Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[CH2:7]1[O:15][C:14]2[C:9](=[CH:10][C:11]([N+]([O-])=O)=[C:12]([N+:16]([O-:18])=[O:17])[CH:13]=2)[O:8]1.C(N(CC)CC)C.C(O)C>C(O)(=O)C>[OH:6][CH:3]([CH2:4][OH:5])[CH2:2][NH:1][C:11]1[CH:10]=[C:9]2[O:8][CH2:7][O:15][C:14]2=[CH:13][C:12]=1[N+:16]([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1cc2c(cc1[N+](=O)[O-])OCO2
Reactant: NCC(O)CO
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc2c(cc1NCC(O)CO)OCO2
Temperature: 0 °C

Procedure:
0.6 mol (56.3 g) of 3-amino-1,2-propanediol is added dropwise to a mixture, brought to reflux, prepared by adding 0.3 mol (63.6 g) of 4,5-methylenedioxy-1,2-dinitrobenzene and 46 ml of triethylamine to 90 ml of 96° strength ethanol. The reaction mixture is heated for 3 hours under reflux. After dilution with 600 ml of ice-cold water and neutralization with acetic acid, the expected product is drained. After recrystallization from acetonitrile, it melts at 120°-121° C.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:15]=1[C:16]([OH:18])=O.C1CCN2C(=NCCC2)CC1.C[Si]([CH:39](C([O-])=O)[C:40]([O:42][CH2:43][CH3:44])=[O:41])(C)C>C1COCC1.C(#N)C>[F:13][C:14]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:15]=1[C:16](=[O:18])[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]
Reactant: O=C(O)c1cc(I)ccc1F
Reactant: CCOC(=O)C(C(=O)[O-])[Si](C)(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)CC(=O)c1cc(I)ccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.4 %

Procedure:
Employing the method utilized by Wang (Wang, X., Monte, W. T., Napier, J. J., Ghannam, A. Tetrahedron. Lett. 1994, 35, 9323), 1,1′-carbonyldiimidazole (1.82 g) in THF (20 mL) at 0° C. is treated with 2-fluoro-5-iodobenzoic acid (2.66 g) prepared according to literature procedures (Blackburn, B. K., Lee, A., Baier, M., Kohl, B., Olivero, A. G., Matamoros, R., Robarge, K. D., McDowell, R. S. J. Med Chem. 1997, 40, 717-729.) in portions over a 10 minute period. The mixture is stirred for 1 h and then allowed to warm to room temperature for an additional 1 h. The solution is then added dropwise into an enolate solution of ethyl trimethylsilymalonate at 5° C. prepared by the addition of DBU (3.35 g) to a solution of ethyl trimethylsilylmalonate (2.25 g) in acetonitrile (20 mL) at 5° C. with stirring for 45 minutes. The reaction mixture is allowed to warm to room temperature and stirred overnight. The orange solution is quenched with 100 mL of aqueous 10% citric acid solution and extracted with ethyl acetate. The organic extract is washed with aqueous 10% sodium bicarbonate solution and water, dried (Na2SO4), and concentrated in vacuo to give 2.4 g of the title compound as a yellow liquid. Physical characteristics: tlc Rf=0.66 (silica gel G; 20% EtOAc/hexane, visualize with I2).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[N:14]=[C:13]([NH:15][C:16]3[N:21]=[CH:20][C:19]([O:22][C:23]4[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=4)=[CH:18][C:17]=3[S:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:38])[S:12][N:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].CO.[BH4-].[Na+].[NH4+].[Cl-]>CCOC(C)=O>[Cl:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[S:31][C:17]1[C:16]([NH:15][C:13]2[S:12][N:11]=[C:10]([CH:7]3[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]3)[N:14]=2)=[N:21][CH:20]=[C:19]([O:22][C:23]2[CH:24]=[CH:25][C:26]([CH2:27][OH:28])=[CH:29][CH:30]=2)[CH:18]=1
Reactant: CC(=O)N1CCC(c2nsc(Nc3ncc(Oc4ccc(C=O)cc4)cc3Sc3ccccc3Cl)n2)CC1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC(c2nsc(Nc3ncc(Oc4ccc(CO)cc4)cc3Sc3ccccc3Cl)n2)CC1
Reaction time: 0.5 h
Yield: 66 %

Procedure:
4-(6-(3-(1-Acetylpiperidin-4-yl)-1,2,4-thiadiazol-5-ylamino)-5-(2-chlorophenylthio)pyridin-3-yloxy)benzaldehyde (30 mg, 0.0530 mmol) was dissolved in 1:1 EtOAc:methanol (2 mL) and NaBH4 (10.0 mg, 0.265 mmol) was added. After stirring 30 minutes the reaction was poured into aqueous NH4Cl, extracted with EtOAc and purified on silica gel (0 to 10% methanol in EtOAc) to afford 1-(4-(5-(3-(2-chlorophenylthio)-5-(4-(hydroxymethyl)phenoxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1-yl)ethanone (19.9 mg, 0.0350 mmol, 66.1% yield) as a white solid. 1H NMR (CDCl3) δ 9.23 (s, 1H), 8.30 (d, 1H), 7.64 (d, 1H), 7.43 (m, 1H), 7.38 (d, 2H), 7.16 (m, 2H), 7.01 (d, 2H), 6.76 (dd, 1H), 4.69 (d, 2H), 4.57 (d, 1H), 3.88 (d, 1H), 3.20 (t, 1H), 3.03 (m, 1H), 2.80 (t, 1H), 2.11 (s, 3H), 2.07 (m, 2H), 1.92-1.71 (m, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]([NH2:25])([CH3:24])[CH3:23]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:25][CH:22]([CH3:24])[CH3:23])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCCCCOc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)N
Product: CC(C)NCCCCCOc1ccc(OCc2ccccc2)cc1

Procedure:
As described in Example 19, 1-benzyloxy-4-(5-bromopentoxy)benzene was reacted with isopropylamine at 100° (12 hours; 150 psi) to give 1-benzyloxy-4-[5-(1-methylethyl)aminopentoxy]benzene. The distilled product was 95.2% pure by gas chromatography.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[Cl:16][C:17]1[CH:22]=[C:21](O)[CH:20]=[CH:19][C:18]=1[CH:24]([CH3:43])[C:25]([C:31]1[CH:42]=[CH:41][C:34]2[N:35]([CH3:40])[C:36](=[O:39])[CH2:37][O:38][C:33]=2[CH:32]=1)([OH:30])[C:26]([F:29])([F:28])[F:27].C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[Cl:16][C:17]1[CH:22]=[C:21]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])[CH:20]=[CH:19][C:18]=1[CH:24]([CH3:43])[C:25]([OH:30])([C:31]1[CH:42]=[CH:41][C:34]2[N:35]([CH3:40])[C:36](=[O:39])[CH2:37][O:38][C:33]=2[CH:32]=1)[C:26]([F:28])([F:29])[F:27]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)OCC(=O)N2C)C(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(c1ccc(OS(=O)(=O)C(F)(F)F)cc1Cl)C(O)(c1ccc2c(c1)OCC(=O)N2C)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoromethanesulfonic anhydride (0.12 ml) was added to 7-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (150 mg, Example 158 step 2) and triethylamine (0.2 ml) in DCM (5 ml). The mixture was stirred for 2 h at room temperature. 10% aqueous citric acid was added and extracted with DCM. The combined organic layers were dried over Na2SO4 and then concentrated to give the title compound (140 mg) as light yellow foam. MS (m/e, ISP neg. ion)=546.2 [M−H+].
Reaction SMILES: [CH2:1]([OH:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:7](=O)([O:10]C)[O:8][CH3:9]>C[O-].[Na+].CO>[C:7](=[O:10])([O:6][CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])[O:8][CH3:9]
Reactant: CC(C)(C)CO
Reactant: COC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)OCC(C)(C)C
Temperature: 100 °C
Yield: 54 %

Procedure:
To a mixed solution of neopentyl alcohol (500 ml, 5.7 mol) and dimethyl carbonate (2070 g, 23.0 mol), a 28% sodium methoxide/methanol solution (11 g) was added and the mixture was heated to 100° C. to remove the methanol by evaporation for 6 hours. After allowing the mixture to cool to room temperature, an aqueous solution of ammonium chloride was added to the mixture and the mixture was shaken to remove the sodium methoxide. The organic layer was washed with water, dried and distilled to give methyl neopentyl carbonate as a colorless liquid (450 g, yield 55%). The chemical structure of the produced compound was determined based on the IR and NMR absorbance spectra shown in FIG. 1 and FIG. 2 respectively and the mass spectrometry spectrum (M/e=146).
Reaction SMILES: Cl.Cl.[CH:3]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)([CH3:5])[CH3:4].[CH:12]([C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)=[O:13]>>[CH:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:22]=[CH:21][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=2)=[O:13])[CH2:8][CH2:7]1)([CH3:5])[CH3:4]
Reactant: CC(C)N1CCNCC1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: Cl
Product: CC(C)N1CCN(C(=O)c2ccc(C=O)cc2)CC1

Procedure:
Prepared from the product of Example 10 and 4-formylbenzoic acid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[NH2:33][CH2:34][CH2:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[C:6]([C:24]4[CH:29]=[CH:28][C:27]([C:30](=[O:31])[NH:33][CH2:34][CH2:35][C:36]5[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=5)=[CH:26][CH:25]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: NCCc1cccnc1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Product: O=C(NCCc1cccnc1)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1
Yield: 106.9 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 3-(2-aminoethyl)pyridine (available from Aldrich Chemical Company, Inc.; 76 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(2-pyridin-3-yl-ethylcarbamoyl)-biphenyl-2-carboxylic acid (129 mg, 109%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.14 (br s, 1H), 8.63 (t, J=5.5 Hz, 1H), 8.57 (s, 1H), 8.51 (d, J=4.3 Hz, 1H), 8.47 (s, 1H), 8.39 (d, J=1.8 Hz, 1H), 8.33 (d, J=2.0 Hz, 1H), 8.24 (dd, J=8.0, 2.0 Hz, 1H), 8.09 (dd, J=8.4, 1.9 Hz, 1H), 7.83-7.90 (m, 3H), 7.76 (d, J=8.3 Hz, 1H), 7.58 (d, J=8.3 Hz, 1H), 7.45-7.52 (m, 3H), 3.58 (q, J=6.6 Hz, 2H), 2.95 (t, J=6.9 Hz, 7H).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26]([O:28][CH2:29]Cl)=[O:27])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[Na+].[I-:32]>>[C:1]([NH:11][C@H:12]([C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26]([O:28][CH2:29][I:32])=[O:27])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: [I-]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccccc1CC(=O)OCCl
Agent: [Na+]
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccccc1CC(=O)OCI

Procedure:
Chloromethyl 2-(N-CBZ-L-valyloxy)phenylacetate is treated with NaI and purified as described in the Examples above to yield the title compound.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[NH:3][CH:2]=1.[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]Br.C([O-])([O-])=O.[K+].[K+]>>[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][N:10]([CH2:14][C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=1[F:11])[C:8]1[CH:7]=[CH:6][C:5]2[NH:1][CH:2]=[N:3][C:4]=2[CH:9]=1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1ccccc1CN(Cc1ccccc1F)c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from benzimidazol-5-amine (133 mg; 1 mmol; 1 eq.), 2-fluorobenzylbromide (416 mg; 0.265 ml; 2.2 mmol; 2.2 eq.) and K2CO3 (304 mg; 2.2 mmol; 2.2 eq.) according to method 5; Yield: 0.063 g (18.1%); MS m/z: 350.2 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 4.73 (s, 4H); 6.71-6.72 (m, 2H); 7.08-7.11 (m, 2H); 7.17-7.19 (m, 2H); 7.20-7.28 (m, 4H); 7.32 (d, 1H, 3J=9.4 Hz); 7.92 (s, 1H); 11.94 (br s, 1H); HPLC (METHOD [A]): rt 15.61 min (100%)
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].[F:13][C:14]([F:21])([F:20])[C:15](=O)[CH2:16][C:17]#[N:18]>C1(C)C=CC=CC=1>[F:13][C:14]([F:21])([F:20])[C:15]1[CH:16]=[C:17]([NH2:18])[N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:11])([F:12])[F:1])[N:10]=1
Reactant: N#CCC(=O)C(F)(F)F
Reactant: NNc1ccccc1C(F)(F)F
Solvent: Cc1ccccc1
Product: Nc1cc(C(F)(F)F)nn1-c1ccccc1C(F)(F)F
Reaction time: 5 h
Yield: 62.1 %

Procedure:
A solution of 2-trifluoromethyl-phenylhydrazine (1.1 g, 6.3 mmol) and 4,4,4-trifluoro-3-oxobutyronitrile (0.82 g, 6.0 mmol) in toluene (3 mL, anhyd.) was heated at reflux. After 5 h the reaction mixture was allowed to cool, concentrated and purified by chromatography (silica, EtOAc/Hex, 0:100 to 25:75) to yield the title compound (1.1 g, 61%) as an amber liquid. 1H-NMR (CD2Cl2): δ 8.40 (1H, br s), 7.77 (1H, d), 7.59 (2H, m), 7.17 (1H, m), 3.56 (2H, s); Rf 0.45 (20% EtOAc/Hex).
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[C:10]([S:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:9]=[C:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=1[OH:23])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:31][O:32][C:33]([C:35]1[O:36][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:38][CH:39]=1)=[O:34]>ClCCl>[CH3:31][O:32][C:33]([C:35]1[O:36][C:37]([S:40]([N:16]2[CH2:17][CH2:18][CH:13]([S:12][C:10]3[CH:9]=[C:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]([OH:23])=[C:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[CH:11]=3)[CH2:14][CH2:15]2)(=[O:42])=[O:41])=[CH:38][CH:39]=1)=[O:34]
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)o1
Reactant: CC(C)(C)c1cc(SC2CCNCC2)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(S(=O)(=O)N2CCC(Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CC2)o1
Reaction time: 0.05 h
Yield: 74.2 %

Procedure:
To 2,6-di-tert-butyl-4-(piperidin-4-ylsulfanyl)-phenol hydrochloride (Ex. 3c, 280 mg, 0.78 mmol) in 5 mL of dichloromethane was added triethylamine (240 mg, 2.37 mmol). The mixture was stirred for 3 min followed by the addition of 5-chlorosulfonyl-furan-2-carboxylic acid methyl ester (210 mg, 0.94 mmol). The stirring was continued for 2 h at room temperature and then the reaction was quenched with 20 mL of saturated NaH2PO4. The mixture was extracted with Ethyl acetate (40 mL) and the organic phase was dried over Na2SO4 and concentrated under reduced pressure. Chromatography (3-50% Ethyl acetate/hexanes) gave 5-[4-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-piperidine-1-sulfonyl]-furan-2-carboxylic acid methyl ester as a clear oil (295 mg, 74%). ESI/CI-MS m/z 508 ([M−H]−).
Reaction SMILES: [F:1][C:2]1[C:3]([F:12])=[CH:4][C:5]2[S:9][C:8]([SH:10])=[N:7][C:6]=2[CH:11]=1.[C:13](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.O>[F:1][C:2]1[C:3]([F:12])=[CH:4][C:5]2[S:9][C:8]([S:10][CH3:13])=[N:7][C:6]=2[CH:11]=1
Reactant: Fc1cc2nc(S)sc2cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CSc1nc2cc(F)c(F)cc2s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
A suspension (0° C.) of 300 mg (1.476 mmol) 5,6-difluoro-benzothiazole-2-thiol and 306 mg (2.214 mmol) potassium carbonate in 6 mL N,N-dimethylformamide under nitrogen, were added 110.5 μL (1.77 mmol) iodomethane. The mixture was stirred at 0° C. for 1 h. The mixture was diluted with water (30 mL) and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo to provide 294 mg (91.7%) of the title compound as a solid. MS(m/e): 218.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]([OH:13])=[O:12].[H-].[Na+].Br[CH2:17][C:18]([O:20][CH3:21])=[O:19].CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:6]=[C:5]2[C:11]([OH:13])=[O:12]
Reactant: O=C(O)c1c[nH]c2ccc(Cl)cc12
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)Cn1cc(C(=O)O)c2cc(Cl)ccc21
Temperature: -20 °C
Reaction time: 1 h

Procedure:
110 ml of a solution containing 10 g of 5-chloro-1H-indole-3-carboxylic acid (commercial) in DMF is added dropwise to a mixture of 4.50 g of NaH (60% in oil) in 400 ml of DMF at −10° C. After it returns to RT, it is stirred for 1 hour. The reaction mixture is cooled to −20° C. 4.86 ml of methyl bromoacetate is added dropwise, it is returned to RT for a period of 5 hours and is stirred for 15 hours. The reaction mixture is added to 1 L of EtOAc/1N HCl mixture, the organic phase is collected and the aqueous phase is extracted with EtOAc. The organic phases are combined, washed with water and with brine, then dried over Na2SO4 and evaporated to dryness. 8.9 g of the expected compound is obtained in the form of a white powder.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:67])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47](OS(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[CH:46](OC(C)C)[CH2:45]2)[CH:7]([CH3:68])[CH:6]([O:69][Si:70]([C:73]([CH3:76])([CH3:75])[CH3:74])([CH3:72])[CH3:71])[CH2:5][C:4]1=[O:77])[CH3:2].[N-]=[N+]=[N-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:67])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:9][CH:8]([CH3:42])[CH3:7])[CH2:46][CH2:45]2)[CH:7]([CH3:68])[CH:6]([O:69][Si:70]([C:73]([CH3:75])([CH3:76])[CH3:74])([CH3:72])[CH3:71])[CH2:5][C:4]1=[O:77])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OS(=O)(=O)c4ccccc4[N+](=O)[O-])C(OC(C)C)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OC(C)C)CC3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Temperature: 70 °C
Yield: 106.5 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(o-nitrophenyl-sulfonyloxy)-3"-isopropyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (87 mg) in N,N-dimethyl formamide (1 ml) was added an excess of sodium azide (25 mg) and the mixture heated to 70° C. After 7.5 hours the reaction was cooled to room temperature, diluted with ethyl acetate, extracted from half-saturated ammonium chloride, and washed with brine. The combined organics were dried over sodium sulfate and purified by flash chromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol) to give the title compound (38 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[CH:27]=[CH:26][C:25]2[C:24]3=[CH:28][CH:29]=[N:30][N:23]3[CH:22]=[CH:21][C:20]=2[C:19]=1[C:31]([O:33]C)=[O:32])(=[O:16])=[O:15])[CH3:2].[OH-].[Li+]>O1CCOCC1>[CH2:35]([N:3]([CH2:1][CH3:2])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[CH:27]=[CH:26][C:25]2[C:24]3=[CH:28][CH:29]=[N:30][N:23]3[CH:22]=[CH:21][C:20]=2[C:19]=1[C:31]([OH:33])=[O:32])(=[O:15])=[O:16])[CH3:36]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(ccn3nccc23)c1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(ccn3nccc23)c1C(=O)O
Temperature: 80 °C
Yield: 60.3 %

Procedure:
A mixture of methyl 8-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-pyrazolo[5,1-a]isoquinoline-7-carboxylate (Intermediate 1, 0.075 g) and lithium hydroxide (3M aqueous solution, 2 mL) in dioxane (6 mL) was heated to 80° C. for 6 hours. The resultant mixture was cooled and concentrated in vacuo. The residue was acidified using formic acid and then concentrated in vacuo. The residue was partitioned between ethyl acetate and water and the organic layer was dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was triturated with methanol. The mixture was centrifuged and the supernatant was decanted twice. The resultant solid was dried in vacuo overnight to give 8-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-pyrazolo[5,1-a]isoquinoline-7-carboxylic acid (0.044 g) as a solid.
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:22]3[CH:23]=[N:24][S:25][CH:26]=3)[C:13]=2[CH3:27])[CH:6]=1)C.CO.O[Li].O>C1COCC1.O.CCOC(C)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cl:21][C:17]1[CH:16]=[C:15]2[C:20]([C:12]([S:11][C:7]3[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=3)[C:4]([OH:28])=[O:3])=[C:13]([CH3:27])[N:14]2[C:22]2[CH:23]=[N:24][S:25][CH:26]=2)=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnsc3)c3cc(Cl)ccc23)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(Sc2cccc(C(=O)O)c2)c2ccc(Cl)cc2n1-c1cnsc1
Temperature: 25 °C

Procedure:
3-(6-Chloro-1-isothiazol-4-yl-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester (0.073 g, 0.182 mmol) was dissolved in THF (2 mL), H2O (0.75 mL) and MeOH (0.75 mL) and LiOH.H2O (0.040 g, 0.953 mmol) was added. The reaction was stirred at room temperature and monitored by analytical LCMS. When no starting material remained the reaction was diluted with H2O and EtOAc and citric acid was added until pH 3 was reached. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic portions were washed with H2O, dried over MgSO4 and concentrated. The residue was purified via silica gel chromatography (0-5% MeOH in DCM) to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21]CC2C=CC=CC=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.C1COCC1.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 250 mL round bottomed flask which contained a suspension of Pd—C (10% wt 3 g) in EtOH (70 mL) and THF (30 mL) was added (R)-2-(4-benzyloxy-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (3.5 g, 9 mmol). The stirred solution was flushed with a H2 balloon. This process was repeated 3 times. The resulting solution was stirred at rt under hydrogen atmosphere overnight. The reaction mixture was then filtered, washed with THF (30 ml), EtOH (25 ml) and dried in vacuo to provide the crude product which was further purified by recrystallization with ether-EtOAc-hexane to yield the title product, (2.5, 90%); MS; APCI+, Calcd: 293.5. Found m/z: 294.2 (M+1). 1H NMR (400 MHz, CDCl3); δ 1.47 (s, 9H), 1.80-2.10 (m, 4H), 3.40 (br, 2H), 3.69-3.89 (m, 1H), 4.00-4.18 (m 2H), 6.71-6.76 (m, 4H).
Reaction SMILES: CN1CCN(C2C=CC3C(C=2)=CC=C2C=3OC(C(NC3C=CC([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=CC=3)=O)=CC2=O)CC1.N1(C([C:46]2[CH:51]=[CH:50][C:49]([NH:52][C:53]([C:55]3[O:56][C:57]4[C:62]([C:63](=[O:65])[CH:64]=3)=[CH:61][CH:60]=[CH:59][C:58]=4[N:66]3[CH2:71][CH2:70][N:69]([CH3:72])[CH2:68][CH2:67]3)=[O:54])=[CH:48][CH:47]=2)=O)CCOCC1>>[N:30]1([C:51]2[CH:50]=[C:49]([NH:52][C:53]([C:55]3[O:56][C:57]4[C:62]([C:63](=[O:65])[CH:64]=3)=[CH:61][CH:60]=[CH:59][C:58]=4[N:66]3[CH2:67][CH2:68][N:69]([CH3:72])[CH2:70][CH2:71]3)=[O:54])[CH:48]=[CH:47][CH:46]=2)[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: CN1CCN(c2ccc3c(ccc4c(=O)cc(C(=O)Nc5ccc(N6CCOCC6)cc5)oc43)c2)CC1
Reactant: CN1CCN(c2cccc3c(=O)cc(C(=O)Nc4ccc(C(=O)N5CCOCC5)cc4)oc23)CC1
Product: CN1CCN(c2cccc3c(=O)cc(C(=O)Nc4cccc(N5CCOCC5)c4)oc23)CC1

Procedure:
This compound was prepared from 8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 1) and 3-morpholin-4-yl-phenylamine (Reference Example 18) as prepared in Example 12, yielding a yellow solid. (120 mg=86%), LCMS−m/z=449.5