Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([OH:3])=[O:2].OS(O)(=O)=O.[CH2:18](O)[CH3:19]>>[CH2:18]([O:2][C:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)=[O:3])[CH3:19]
Reactant: CCO
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc2cc[nH]c2c1
Reaction time: 4 h

Procedure:
Combine 6-carboxy-1H-indole and ethanol (110 ml) and cool to 5° C. Add dropwise concentrated H2SO4 (96%, 11.08 ml) while keeping the temperature below 10° C. Heat to reflux. After 4 hours, cool and pour onto ice/water, adjust the pH to about pH 9 and extract with ethyl acetate. Combine the organic extracts, wash with brine, dry Na2SO4), then concentrate to residue. Chromatograph the residue on silica gel eluting with chloroform to give, after evaporation, the title compound: mp 72-75° C. MS (ACPI): m/e 189.9 (M+1).
Reaction SMILES: [C:1]([Si:5]([O:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[F:26])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].CN(C)CCN(C)CCN(C)C.[Li]CCCC.[CH2:44]([O:46][C:47](=[O:50])[CH:48]=[O:49])[CH3:45].Cl>COCCOC.CCCCCC.C1(C)C=CC=CC=1>[CH2:44]([O:46][C:47](=[O:50])[CH:48]([C:21]1[C:22]([F:25])=[CH:23][CH:24]=[C:19]([O:18][Si:5]([C:1]([CH3:4])([CH3:2])[CH3:3])([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:20]=1[F:26])[OH:49])[CH3:45]
Reactant: CC(C)(C)[Si](Oc1ccc(F)cc1F)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C=O
Agent: CN(C)CCN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: COCCOC
Solvent: CCCCCC
Product: CCOC(=O)C(O)c1c(F)ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1F
Temperature: -70 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
A solution under Ar of tert-butyl-(2,4-difluoro-phenoxy)-diphenyl-silane (102 g) and 1,1,4,7,7-pentamethyldiethylenetriamine (50.6 g) in DME (800 ml) was cooled to −70° C. before addition of 1.6 N n-BuLi in hexane (182 ml) over a period of 1 h. The yellow solution was stirred 1 h at −70° C. 50% glyoxalic acid ethylester in toluene (113 g) was added over a period of 1 h. The reaction mixture was stirred 2 h more at −70° C. before heating up over 1 h to 0° C. Sat. NH4 sol. (300 ml) was added and the pH was lowered to pH=6 with 2 N HCl. The product was extracted with AcOEt (2×400 ml). The organic layers were washed with brine (500 ml) and dried (Na2SO4) and the solvent was evaporated. CC (Hept to Hept/AcOEt 9:1) afforded 70.8 g (54%) of (RS)-[3-(tert-butyl-diphenyl-silanyloxy)-2,6-difluoro-phenyl]-hydroxy-acetic acid ethyl ester. Yellowish oil. MS 488.5 ([M+H]+).
Reaction SMILES: [CH:1]1([CH2:5][N:6]([C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])[C@H:7]2[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)[CH2:4][CH2:3][CH2:2]1.[ClH:31]>O1CCOCC1.CCOCC>[ClH:31].[CH:1]1([CH2:5][N:6]([C@H:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)[C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N(CC2CCC2)C(=O)c2ccccc2C(F)(F)F)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(c1ccccc1C(F)(F)F)N(CC1CCC1)[C@H]1CCNC1
Reaction time: 1 h
Yield: 86 %

Procedure:
Tert-butyl (3S)-3-{(cyclobutylmethyl) [2-(trifluoromethyl) benzoyl]amino}pyrrolidine-1-carboxylate from preparation 28 (1.40 g, 3.3 mmol) was dissolved in 4N hydrogen chloride in Dioxane. The solution was stirred for 1 hour and the solvent removed under reduced pressure. The residue was dissolved in water and the solution washed with ether. The aqueous phase was basified by adding aqueous NaOH and extracted with ether. This ether phase was dried over Magnesium Sulfate, filtered and the solvent removed under reduced pressure to afford a gum, which was treated with 2N hydrogen chloride in ether, to afford 0.99 g (86%) of the title compound as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12]O)[CH:6]=[CH:5]2.P(Br)(Br)[Br:15]>C(Cl)Cl>[Br:15][CH2:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[CH:8]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccc2cc(F)ccc2c1
Solvent: ClCCl
Product: Fc1ccc2cc(CBr)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.5 %

Procedure:
To a solution of (6-fluoro-naphthalen-2-yl)-methanol (2.0 g, 11.3 mmol) in CH2Cl2 (30 mL) was added PBr3 (1.0 M in CH2Cl2, 22.6 mmol). The reaction mixture was stirred for 3 h at room temperature before being quenched by NH4Cl (30 mL). The organic layer was separated, dried and concentrated. The resultant residue was purified by silica gel column chromatography (ethyl acetate/hexane=1:10) to afford 2-bromomethyl-6-fluoro-naphthalene (2.23 g, 74%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][N:7]([CH2:9][C:10]([OH:12])=O)[CH3:8])=[O:5])[CH3:2].[NH2:13][C@H:14]([C:27]([N:29]([CH2:39][C:40]1[C:41]2[CH:48]=[CH:47][CH:46]=[CH:45][C:42]=2[S:43][CH:44]=1)[C@@H:30]([CH3:38])[CH:31]([O:35][CH2:36][CH3:37])[O:32][CH2:33][CH3:34])=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23]>>[S:43]1[CH:44]=[C:40]([CH2:39][N:29]([C@@H:30]([CH3:38])[CH:31]([O:32][CH2:33][CH3:34])[O:35][CH2:36][CH3:37])[C:27](=[O:28])[C@@H:14]([NH:13][C:10](=[O:12])[CH2:9][N:7]([CH3:8])[NH:6][C:4](=[O:5])[NH:3][CH2:1][CH3:2])[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[C:41]2[CH:48]=[CH:47][CH:46]=[CH:45][C:42]1=2
Reactant: CCNC(=O)NN(C)CC(=O)O
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Product: CCNC(=O)NN(C)CC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N(Cc1csc2ccccc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(ethylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-9) 50 mg (0.29 mmol) was coupled with tert-butyl (S)-5-amino-6-((benzo[b]thiophen-3-ylmethyl)((S)-1,1-diethoxy-propan-2-yl)amino)-6-oxohexylcarbamate (Compound IV-15) 100 mg (0.19 mmol) to obtain the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][N:12]([CH3:14])[N:13]=2)=[CH:5][CH:4]=1.Cl.O.[NH:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:14][N:12]1[N:11]=[N:10][C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:17]3[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]3)=[CH:4][CH:5]=2)=[N:13]1
Reactant: O=C1CCNCC1
Reactant: Cn1nnc(-c2ccc(CBr)cc2)n1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cn1nnc(-c2ccc(CN3CCC(=O)CC3)cc2)n1
Temperature: 35 °C
Yield: 36.9 %

Procedure:
A solution of 23 grams (0.091 mole) of 5-[4-(bromomethyl)phenyl]-2-methyl-1,2,3,4-tetrazole, 14 grams (0.091 mole) of 4-piperidone monohydrate hydrochloride, and 47 mL (3 equivalents) of N,N-diisopropylethylamine in 200 mL of dimethylsulfoxide (DMSO) was stirred for about 3 days. The reaction was quenched by pouring the reaction mixture onto 400 mL of dilute, cold sodium hydroxide. The resultant solution was extracted one time with 300 mL of ethyl acetate. An emulsion formed, which was broken up by warming it to about 35° C. The organic layer was separated and concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using 40:1 methylene chloride:methanol as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 9.12 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[N:21]=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([S:28]([OH:31])(=O)=[O:29])=[CH:24][CH:23]=5)[CH:19]=[CH:18][CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.O=S(Cl)[Cl:34].CN(C=O)C>O=P(Cl)(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[N:21]=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([S:28]([Cl:34])(=[O:31])=[O:29])=[CH:24][CH:23]=5)[CH:19]=[CH:18][CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(Nc1cccc(-c2ccc(S(=O)(=O)O)cc2)n1)C1(c2ccc3c(c2)OCO3)CC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2ccc(S(=O)(=O)Cl)cc2)n1)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 75 °C

Procedure:
4-(6-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)pyridin-2-yl)benzenesulfonic acid (1.9 g, 4.3 mmol) was dissolved in POCl3 (30 mL) followed by the addition of SOCl2 (3 mL) and DMF (100 μl). The reaction mixture was heated at 70-80° C. for 15 min. The volatiles were evaporated and then re-evaporated with chloroform-toluene. The residual brown oil was diluted with chloroform (22 mL) and used for sulfonylation immediately. ESI-MS m/z calc. 456.0, found 457.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]2=[O:16])=[CH:4][CH:3]=1.[C:17]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:18].N1C=CN=C1.Cl>>[C:17]([Si:21]([CH3:23])([CH3:22])[O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:9](=[O:16])[NH:10][C:11](=[O:15])[NH:12][C:13]2=[O:14])=[CH:6][CH:7]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1NC(=O)C(c2ccc(O)cc2)C(=O)N1
Agent: Cl
Agent: c1c[nH]cn1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C2C(=O)NC(=O)NC2=O)cc1
Temperature: 55 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To a solution of 5-(4-hydroxyphenyl)barbituric acid (1.9 g) and tertbutyl dimethylsilyl chloride (4.68 g) in 20 ml of anhydrous dimethylformlamde are added 4.4 g of imidazole and the mixture is heated to 55° C. for 5 hours. The temperature is then brought to room temperature and the reaction mixture is poured into 1 N hydrochloric acid and extracted twice with ethyl acetate. The pooled organic extracts are washed with water and dried over sodium sulfate. By concentration of the solution a white solid separates, which is kept at 0° C. overnight, then it is filtered to give 2.185 g of the product
Reaction SMILES: F[C:2]1[CH:10]=[N:9][CH:8]=[C:7]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])[C:3]=1[C:4]([NH2:6])=[O:5].[OH:20][C:21]1[CH:22]=[C:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:4]([C:3]1[C:7]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[CH:8][N:9]=[CH:10][C:2]=1[O:20][C:21]1[CH:22]=[C:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH:24]=[CH:25][CH:26]=1)(=[O:5])[NH2:6]
Reactant: NC(=O)c1c(F)cncc1Nc1ccc(I)cc1F
Reactant: CC(C)(C)OC(=O)Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2cncc(Nc3ccc(I)cc3F)c2C(N)=O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
31 mg of 3-fluoro-5-[(2-fluoro-4-iodophenyl)amino]isonicotinamide (0.083 mmol, 1. eq.) and 17 mg of tert-butyl (3-hydroxyphenyl)carbamate (0.083 mmol, 1 eq.) were dissolved in 1 ml of DMF, then 81 mg of cesium carbonate (0.248 mmol, 3 eq.) were added. The resulting mixture was stirred at room temperature for 18 hours. Since the reaction was not complete, the mixture was stirred for another 3 days at 50° C. bath temperature. The mixture was then partitioned between aq. NH4Cl solution (10 ml) and dichloromethane (10 ml). The phases were separated and the aqueouse layer was reextracted twice with dichloromethane (10 ml each). The combined organic layers were washed with brine (20 ml), dried over a silicone filter and concentrated in vacuo. The residue was purified by flash chromatography to yield 17 mg (0.03 mmol, 30%) of the analytically pure target compound.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:19]2[C:18](=[O:24])[CH2:17][C@@:16]2([CH3:25])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:15])[CH:13]=[CH2:14])[CH2:3]1.O.[C:27]([OH:30])(=[S:29])[CH3:28]>>[C:27]([S:29][CH2:14][CH2:13][C:12](=[O:15])[C@@H:11]1[C@:16]2([CH3:25])[C@H:8]([C@H:7]3[C@H:19]([C:18](=[O:24])[CH2:17]2)[C@:20]2([CH3:23])[C@H:4]([CH2:3][C@H:2]([OH:1])[CH2:22][CH2:21]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1)(=[O:30])[CH3:28]
Reactant: C=CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: CC(O)=S
Solvent: O
Product: CC(=O)SCCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reaction time: 3 h

Procedure:
3α-Hydroxy-21-methylene-5α-pregnane-11,20-dione (300 mg) was dissolved in thioacetic acid (2 ml) and left at room temperature for 3 hours. The mixture was poured into water and the precipitated oil extracted into ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and water, dried over anhydrous sodium sulphate, evaporated to a pale yellow foam and purified by preparative t.l.c. in ethyl acetate/petrol (1:1). The main band gave title compound (150 mg) as an off-white foam. [α]D + 60.5° (c 0.98).
Reaction SMILES: [CH2:1]([CH:3]([CH2:17][CH3:18])[C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[BH4-].[Na+].O>CO.O1CCCC1>[CH2:17]([CH:3]([CH2:1][CH3:2])[CH:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:9]=2[C:10]=1[CH3:11])[OH:5])[CH3:18]
Reactant: CCC(CC)C(=O)c1oc2ccc(F)cc2c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCC(CC)C(O)c1oc2ccc(F)cc2c1C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 106.9 %

Procedure:
2-Ethyl-1-(5-fluoro-3-methyl-1-benzofuran-2-yl)butan-1-one (15.0 g) synthesized above was dissolved in a mixed solvent of methanol (50 mL)-tetrahydrofuran (250 mL), and sodium tetrahydroborate (90%, 5.1 g) was added at 0° C. The reaction mixture was stirred at 0° C. for 1.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to give the title compound (16.17 g, 100%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[CH:10]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Product: COc1ccc(Nc2cc(Cl)ccc2C(=O)O)cc1
Yield: 60 %

Procedure:
4-Chloro-2-(4-methoxyphenylamino)benzoic acid [VII; R=4-Cl, R"=H, OR°=4-OCH3 ] was prepared from 2,4-dichlorobenzoic acid and 4-methoxyaniline according to the procedure of Example 1, part (a), and was obtained in about 60% yield as a green-grey solid.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@H:4]1[OH:12].[H-].[Na+].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](F)=[CH:18][C:17]=1[Cl:23]>>[ClH:15].[Cl:15][C:16]1[CH:21]=[C:20]([CH:19]=[CH:18][C:17]=1[Cl:23])[O:12][C@@H:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:11][C@@H:3]1[NH:2][CH3:1]
Reactant: CN[C@H]1Cc2ccccc2[C@H]1O
Reactant: Fc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: CN[C@H]1Cc2ccccc2[C@H]1Oc1ccc(Cl)c(Cl)c1
Product: Cl

Procedure:
The title compound was prepared in a similar manner to Example 26 from (±) cis 2-methylamino-1-indanol (0.815 g, 5.0 mmol), sodium hydride (0.18 g of an 80% dispersion in oil; 6.0 mmol) and 1,2-dichloro-4-fluorobenzene (0.99 g, 6.0 mmol). The crude product was purified by chromatography on silica eluting with 0-3% ethanol in diethyl ether. The resulting brown oil (1.3 g) was dissolved in hexane and treated with ethereal HCl to give the hydrochloride salt. Recrystallisation afforded the title compound as a colourless solid, m.p. 238°-239° C. (dec) (from methanoildiethyl ether).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24].[C:27]1([S:37]([Cl:40])(=[O:39])=[O:38])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1>>[ClH:40].[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:37]([C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29][CH:28]=3)(=[O:39])=[O:38])=[C:3]([NH:22][S:23]([CH3:26])(=[O:24])=[O:25])[CH:4]=2)[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)c(NS(C)(=O)=O)c2)CC1
Product: CS(=O)(=O)Nc1cc(N2CCCNCC2)ccc1NS(=O)(=O)c1cccc2ccccc12
Product: Cl

Procedure:
The compound was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}methanesulfonamide and 1-napthalenesufonylchloride (103 mg, 0.455 mmol) to give before Boc-deprotection 150 mg of a purple solid. M+1 475.1 Calcd 474.14.
Reaction SMILES: [Se](=O)=[O:2].Br[CH2:5][C:6]([C:8]1[CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=1)=[O:7].[CH2:15]([OH:17])[CH3:16]>>[CH3:14][C:10]1[CH:9]=[C:8]([C:6](=[O:7])[C:5]([O:17][CH2:15][CH3:16])=[O:2])[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cccc(C(=O)CBr)c1
Reactant: O=[Se]=O
Reactant: CCO
Product: CCOC(=O)C(=O)c1cccc(C)c1
Yield: 81 %

Procedure:
A suspension of selenium dioxide (6.82 g, 61.4 mmol) in ethanol (60 mL) was refluxed for 10 minutes and then, 2-bromo-1-m-tolylethanone (13.1 g, 61.4 mmol) was added. The mixture was refluxed overnight. The cooled reaction was filtered through Celite and the solvent removed under reduced pressure. The residue was diluted with methylene chloride (50 mL), washed with water (2×25 mL), dried (Na2SO4), and concentrated. Purification by column chromatography with silica gel using methylene chloride as eluent gave the title compound (9.6 g, 81%) as oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([C:36](O)=[O:37])=[CH:28][N:27]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:36]([C:29]4[C:30]5[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH:26]=[N:27][CH:28]=4)=[O:37])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=C(O)c1cncc2ccccc12
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cncc5ccccc45)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and isoquinoline-4-carboxylic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM/Methanol=97:3) to yield the title compound.
Reaction SMILES: C(OC[CH:16]([CH2:18][OH:19])O)(=O)CCCCCCCCCCC.[CH2:20]([OH:36])[CH2:21]CCCCCCCCCCCCCC.[C:37]([OH:56])(=[O:55])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54].CCCCCCCC[CH2:65][CH2:66][N+:67](CCCCCCCCCC)(C)C.[Cl-]>>[C:37]([OH:56])(=[O:55])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54].[N:67]([CH2:16][CH2:18][OH:19])([CH2:21][CH2:20][OH:36])[CH2:66][CH2:65][OH:55]
Reactant: CCCCCCCCCCCCCCCCO
Reactant: CCCCCCCCCCCC(=O)OCC(O)CO
Reactant: CCCCCCCCCC[N+](C)(C)CCCCCCCCCC
Agent: CCCCCCCCCCCCCCCCCC(=O)O
Agent: [Cl-]
Product: OCCN(CCO)CCO

Procedure:
Example 2A was repeated but for the sequence of addition of glycerol monolaurate and cetyl alcohol. Instead of being added in the second step, after the equimolar mixture of stearic acid and DDAC, the same amount of the glycerol monolaurate and cetyl alcohol added in Example 2 was added after the addition of TEA.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5]C=CC=1.[CH2:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][N:12]1[C:20]([NH:22][C:23]1[N:28]=[N:27][C:26]([C:29]([OH:31])=O)=[CH:25][CH:24]=1)=[O:21].C1C2C(=CC=CC=2)CN1C(NC1C=CC(C(O)=O)=CC=1)=O>>[CH:8]1([CH2:9][NH:10][C:29]([C:26]2[N:27]=[N:28][C:23]([NH:22][C:20]([N:12]3[CH2:11][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:13]3)=[O:21])=[CH:24][CH:25]=2)=[O:31])[CH2:5][CH2:6][CH2:1][CH2:7]1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)nn1
Reactant: NCCCc1ccccc1
Agent: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Product: O=C(NCC1CCCC1)c1ccc(NC(=O)N2Cc3ccccc3C2)nn1

Procedure:
The title compound was prepared as described in Example 1C, substituting cyclopentylmethamine for 3-phenylpropan-1-amine and 6-(isoindoline-2-carboxamido)pyridazine-3-carboxylic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ 9.97 (s, 1H), 9.00 (t, J=6.1 Hz, 1H), 8.31 (d, J=9.3 Hz, 1H), 8.11 (d, J=9.3 Hz, 1H), 7.41-7.28 (m, 4H), 5.13-4.72 (m, 4H), 3.31-3.16 (m, 2H), 2.22 (p, J=7.3 Hz, 1H), 1.70-1.45 (m, 6H), 1.38-1.20 (m, 2H); MS (ESI(+)) m/e 366 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[C:3]=1[CH3:19].[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:31]([NH2:32])=[CH:30][C:29]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:28][N:27]=2)[CH2:22][CH2:21]1.Cl.O1CCOCC1>CN1C(=O)CCC1>[N:23]1([C:26]2[C:31]([NH:32][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=4)[N:5]=[C:4]([C:13]4[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=4)[C:3]=3[CH3:19])=[CH:30][C:29]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:28][N:27]=2)[CH2:22][CH2:21][O:20][CH2:25][CH2:24]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2cccnc2)nc2cc(F)ccc2c1Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1c(-c2cccnc2)nc2cc(F)ccc2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
Prepared according to general Procedure K using 4-chloro-7-fluoro-3-methyl-2-(pyridin-3-yl)quinoline (95 mg, 0.35 mmol), 2,5-dimorpholinopyridin-3-amine (92 mg, 0.35 mmol) and a 4.0M solution of HCl in dioxane (0.017 mL, 0.07 mmol) in NMP (1.0 mL) and heating in the microwave for 2 h at 150° C. After purification N-(2,5-di-4-morpholinyl-3-pyridinyl)-7-fluoro-3-methyl-2-(3-pyridinyl)-4-quinolinamine was obtained. 1H NMR (400 MHz, chloroform-d) δ ppm 8.87 (1H, d, J=2.7 Hz), 8.73 (1H, dd, J=5.1, 2.0 Hz), 7.99 (1H, dt, J=7.8, 2.0 Hz), 7.74-7.89 (2H, m), 7.62 (1H, d, J=2.7 Hz), 7.49 (1H, dd, J=8.0, 4.9 Hz), 7.31 (1H, ddd, J=9.3, 7.9, 2.7 Hz), 6.80 (1H, s), 6.21 (1H, d, J=2.7 Hz), 3.89-3.99 (4H, m), 3.75 (4H, ddd, J=4.3, 2.7, 2.3 Hz), 3.23 (4H, t, J=4.9 Hz), 2.87-3.01 (4H, m), 2.31 (3H, s). Mass Spectrum (ESI) m/e=501.2 (M+1).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].[Br:37]Br.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([Br:37])=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3cccs3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 55.9 %

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-methyl3-(2-thienylmethyl)benzene (11.08 g) obtained in Example 158-(1) was dissolved in chloroform (100 ml), and added dropwise thereto at 0° C. was a solution of bromine (3.71 g) in chloroform (13 ml). The mixture was stirred at 0° C. for 1.5 hours, and then, at room temperature for 1 hour, and the mixture was poured into a 10% aqueous sodium thiosulfate solution and a saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted twice with chloroform, washed with brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20-67:33) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzene (7.13 g) as a colorless solid. APCI-Mass m/Z 614/616 (M+NH4).