for 16 hours in the atmosphere of hydrogen. Post-treatment and recrystallization (methanol-ether) were performed in a manner similar to that described in Example 280 to obtain 957 mg of the title compound as colorless crystals (80.6%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:12]([N:14]([CH2:15][CH3:16])[C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[C:3]=1[OH:11])[CH3:13]
Reactant: O=C(O)c1cccc(Cl)c1O
Reactant: CCNCC
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Product: CCN(CC)C(=O)c1cccc(Cl)c1O
Reaction time: 8 h
Yield: 79.5 %

Procedure:
To a stirring solution of 3-chloro-2-hydroxybenzoic acid (7.2 g, 42 mmol) and diethyl amine (15.2 g, 209 mmol) in dry CH2Cl2 (200 mL) was added benzotriazol-1-yloxy tripyrrolidinophosphonium hexafluorophosphate (22.8 g, 44 mmol) in dry CH2Cl2 (200 mL). The reaction was stirred overnight and then quenched with 6M HCl. The layers were separated and the aqueous layer was extracted with EtOAc (3×100 mL). The organic layers were combined, dried over Na2SO4, and conc. in vacuo to a brown oil. The oil was purified by flash chromatography (silica gel, 0-50% EtOAc in hexanes) to yield 7.6 g of the desired product as a reddish oil.