Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11](=O)[NH:12][CH:13]([C:30]2[C:35]([Cl:36])=[N:34][CH:33]=[CH:32][N:31]=2)[C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:21]3)=[CH:16][CH:15]=2)[CH2:7][CH2:6]1)=[O:4].O=P(Cl)(Cl)Cl>C(Cl)Cl>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[N:31]3[CH:32]=[CH:33][N:34]=[C:35]([Cl:36])[C:30]3=[C:13]([C:14]3[CH:23]=[C:22]4[C:17]([CH:18]=[CH:19][C:20]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[N:21]4)=[CH:16][CH:15]=3)[N:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)NC(c2ccc3ccc(-c4ccccc4)nc3c2)c2nccnc2Cl)CC1
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)[C@H]1CC[C@H](c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(Cl)nccn32)CC1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
A CH2Cl2 solution (2 mL) of trans-4-{[(3-chloropyrazin-2-yl)-(2-phenyl-quinolin-7-yl)-methyl]-carbamoyl}-cyclohexanecarboxylic acid methyl ester (2.3 g, 4.5 mmol) in a round bottom flask equipped with a condenser was charged with POCl3 (15 mL) and stirred at 80° C. for 72 h. The reaction mixture was concentrated in vacuo to a foam, cooled to 0° C., and charged with cold 2M NH3 in isopropanol to basic pH. The mixture was concentrated in vacuo to solids and partitioned between EtOAc and water. The organic layer was washed with water (1×), brine (1×), dried over Na2SO4, filtered, and concentrated to a brown oil. The resulting residue was purified by silica gel chromatography (CH2Cl2 to 1% ˜7N NH3 in MeOH/CH2Cl2) to provide the desired product as a yellow solid; NMR (CDCl3, 400 MHz) δ 1.62-1.73 (m, 2H), 1.92-2.02 (m, 2H), 2.15-2.27 (m, 4H), 2.44-2.60 (m, 1H), 2.99-3.08 (m, 1H), 3.72 (s, 3H), 7.39 (d, 1H, J=5.2 Hz), 7.45-7.50 (m, 1H), 7.51-7.57 (m, 2H), 7.61 (d, 1H, J=5.2 Hz), 7.85-7.93 (m, 3H), 8.19 (d, 2H, J=7.6 Hz), 8.27 (d, 1H, J=8.4 Hz), 8.50 (s, 1H); MS (ES+): m/z 496.9 [MH+]; HPLC: tR=3.6 min (Micromass Platform II, nonpolar—5 min).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]3[CH:17]=[CH:16][N:15]([Si](C(C)C)(C(C)C)C(C)C)[CH:14]=3)=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[NH:15]1[CH:16]=[CH:17][C:13]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=3)[O:9][C:8](=[O:12])[CH:7]=2)=[CH:14]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(-c2cc(=O)oc3cc(Br)ccc23)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=c1cc(-c2cc[nH]c2)c2ccc(Br)cc2o1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of the silyl compound from Step 1 (42 mg, 0.094 mmol) in THF (1 mL) was added Bu4NF 1M in THF (94 (L, 0.094 mmol) and the reaction mixture was stirred at r.t. for 15 min. The mixture was diluted with EtOAc, washed with brine, dried over MgSO4, filtered and evaporated to give the title compound as an oil.
Reaction SMILES: Br[CH2:2][C:3]([N:5]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:4].[CH2:22]([OH:33])[CH2:23][C:24]1[CH:32]=[CH:31][C:29]([OH:30])=[C:26]([O:27][CH3:28])[CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH2:13][N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:3](=[O:4])[CH2:2][O:30][C:29]1[CH:31]=[CH:32][C:24]([CH2:23][CH2:22][OH:33])=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1cc(CCO)ccc1O
Reactant: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)COc1ccc(CCO)cc1OC
Yield: 79 %

Procedure:
2-Bromo-N-(2,4-difluorobenzyl)-N-heptylacetamide (135 mg, 0.373 mmol), homovanillyl alcohol (63 mg, 0.373 mmol) and potassium carbonate anhydrous (77 mg, 0.559 mmol) were mixed in acetonitrile (10 ml). The mixture was heated to reflux for 4 hours and then evaporated to dryness. The residue (with additional DCM, 1 ml×2) was loaded onto a column (ISOLUTE® SI, 1 g/6 ml). It was eluted with DCM and then MeOH/DCM (0.5:99.5, then 1:99). The product fractions were combined and evaporated Oil product 132 mg was obtained yield 79%.
Reaction SMILES: [C:1]([N:18]([CH3:33])[C@H:19]([C:23](ON1C(=O)CCC1=O)=[O:24])[CH:20]([CH3:22])[CH3:21])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].[NH2:34][C@H:35]([C:43]([OH:45])=[O:44])[CH2:36][CH2:37][CH2:38][NH:39][C:40]([NH2:42])=[O:41].C([O-])(O)=O.[Na+]>COCCOC.C1COCC1.O>[C:1]([N:18]([CH3:33])[C@H:19]([C:23]([NH:34][C@H:35]([C:43]([OH:45])=[O:44])[CH2:36][CH2:37][CH2:38][NH:39][C:40]([NH2:42])=[O:41])=[O:24])[CH:20]([CH3:21])[CH3:22])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]
Reactant: NC(=O)NCCC[C@H](N)C(=O)O
Reactant: CC(C)[C@@H](C(=O)ON1C(=O)CCC1=O)N(C)C(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@@H](C(=O)N[C@@H](CCCNC(N)=O)C(=O)O)N(C)C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.3 %

Procedure:
To a room temperature suspension of Fmoc-MeVal-OSu (2.18 g, 4.84 mmol) in DME (13 mL) and THF (6.5 mL) is added a solution of L-citrulline (0.85 g, 4.84 mmol) and NaHCO3 (0.41 g, 4.84 mmol) in H2O (13 mL). The suspension is allowed to stir at room temperature for 16 hr, then it is extracted into tert-BuOH/CHCl3/H2O and acidified to pH=2-3 with 1 M HCl. The organic phase is separated, dried and concentrated under reduced pressure. The residue is triturated with diethyl ether resulting Fmoc-MeVal-Cit-COOH (e.g., 2.01 g) which is used without further purification.
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=1)[O:11][CH2:12][CH:13]([OH:24])[CH2:14][S:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].CO.[OH-].[Na+]>O>[OH:1][CH:2]([C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=1)[O:11][CH2:12][CH:13]([OH:24])[CH2:14][S:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC(O)c1cccc(OCC(O)CSCCCC(=O)OCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCC(O)c1cccc(OCC(O)CSCCCC(=O)O)c1

Procedure:
10.0 g. Ethyl S-[3-(3-{1-hydroxyhexyl}-phenoxy)-2-hydroxypropyl]-4-mercaptobutyrate are stirred for 2 hours at 50° C. with 50 ml. methanol and 50 ml. 2M aqueous sodium hydroxide solution. The solvent is subsequently stripped off and the residue is taken up in water and extracted three times with ethyl acetate. The aqueous phase is acidified with 2M hydrochloric acid and extracted three times with ethyl acetate. The organic phase is washed natural, dried and evaporated. There are obtained 7.4 g. (80% of theory) of the title compound in the form of an oil.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Cl:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][S:16]([CH2:19][C:20](O)=[O:21])(=[O:18])=[O:17])=[CH:13][CH:12]=1>C(O)(=O)C>[Cl:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][S:16]([C:19]2[C:20](=[O:21])[O:4][C:3]3[C:2]([CH:1]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)(=[O:17])=[O:18])=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1O
Reactant: O=C(O)CS(=O)(=O)Cc1ccc(Cl)cc1
Solvent: CC(=O)O
Product: O=c1oc2ccccc2cc1S(=O)(=O)Cc1ccc(Cl)cc1
Yield: 99 %

Procedure:
A solution of salicylaldehyde (1 mmol) and 2-(4-chlorobenzylsulfonyl)acetic acid (1 mmol) in acetic acid (10 mL) was subjected to the General Procedure 2, Method A to generate a 99% yield of the title compound; m.p. 195-196° C.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2([CH2:13][NH2:14])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[N:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[F:21][C:22]([F:38])([F:37])[C:23]1[O:27][N:26]=[C:25]([C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31](O)=[O:32])[N:24]=1>>[CH3:1][C:2]1[S:6][C:5]([C:7]2([CH2:13][NH:14][C:31](=[O:32])[C:30]3[CH:34]=[CH:35][CH:36]=[C:28]([C:25]4[N:24]=[C:23]([C:22]([F:38])([F:37])[F:21])[O:27][N:26]=4)[CH:29]=3)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[N:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1sc(C2(CN)CCOCC2)nc1-c1ccccc1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: Cc1sc(C2(CNC(=O)c3cccc(-c4noc(C(F)(F)F)n4)c3)CCOCC2)nc1-c1ccccc1
Yield: 89 %

Procedure:
This compound was synthesized from (4-(5-methyl-4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (55 mg, 89% yield): 1H NMR (300 MHz, CDCl3) δ 8.48 (t, J=1.1 Hz, 1H), 8.23 (dt, J=6.2 Hz, 1.1, 1H), 7.98 (dt, J=7.9 Hz, 1.1 Hz, 1H), 7.74 (bs, 1H), 7.64 (m, 2H), 7.49 (t, J=7.7 Hz, 1H), 7.39-7.29 (m, 2H), 3.92 (m, 2H), 3.85 (d, J=5.7 Hz, 2H), 3.74 (m, 2H), 2.59 (s, 3H), 2.24 (m, 2H), 1.95 (m, 2H). MS (ESI) m/z: Calculated for C26H23F3N4O3S: 528.14. found: 529.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:44]=[CH:45][CH:46]=1)[CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([O:32][CH3:33])=[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:26]=4)[CH:19]=3)[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH:13]=2)[CH:9]=[N:8]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:44]=[CH:45][CH:46]=1)[CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([O:32][CH3:33])=[C:25]([NH:27][S:28]([CH3:31])(=[O:29])=[O:30])[CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH:9]=[N:8]1
Reactant: COc1ccc(-c2cnc3c(c2)c(-c2cnn(CCc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(-c2cnc3[nH]cc(-c4cnn(CCc5cccc(F)c5)c4)c3c2)cc1NS(C)(=O)=O
Yield: 38.7 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(5-(3-(1-(3-fluorophenethyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxyphenyl)methane sulfonamide (27 mg, 0.0409 mmol) was hydrolyzed by lithium hydroxide (34 mg, 0.818 mmol) in THF/methanol/water (2/2/1 ml) to yield 8 mg (40.0% yield) of the titled compound. 1H NMR (DMSO-d6, 300 MHz): δ 11.7 (s, 1H), 9.04 (s, 1H), 8.43-8.42 (d, 1H), 8.176-8.170 (d, 1H), 8.13 (s, 1H), 7.87 (s, 1H), 7.69-7.68 (d, 1H), 7.58-7.57 (m, 2H), 7.32-7.19 (m, 2H), 7.06-7.01 (m, 2H), 4.33-4.38 (t, 2H), 3.89 (s, 3H), 3.21-3.16 (t, 2H), 3.00 (s, 3H). MS: m/z=506.1 (M+1), HPLC: 91.31% in method B.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[N+]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O-])=O>>[C:1]([C:14]1[CH:15]=[CH:16][C:17]2[C:12](=[CH:17][CH:12]=[CH:13][CH:14]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1ccc2ccccc2c1

Procedure:
One such method by which they can be prepared involves the reaction of an unsubstituted or substituted naphthalene with acetyl chloride in nitrobenzene in the presence of about three molar equivalents of aluminum chloride to afford the corresponding 2-acetylnaphthalene derivative. The resulting derivative is heated with morpholine in the presence of sulfur at 150°C; the resulting product is refluxed with concentrated hydrochloric acid to furnish the corresponding 2-naphthylacetic acid derivative.
Reaction SMILES: [CH2:1]([N:8]1[CH2:24][CH2:23][C:12]2=[C:13]([CH2:20][CH2:21]O)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[N:11]2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(Cl)(=O)=O.C(N(CC)CC)C.[CH2:37]([NH2:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(#N)C>[CH2:37]([NH:44][CH2:21][CH2:20][C:13]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[N:11]2[CH2:10][CH2:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:24][CH2:23][C:12]=12)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: OCCc1c2n(c3ccccc13)CCN(Cc1ccccc1)CC2
Reactant: NCc1ccccc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC#N
Product: c1ccc(CNCCc2c3n(c4ccccc24)CCN(Cc2ccccc2)CC3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
A solution of 2-(3-benzyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-11-yl)-1-ethanol (320 mg, 1.0 mmol) in dichloromethane (10 mL) is cooled to 0° C., treated with methanesulfonyl chloride (93 μL, 1.2 mmol), and triethylamine (0.21 mL, 1.5 mmol). After 30 min, the yellow solution is diluted with additional dichloromethane (15 mL) and washed once with water (15 mL), once with brine (15 mL), dried over MgSO4, filtered, and concentrated to give a yellow oil. This crude material is diluted with acetonitrile (10 mL) and treated with benzylamine (0.33 mL, 3.0 mmol), and powdered potassium carbonate (415 mg, 3.0 mmol) followed by heating to reflux. After 18 hrs, the yellow suspension is cooled to rt, concentrated, diluted with water (15 mL), and extracted twice with dichloromethane (20 mL). The combined organics are washed with brine (20 mL), dried over MgSO4, filtered, and concentrated to give a crude oil. This material is purified by LC (230-400 silica gel) eluting with 4:0.5:95.5 methanol/NH4OH/dichloromethane to afford 220 mg of N-benzyl-2-(3-benzyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-11-yl)-1-ethanamine as a yellow oil. IR (liq.) 3025, 2913, 2811, 1494, 1478, 1469, 1453, 1427, 1372, 1363, 1347, 1324, 1120, 733, 698 cm−1; MS (EI) m/z 409 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH:12]1[CH2:14][CH2:13]1)[CH:5]=[O:6].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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:12]1([CH2:11][O:10][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[CH2:14][CH2:13]1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=Cc1ccc(OCC2CC2)c(Br)c1
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: Cc1ccccc1
Product: COc1ccc(-c2cc(C=O)ccc2OCC2CC2)cc1
Yield: 89.7 %

Procedure:
To a degassed solution of 3-bromo-4-cyclopropylmethoxybenzaldehyde (1.53 g, 6 mmol), 4-methoxybenzeneboronic acid (1.22 g, 8 mmol) and potassium carbonate (2.74 g, 20 mmol) in toluene/ethanol 2/1 (40 mL), Pd(PPh3)4 (100 mg) was added and the mixture was degassed for further 5 minutes. The mixture was then refluxed for 12 hours. The solid is filtered off, and the solvent partitioned between ethyl acetate and water and extracted. The organic solvent was removed under reduced pressure, dried over sodium sulphate and purified by column chromatography on silica (hexane/ethyl acetate 8/2) to afford 1.52 g of product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[C:16][Si](C)(C)C)[CH:13]=2)[CH:8]=[N:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+].C(O)(=O)C>CO>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[CH:16])[CH:13]=2)[CH:8]=[N:7][CH:6]=1
Reactant: COC(=O)Cc1cncc2ccc(C#C[Si](C)(C)C)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: C#Cc1ccc2cncc(CC(=O)OC)c2c1
Reaction time: 1 h

Procedure:
To a solution of (6-trimethylsilanylethynyl-isoquinolin-4-yl)-acetic acid methyl ester, as prepared for Intermediate 32 (0.19 g, 0.64 mmol), in anhydrous methanol (7 ml) is added K2CO3 (72 mg) and the resulting mixture stirred for 1 h. Additional K2CO3 (11 mg) is then added and stirring continued for 30 min. The mixture is then neutralised with glacial acetic acid and concentrated. Purification by flash silica column chromatography (ethylacetate/hexane 1:1) gives (6-ethynyl-isoquinolin-4-yl)-acetic acid methyl ester M+ 225. This intermediate (79 mg, 0.35 mmol) is dissolved in methanol under an inert atmosphere and 10% Pd on carbon (79 mg) added. The resulting suspension is stirred vigorously under an atmosphere of gaseous hydrogen. After 90 mins, filtration, washing with methanol and concentration give (6-ethyl-isoquinolin-4-yl)-acetic acid methyl ester M+ 229. To a solution of this intermediate (68 mg, 0.30 mmol) in THF/methanol/water (3:1:1, 3.5 ml) is added LiOH (12.5 mg) and the mixture stirred for 20 h at room temperature. Concentration under reduced pressure gives lithium (6-ethyl-isoquinolin-4-yl)-acetate M+ 221.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([OH:18])=O)=[CH:11][CH:10]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:56][C:57]1[C:58]([OH:68])=[N:59][C:60]([N:63]2[CH:67]=[CH:66][CH:65]=[N:64]2)=[N:61][CH:62]=1>CC#N>[OH:68][C:58]1[C:57]([NH:56][C:16](=[O:18])[CH:15]([C:12]2[CH:11]=[CH:10][C:9]([P:4](=[O:5])([O:6][CH2:7][CH3:8])[O:3][CH2:1][CH3:2])=[CH:14][CH:13]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:62][N:61]=[C:60]([N:63]2[CH:67]=[CH:66][CH:65]=[N:64]2)[N:59]=1
Reactant: Nc1cnc(-n2cccn2)nc1O
Reactant: CCOP(=O)(OCC)c1ccc(C(C(=O)O)c2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)c1ccc(C(C(=O)Nc2cnc(-n3cccn3)nc2O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4-(Diethoxyphosphoryl)phenyl)-2-phenylacetic acid, 14-f, (1.18 g, 3.4 mmol), HATU (1.86 g, 4.9 mmol) and triethylamine (989 mg, 9.8 mmol) in CH3CN (20 mL) was added 5-amino-2-(1H-pyrazol-1-yl)pyrimidin-4-ol (11-e, 577 mg, 3.30 mmol). The mixture was stirred at room temperature overnight and concentrated. The residue was taken up in EA and water. The aqueous layer was extracted with EA. The combined layers were washed with brine, dried over Na2SO4, and concentrated to give the crude product of 14-1 which was purified by pre-HPLC (766 mg, 45%). 1H NMR (300 MHz, DMSO-d6) δ1.18-1.23 (m, 6H), 3.92-4.03 (m, 4H), 6.64 (s, 1H), 7.25-7.35 (m, 6H), 7.47-7.51 (m, 2H), 7.64-7.71 (m, 2H), 7.97 (s, 1H), 8.61-8.52 (m, 1H), 8.63 (br s, 1H); LC-MS: (M+H)+ 508.
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1.[CH2:14](O)[CH2:15][OH:16]>CC1C=CC(S(O)(=O)=O)=CC=1>[O:13]1[CH2:14][CH2:15][O:16][CH:12]1[C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2
Reactant: OCCO
Reactant: O=Cc1ccc(O)c2ncccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Oc1ccc(C2OCCO2)c2cccnc12

Procedure:
To a solution of 8-hydroxyquinoline-5-carbaldehyde (A,Oakwood Products) in ethylene glycol, p-TsOH is added to form 5-(1,3-dioxolan-2-yl)quinolin-8-ol (B). After purification, 5-(1,3-dioxolan-2-yl)quinolin-8-ol is added to a solution of MeI and NaH in THF to give C. A solution of C in THF is added to 1 eq of the Grignard reagent formed from magnesium turnings and L-N-Boc-2-bromomethyl glycine allyl ester (Advanced Technology & Industrial Co., Ltd., Hong Kong) at 0° C.; the reaction mixture is monitored by TLC until allyl(S)-vinyl 2-(tert-butoxycarbonylamino)-3-(5-formyl-8-methoxyquinolin-2-yl)propanoate (D) is formed. The reaction mixture is quenched with aqueous acetic acid, and purified by flash chromatography. The O-methyl and N-t-BOC protecting groups are simultaneously removed by treatment of D with warm 48% HBr/HOAc. The freed aliphatic amino group is protected as a fluorenoxymethylenecarbonyl carbamate, followed by condensation of the benzaldehyde moiety with two equivalents of 4-fluororesorcinol in methanesulfonic acid at rt. The resulting pro-fluorophore G is isolated by precipitation from water and filtration, followed by dehydrogenative oxidation with p-choranil in methane/chloroform. The resulting dye H is purified by flash chromatography using methanol in chloroform as eluant, and then readied for peptide synthesis of allyl ester deprotection using sodium 2-ethylhexanoate and catalytic Pd(PPh3)4 in ethyl acetate and dichloromethane to give compound I.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([N:11]=[C:12]=[O:13])[CH2:8][CH2:9][CH3:10].[Cl:14][C:15]1[N:24]=[C:23]2[C:18]([CH:19]=[CH:20][C:21]([N:25]3[CH:33]([OH:34])[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([C:35]([F:38])([F:37])[F:36])[CH:31]=4)[C:26]3=[O:39])=[N:22]2)=[CH:17][CH:16]=1.C(N(CC)CC)C>C(#N)C>[CH2:7]([NH:11][C:12]([O:34][CH:33]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:35]([F:37])([F:38])[F:36])[CH:31]=2)[C:26](=[O:39])[N:25]1[C:21]1[CH:20]=[CH:19][C:18]2[C:23](=[N:24][C:15]([Cl:14])=[CH:16][CH:17]=2)[N:22]=1)=[O:13])[CH2:8][CH2:9][CH3:10]
Reactant: CCCCN=C=O
Reactant: O=C1c2ccc(C(F)(F)F)cc2C(O)N1c1ccc2ccc(Cl)nc2n1
Solvent: c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCNC(=O)OC1c2cc(C(F)(F)F)ccc2C(=O)N1c1ccc2ccc(Cl)nc2n1

Procedure:
Pyridine (10 cc.) and n-butyl isocyanate (11.2 cc.) are added to a suspension of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxy-5-trifluoromethyl-isoindolin-1-one (3.8 g.) in acetonitrile (380 cc.). The mixture is heated to the reflux temperature and triethylamine (0.5 cc.) is then added. Refluxing is continued for 1 hour and 30 minutes until dissolution. The reaction mixture is then concentrated under reduced pressure (40 mm.Hg), and the residue is recrystallised from acetonitrile (48 cc.) to give 3-n-butylaminocarbonyloxy-2-(7-chloro-1,8-naphthyridin-2-yl)-5-trifluoromethyl-isoindolin-1-one (3.5 g.) melting at 120° C. and then at 176° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:17])[CH2:13][CH2:14][CH2:15][NH2:16].C(=O)([O-])[O-].[K+].[K+].C(N(CCOCCOC)CCOCCOC)COCCOC>>[CH3:11][N:12]([CH3:17])[CH2:13][CH2:14][CH2:15][NH:16][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CN(C)CCCN
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN(C)CCCNc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 85 %

Procedure:
To a stirred solution of 4-fluoronitrobenzene (7 g, 50 mmol), 3-dimethylaminopropylamine (6.1 g, 60 mmol) and potassium carbonate (7 g, 50 mmol) in 25 ml of dimethylsulfoixde was added 0.2 g of tris(3,6-dioxaheptyl)amine (TDA-1). The heterogenous mixture was heated at 90° for 2 h. After cooling to room temperature, 110 g of crushed ice was added to precipitate out the yellow product in 85% yield (9.5 g, 43 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].I[CH2:13][C:14]([F:17])([F:16])[F:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[O:1][CH2:13][C:14]([F:17])([F:16])[F:15]
Reactant: COc1ccc(C=O)cc1O
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C=O)cc1OCC(F)(F)F
Temperature: 90 °C
Reaction time: 8 h

Procedure:
3-Hydroxy-4-methoxy-benzaldehyde (560, 2.9 g, 19.5 mmol), 2-iodo-1,1,1-trifluoroethane (561, 2.2 mL, 23 mmol), and potassium carbonate (3.7 g, 27 mmol) were dissolved in N,N-dimethylformamide (100 mL). The solution was stirred at 90° C. overnight under an atmosphere of nitrogen. The reaction was poured into water, extracted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The compound was isolated by silica gel column chromatography eluting with 25% to 50% ethyl acetate in hexanes to give white powder (562, 1.6 g, 40%).