Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I(O)(=O)(=O)=[O:2].[CH:6]([C:8]1[O:9][C:10]2[CH:16]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:14]=[C:13]([O:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[C:11]=2[CH:12]=1)=[O:7]>CC#N.C(OCC)(=O)C.C1C=CC(N=NC2C=CC(N)=NC=2N)=CC=1.Cl.[Cr](F)([O-])(=O)=O>[CH2:20]([O:19][C:17]([C:15]1[CH:14]=[C:13]([O:22][C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)[C:11]2[CH:12]=[C:8]([C:6]([OH:2])=[O:7])[O:9][C:10]=2[CH:16]=1)=[O:18])[CH3:21]
Reactant: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(C=O)oc2c1
Reactant: [O-][I+3]([O-])([O-])O
Agent: O=[Cr](=O)([O-])F
Agent: Cl
Agent: Nc1ccc(N=Nc2ccccc2)c(N)n1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(C(=O)O)oc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.7 %

Procedure:
To 10 mL of acetonitrile was added periodic acid (232 mg, 1.02 mmol), and the solution was stirred vigorously at room temperature for 15 min. Ethyl 2-formyl-4-(4-(methylsulfonyl)phenoxy)-benzofuran-6-carboxylate (360 mg, 0.927 mmol) was then added at 0° C. followed by the addition of pyridium fluorochromate (3.69 mg, 0.0185 mmol) in CH3CN (1 mL). The reaction was stirred at 0° C. for 1 hour. The reaction was diluted with ethyl acetate and washed with brine. The organic layer was dried and concentrated to give the title compound (355 mg, 95%) as an orange solid. The crude product was used in the next step without further purification. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.40 (t, J=7.16 Hz, 3 H) 3.09 (s, 3 H) 4.41 (q, J=7.16 Hz, 2 H) 7.12-7.22 (m, 2 H) 7.55 (d, J=1.13 Hz, 1 H) 7.63 (d, J=1.13 Hz, 1 H) 7.92-8.02 (m, 2 H) 8.17 (s, 1 H).
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:7]=[C:8]([CH:31]=[CH:32][CH:33]=1)[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20]3[C:25]4=[C:26]([CH2:29][OH:30])[CH:27]=[CH:28][N:24]4[N:23]=[CH:22][N:21]=3)=[CH:16][CH:17]=2)[CH:12]=[N:11]1.[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][O:44][C@H:43]([CH2:47]O)[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][O:44][CH:43]([CH2:47][O:30][CH2:29][C:26]2[CH:27]=[CH:28][N:24]3[C:25]=2[C:20]([NH:19][C:15]2[CH:14]=[C:13]4[C:18](=[CH:17][CH:16]=2)[N:10]([CH2:9][C:8]2[CH:31]=[CH:32][CH:33]=[C:6]([F:5])[CH:7]=2)[N:11]=[CH:12]4)=[N:21][CH:22]=[N:23]3)[CH2:42]1)=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CO)C1
Reactant: OCc1ccn2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCOC(COCc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)C1
Reaction time: 0.2 h
Yield: 49.8 %

Procedure:
Thionyl chloride (18 μL, 1.1 equiv) was added to a solution of {4-[1-(3-Fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-yl}-methanol (80 mg, 0.205 mmole) in dry DCM (4 mL) at RT. After 12 min, (2S)-2-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (65.3 mg, 1.5 equiv, H. Yanagisawa et al., Heterocycles, 1993, 35, 105.) was added followed by DIPEA (39.5 μL, 1.1 equiv). After 72 hr at RT, the solvent was removed and silica gel chromatography of the residue (gradient elution with 0 to 50% EtOAc in hexane) afforded 2-{4-[1-(3-Fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethoxymethyl}-morpholine-4-carboxylic acid tert-butyl ester (60 mg, 50% yield); MS: 588 (M+H)+; HPLC Ret Time: 2.69 min (Xterra C18 S5, 3.0×50 mm, 3 min gradient, 4 mL/min. A solution of this material in DCM (2 mL) was cooled to 0° C. and treated with TFA (1 mL). After 90 min, the solvents were removed and the residue was dissolved in DCM. This was washed with saturated NaHCO3 solution and the organic phase was dried (Na2SO4) and the solvents removed. Purification by preparative HPLC and then radial chromatography (1 mm silica gel plate, gradient elution with 0 to 3% NH3 (2N in MeOH) in DCM gave the title compound (30 mg, 60% yield): 1H NMR (CDCl3) δ 2.84-2.58 (m, 4H), 3.65-3.35 (m, 4H) 3.65-3.35 (m, 4H), 4.87 (s, 2H), 5.58 (s, 2H), 6.54 (d, J=2.5 Hz, 1H), 6.83 (d, J=9.5 Hz, 1H), 6.98-6.90 (m, 2H), 7.32-7.20 (m, 3H), 7.48 (d, J=2.5 Hz, 1H), 7.58 (dd, J=1.8, 8.8 Hz, 1H), 7.94 (s, 1H), 8.19 (s, 1H), 9.58 (s, 1H); MS: 488 (M+H)+; HPLC Ret Time: 1.65 min (Xterra C18 S5, 3.0×50 mm, 3 min gradient, 4 mL/min).
Reaction SMILES: C(O)[C:2]([NH2:7])([CH2:5][OH:6])[CH2:3]O.Cl.C(S)[C@@H](O)[C@H]([OH:15])CS.[Mg+2].[Cl-].[Cl-].P(O[CH2:34][C@H:35]1O[C@@H:38]([N:40]2[C:49]3N=CN=[C:44](N)[C:43]=3N=C2)[C@H:37](O)[C@@H:36]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O>>[NH2:7][C@H:2]([C:5]([OH:15])=[O:6])[CH2:3][C:37]1[C:36]2[C:49](=[CH:43][CH:44]=[CH:34][CH:35]=2)[NH:40][CH:38]=1
Reactant: O[C@H](CS)[C@H](O)CS
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Reactant: NC(CO)(CO)CO
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Product: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reaction time: 0.5 h

Procedure:
The ten oligodeoxynucleotides shown in FIG. 14 were synthesized by the phosphotriester method and purified. 500 pmole of each oligodeoxynucleotide except 1 and 10 were phosphorylated individually in 20 ul containing 60 mM Tris-HCl, pH 8, 15 mM DTT, 10 mM MgCl2, 20 uCi of [lambda-32P]-ATP and 20 units of polynucleotide kinase (P/L Biochemicals) for 30 min. at 37° C. This was followed by the addition of 10 ul containing 60 mM Tris-HCl, pH 8, 15 mM DTT, 10 mM MgCl2, 1.5 mM ATP and 20 additional units of polynucleotide kinase followed by another 30 min incubation at 37° C. Following incubation the samples were incubated at 100° C. for 5 min. 500 pmole of oligodeoxynucleotides 1 and 10 were diluted to 30 ul in the above buffer without ATP.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.Br[CH2:17][C:18]([O:20]CC)=[O:19].[OH-].[K+].Cl>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc(S)cc2)cc1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2ccc(SCC(=O)O)cc2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 77.2 %

Procedure:
To a solution of 4.30 g of 4′-methoxy-biphenyl-4-thiol and 3.34 g of ethyl 2-bromo-acetate in 10 ml of ethanol was added over 5 min a solution of 1.12 g of potassium hydroxide in 20 ml of ethanol. The reaction mixture was stirred at 20° for 4 h and then, 1.68 g of potassium hydroxide and 3 ml of water were added and stirring was continued for 15 h at 20°. The mixture was poured onto 150 ml of ice/water and the pH of the mixture set to 2 by the addition of 3N hydrochloric acid. The precipitate was collected by filtration, washed with water and dried to give 4.21 g of 2-(4′-methoxy-biphenyl-4-ylsulfanyl)-acetic acid as white crystals.
Reaction SMILES: [Zn:1].[C:2]([O:10][CH2:11][I:12])(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(OC)(=O)C1C=CC=CC=1>C1COCC1>[I-:12].[C:2]([O:10][CH2:11][Zn+:1])(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(OCI)c1ccccc1
Reactant: [Zn]
Solvent: C1CCOC1
Solvent: COC(=O)c1ccccc1
Product: O=C(OC[Zn+])c1ccccc1
Product: [I-]
Temperature: 10 °C

Procedure:
Title compound was prepared according to the procedure described in: Silhar, P.; Pohl, R.; Votruba, I.; Hocek, M. Org. Lett. 2004, 6, 3225. To a 10° C. solution of zinc (dust) (0.604 g, 9.24 mmol) in THF (1.7 mL) was added a solution of iodomethyl benzoate Part A (1.21 g, 4.62 mmol) in THF (2.1 mL) and the reaction was stirred at 10° C. 1.5 h. Reaction monitored by LCMS by observing the formation of hydrolyzed product (methyl benzoate). Material was used in the next step without purification as a 0.9 M THF solution.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[C:4]([F:28])[CH:3]=1.[CH3:29][C:30]1[O:34][C:33](B(O)O)=[CH:32][CH:31]=1.CC(C)([O-])C.[K+]>COCCOC.O.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>[CH3:25][C@H:20]1[NH:21][C@@H:22]([CH3:24])[CH2:23][N:18]([C:16]2[CH:15]=[CH:14][C:13]([O:26][CH3:27])=[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([C:33]4[O:34][C:30]([CH3:29])=[CH:31][CH:32]=4)=[CH:3][C:4]=3[F:28])(=[O:10])=[O:9])[CH:17]=2)[CH2:19]1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1F
Reactant: Cc1ccc(B(O)O)o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2ccc(C)o2)cc1F
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]-2-fluorobenzenesulfonamide (E103) (200 mg, 0.42 mmol) and (5-methyl-2-furanyl)boronic acid (106 mg, 0.84 mmol) in DME (3 ml) was added potassium tert-butoxide (430 mg, 3.8 mmol) and tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.017 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. The solvent was evaporated in vacuo and residue purified using an SCX column followed by mass directed autoprep HPLC (with addition of 0.1 ml of 10% citric acid in water to the DMSO/MeCN sample to help dissolution) to afford the title compound (E309). MS (ES+) m/e 474 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:24])[CH2:15][CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([O:19]C)=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:26]1[S:27][C:28]2[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:29]=2[N:30]=1.S1C2C=CC=CC=2N=C1NC1C=CC(C2C=CC(C(=O)CC(C)(C)C(O)=O)=CC=2)=CC=1>>[Cl:35][C:33]1[CH:32]=[CH:31][C:29]2[N:30]=[C:26]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14](=[O:24])[CH2:15][CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([OH:19])=[O:18])=[CH:10][CH:9]=4)=[CH:6][CH:7]=3)[S:27][C:28]=2[CH:34]=1
Reactant: CCCC(CC(=O)c1ccc(-c2ccc(N)cc2)cc1)C(=O)OC
Reactant: Clc1ccc2nc(Cl)sc2c1
Agent: CC(C)(CC(=O)c1ccc(-c2ccc(Nc3nc4ccccc4s3)cc2)cc1)C(=O)O
Product: CCCC(CC(=O)c1ccc(-c2ccc(Nc3nc4ccc(Cl)cc4s3)cc2)cc1)C(=O)O
Yield: 18 %

Procedure:
This compound was prepared from methyl 2-[2-(4′-amino-1,1′-biphenyl-4-yl)-2-oxoethyl]-pentanoate (68 mg, 0.20 mmol) and 2,6-dichloro-1,3-benzothiazole (61.3 mg, 0.30 mmol) in a similar manner to the method described for 4-[4′-(1,3-benzothiazol-2-ylamino)-1,1′-biphenyl-4-yl]-2,2-dimethyl-4-oxobutanoic acid, providing 17.2 mg (18%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 12.10 (br s, 1H), 10.75 (br s, 1H), 7.75-8.05 (m, 9H), 7.60 (d, 1H), 7.35 (m, 1H), 3.40 (q, 1H), 3.10 (m, 1H), 1.55 (m, 2H), 1.35 (m, 2H), 0.85 (t, 3H). LC-MS m/z 479.3 (MH+), ret. time 3.88 min.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][C:10]([O:12]C)=[O:11])[CH2:3][CH2:2]1.[BrH:14]>O>[BrH:14].[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH2:5][CH2:6]1
Reactant: COC(=O)CCCN1CCOCC1
Agent: Br
Solvent: O
Product: O=C(O)CCCN1CCOCC1

Procedure:
15 g. (0.052 mole) of Methyl γ-morpholinobutyrate (Cruickshank and Sheehan, J. Am. Chem. Soc. 83, 2891 (1961) was dissolved in a mixture of 45 ml. of 47% hydrobromic acid and 45 ml. of water and heated for 16 hours at reflux. The solution was taken to dryness under reduced pressure, and the solid which formed was triturated with acetone. The material was filtered and crystallized from 60 ml. of acetic acid to give 12.4 g. (95%) of product as colorless crystals, m.p. 151°-152.5°. The infrared and nmr spectra are consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[O:15][CH:14]=[N:13][CH:12]=3)[NH:10][C:4]=2[CH:3]=1.C1C=CC=CC=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].Cl[C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[O:15][CH:14]=[N:13][CH:12]=3)[N:10]([C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])[C:4]=2[CH:3]=1
Reactant: CC(C)OC(=O)Cl
Reactant: Brc1cc2[nH]c(-c3cnco3)cc2cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)n1c(-c2cnco2)cc2cnc(Br)cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.5 %

Procedure:
5-(6-Bromo-1H-pyrrolo[3,2-c]pyridin-2-yl)oxazole (Preparation 139, 156 mg 0.59 mmole) was azeotroped with benzene (3 mL) and then dissolved in DMF (1.5 mL). The solution was placed under nitrogen and a solution of sodium hexamethyldisilazide (1M in THF, 0.9 mL, 0.9 mmole) was added and stirred at room temperature for 20 minutes. A solution of isopropyl chloroformate (1M in toluene, 0.9 mL, 0.9 mmole) was added and stirred at room temperature for 4 hours. The reaction was diluted with ethyl acetate (25 mL) and the solution was washed with water (3×10 mL), brine, dried and evaporated to a residue. This was purified using preparative TLC eluting with 3:1 ethyl acetate:cyclohexane. The product band was recovered with acetone to afford the title compound (154 mg, 74%). 1H-NMR (CDCl3, 500 MHz): δ 1.36 (d, J=6.31 Hz, 6H), 5.23 (sept, J=6.31 Hz, 1H), 6.94 (d, J=0.63 Hz, 1H), 7.41 (s, 1H), 8.02 (s, 1H), 8.32 (t, J=0.95 Hz, 1H), 8.69 (d, J=0.95 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[OH:63][CH:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:67]1[CH2:68][CH2:69][CH:64]([OH:63])[CH2:65][CH2:66]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: OC1CCNCC1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3CCC(O)CC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 4-hydroxypiperidine in DMSO at ambient temperature.
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)(O)[O-].[Na+]>O>[N+:15]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])[C:2]=1[O:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:6]([OH:8])=[O:7])([O-:17])=[O:16]
Reactant: Oc1ccccc1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Oc1ccccc1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (140 g), phenol (100 g), sodium bicarbonate (170 g), and water (1000 ml) was heated to 85°C while stirring and kept at this temperature for 16 hours. After cooling to 4°C, the precipitated sodium salt of 3-nitro-4-phenoxy-5-sulphamyl-benzoic acid was filtered off and washed with ice-water. The sodium salt was dissolved in boiling water (3000 ml), and the 3-nitro-4-phenoxy-5-sulphamyl-benzoic acid was precipitated by the addition of 4N hydrochloric acid. After cooling, the acid was isolated by suction and dried. The melting point was 255°-256°C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[C:19]([CH3:31])[CH:18]=3)=[O:16])[CH2:6][C:5]=12.C(N(CC)C(C)C)(C)C.[Cl:41][C:42]([Cl:47])([Cl:46])[C:43](Cl)=[O:44]>ClCCl>[Cl:41][C:42]([Cl:47])([Cl:46])[C:43]([C:3]1[N:4]2[C:5]([CH2:6][N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[C:19]([CH3:31])[CH:18]=3)=[O:16])[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10]2)=[CH:1][CH:2]=1)=[O:44]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: COc1ccccc1-c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)-methanone of Step C (1.5 g, 3.67 mmol) in dichloromethane (20 mL) was added N,N-diisopropylethyl amine (1.28 mL, 7.35 mmol) followed by slow addition of trichloroacetyl chloride (1.23 mL, 11.0 mmol). The reaction mixture was stirred overnight at room temperature then quenched with water. The organic phase was washed with 0.1 N hydrochloric acid followed by water, then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a green oil. Purification by flash chromatography on silica gel using a solvent system of 20% ethyl acetate in hexane provided the title compound, which was redissolved in dichloromethane and evaporated to dryness in vacuo to a yellow foam (2.1 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([OH:7])[CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:15][S:16]([O:1][CH2:2][CH2:3][C:4]1([OH:7])[CH2:6][CH2:5]1)(=[O:18])=[O:17]
Reactant: OCCC1(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCC1(O)CC1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-(2-hydroxyethyl)cyclopropanol (310 mg, 3.04 mmol) and triethylamine (614.1 mg, 6.08 mmol) in 10 mL of dichloromethane was stirred at −10° C. for 30 min. Methanesulfonyl chloride (348 mg, 3.04 mmol) was added via a syringe. After stirring at −10° C. for 1 hr, the reaction mixture was quenched with ice-water (2 mL) and extracted with dichloromethane (20 mL×4). The combined organic phases were dried over Na2SO4 and concentrated in vacuo to give yellow oil (used for the next step quickly).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C[O:12][C:13](=O)[C@@H:14]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:15][C@@H:16]([CH:28]([CH3:30])[CH3:29])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=1.CO.Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:35]([O:34][C:32]([NH:31][C@@H:14]([CH2:15][C@@H:16]([CH:28]([CH3:30])[CH3:29])[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:22][CH:23]=1)[CH:13]=[O:12])=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: COC(=O)[C@H](C[C@H](Cc1ccc(C(C)(C)C)cc1)C(C)C)NC(=O)OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)[C@@H](Cc1ccc(C(C)(C)C)cc1)C[C@@H](C=O)NC(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
At -75° C., 4.2 ml of 1.2M diisobutylaluminium hydride solution in toluene are slowly added dropwise to a solution of 1 g of 2(S)-tert-butoxycarbonylamino-4(S)-isopropyl-5-(p-tert-butyl-phenyl)-pentanoic acid methyl ester in 20 ml of toluene. The reaction mixture is then stirred for a further 30 minutes at -70° C., 10 ml of methanol are added, the mixture is poured onto a mixture of ice and 10 ml of 1N hydrochloric acid, and extraction is carried out with ethyl acetate. The title compound is obtained: Rf (dichloromethane)=0.35.
Reaction SMILES: [F:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=2[C:18]2[N:19]([CH3:23])[N:20]=[CH:21][CH:22]=2)[CH2:4][CH2:3]1.[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][C:26]=1[Cl:34].C(N(CC)CC)C>C1COCC1>[Cl:34][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:25]=1[F:24])[C:29]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][CH:2]([F:1])[CH2:3][CH2:4]2)=[C:12]([C:18]2[N:19]([CH3:23])[N:20]=[CH:21][CH:22]=2)[CH:13]=1)=[O:30]
Reactant: O=C(Cl)c1ccc(F)c(Cl)c1
Reactant: Cn1nccc1-c1cc(N)ccc1OCCN1CCC(F)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1nccc1-c1cc(NC(=O)c2ccc(F)c(Cl)c2)ccc1OCCN1CCC(F)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 48.8 %

Procedure:
A mixture of 4-[2-(4-fluoro-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (80 mg, 0.25 mmol), 4-fluoro-3-chlorobenzoyl chloride (48 mg, 0.25 mmol), and triethylamine (0.3 mL) in THF (3 mL) was stirred at r.t. for 10 min. The solvent was concentrated in vacuo and the crude was purified by HPLC to give the title compound (58 mg, 50%) as a white solid as TFA salt. 1H NMR (acetone-d6, 400 MHz) δ 2.02-2.24 (m, 4H), 3.08-3.18 (m, 2H), 3.32-3.42 (m, 2H), 3.63 (t, J=4.55 Hz, 2H), 3.80 (s, 3H), 4.59 (t, J=4.55 Hz, 2H), 4.91-5.03 (m, 1H), 6.30 (d, J=1.77 Hz, 1H), 7.23 (d, J=8.84 Hz, 1H), 7.43-7.51 (m, 2H), 7.81 (t, J=2.27 Hz, 1H), 7.91-7.97 (m, 1H), 8.02-8.08 (m, 1H), 8.18 (dd, J=2.53, 7.33 Hz, 1H), 9.71 (s, 1H). Exact mass calculated for C24H25ClF2N4O2 503.1, found 504.1/506.1 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:5][CH:4]=1>[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:7][CH:8]=1
Reactant: COc1ccc(C=CCCCCCC(=O)O)cc1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Product: COc1ccc(CCCCCCCC(=O)O)cc1
Yield: 95.9 %

Procedure:
This compound was synthesized from 8-(p-methoxyphenyl)-7-octenoic acid (1.24 g, 5 mmol) and Pd/BaSO4 (125 mg) by hydrogenation. Crystallization (petroleum ether) afforded the product (1.20 g, 96%) as white crystals (mp 42-43° C.). IR: 3400-2500, 1705 cm-1 ; 1H-NMR: 1.40 (m, 10 H), 2.40 (m, 4 H), 3.80 (s, 3 H), 6.95 (q, 4 H), 10.10 (bs, 1 H). Anal. Calcd. for C15H22O2 : C, 71.97, H, 8.86%; Found: C, 72.07, H, 8.88%.
Reaction SMILES: Br[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[C:10]([O:18][C:19]([CH3:22])(C)C)(=[O:17])[CH2:11][C:12](OCC)=O.Cl.[F:24][C:25]1[C:33]([F:34])=C(F)[C:31]([F:36])=[CH:30][C:26]=1[C:27]([OH:29])=[O:28]>CS(C)=O.C1(C)C=CC=CC=1.O>[CH2:2]([O:29][C:27]([C:26]1[CH:30]=[C:31]([F:36])[C:12]([CH2:11][C:10]([O:18][CH2:19][CH3:22])=[O:17])=[C:33]([F:34])[C:25]=1[F:24])=[O:28])[CH3:3]
Reactant: CCBr
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Reactant: O=C(O)c1cc(F)c(F)c(F)c1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1c(F)cc(C(=O)OCC)c(F)c1F
Temperature: 70 °C
Reaction time: 2 h

Procedure:
In 50 mL of dimethyl sulfoxide is dissolved 2,3,4,5-tetrafluorobenzoic acid, to which are added 4.6 mL of bromoethane and 8.19 g of potassium carbonate. The mixture is stirred at 70° C. for 2 hours. Then, 18.52 g of potassium carbonate and 15.02 g of tert-butyl ethyl malonate, and the mixture is stirred at 90° C. for 2 hours. Water and toluene are added to the reaction mixture, pH is adjusted to 4 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water, saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is dissolved in 50 mL of toluene and heated under reflux for 3.5 hours together with 0.2 g of p-toluenesulfonic acid monohydrate. Water and ethyl acetate are added to the reaction mixture, and the organic layer is separated. The organic layer is washed with water, saturated aqueous solution of sodium bicarbonate and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. By distilling off the solvent under reduced pressure, there is obtained 15.2 g of ethyl 4-ethoxycarbonyl-2,3,6-trifluorophenylacetate.