Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:6][C@@H:5]([CH2:7][N:8]2[C:12]([CH3:13])=[C:11](I)[CH:10]=[N:9]2)[CH2:4][O:3]1.C1COCC1.C([Mg]Cl)(C)C.CO[B:28]1[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]1.[NH4+].[Cl-]>>[CH3:1][C:2]1([CH3:15])[O:6][C@@H:5]([CH2:7][N:8]2[C:12]([CH3:13])=[C:11]([B:28]3[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]3)[CH:10]=[N:9]2)[CH2:4][O:3]1
Reactant: COB1OC(C)(C)C(C)(C)O1
Reactant: Cc1c(I)cnn1C[C@H]1COC(C)(C)O1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1C[C@H]1COC(C)(C)O1
Reaction time: 1 h

Procedure:
To a solution of 1-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-4-iodo-5-methyl-1H-pyrazole (55.0 mg, 0.171 mmol) in THF (1 mL, 20 mmol) at rt was added 1.3 M of isopropylmagnesium chloride in THF (0.53 mL, 0.68 mmol), and the mixture was stirred for 1 h. The reaction was quenched with 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.14 mL, 0.85 mmol) and allowed to stir at rt for 1 h. Sat. NH4Cl was added, and the organic solvent was removed in vacuo. The material was extracted with DCM and water. The organic layer was purified via column chromatography, eluting with 5-10% EtOAc/hexanes. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. MS (ES+): m/z=322.21/323.20/324.20 (50/100/50) [MH+]. HPLC: tR=1.49 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: Cl.[NH2:2][C:3]1([CH2:8]Cl)[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH2:10]([C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:22]=[C:23]=[S:24])[CH2:11][CH3:12]>>[CH2:10]([C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:22]=[C:23]1[S:24][CH2:8][C:3]2([CH2:7][CH2:6][CH2:5][CH2:4]2)[NH:2]1)[CH2:11][CH3:12]
Reactant: CCCc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: NC1(CCl)CCCC1
Agent: Cl
Product: CCCc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1

Procedure:
2-n-Propylaniline was converted to 2-n-propylacetanilide according to Method A2a, Step 1. The acetanilide was converted to 2-n-propyl-4-nitroacetanilide according to Method A2a, Step 2. The acetanilide was deprotected according to Method A2a, Step 3 to give 2-n-propyl-4-nitroaniline. The aniline was converted to 2-n-propyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3. 1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 2-n-propyl-4-nitrophenyl isothiocyanate according to Method C1a to give 2-(2-n-propyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2-(2-n-propyl-14-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [CH:1]1([NH:7][C:8]([O:16][N:17]2[C:22]([CH3:24])([CH3:23])[CH2:21][CH:20]([O:25][C:26](=[O:28])[CH3:27])[CH2:19][C:18]2([CH3:30])[CH3:29])=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C1(C)C=CC=CC=1>[C:38]([N:9]([CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)[C:8]([O:16][N:17]1[C:18]([CH3:30])([CH3:29])[CH2:19][CH:20]([O:25][C:26](=[O:28])[CH3:27])[CH2:21][C:22]1([CH3:24])[CH3:23])=[N:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)OC1CC(C)(C)N(OC(=NC2CCCCC2)NC2CCCCC2)C(C)(C)C1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)OC1CC(C)(C)N(OC(=NC2CCCCC2)N(C(=O)c2ccccc2)C2CCCCC2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 18.6 %

Procedure:
To a solution of compound 1 (4.21 g, 10 mmol) [prepared according to Example 1] in toluene (25 ml) is added triethylamine (1.55 ml, 11 mmol) and benzoyl chloride (1.55 g, 11 mmol). The mixture is stirred at room temperature for 24 hours, then washed with water (2×10 ml), dried over MgSO4 and evaporated. The residue is chromatographed over silica gel with hexane-ethyl acetate (4:1) and the pure fractions are recristallized from acetonitrile to afford 0.98 g of the title compound as a white solid, mp. 147-152° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=[CH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][C:12]1[CH2:17][CH2:16][CH2:15][C:14](=[O:18])[CH:13]=1.C[Si](Cl)(C)C>C(Cl)Cl.CCOCC>[CH3:11][C:12]1([CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:17]=[CH:16][CH2:15][C:14](=[O:18])[CH2:13]1
Reactant: C=CCCc1ccccc1
Reactant: CC1=CC(=O)CCC1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC1(CCCCc2ccccc2)C=CCC(=O)C1
Reaction time: 0.33 h
Yield: 45 %

Procedure:
Cp2ZrHCl (103 mg, 0.40 mmol, 2.0 eq.) was added to a stirred, room temperature, solution of 4-phenyl-1-butene (0.08 mL, 0.5 mmol, 2.5 eq.) in CH2Cl2 (0.40 mL) under an argon atmosphere. After stirring for about 20 min, the resulting clear yellow solution was transferred via syringe over about 1 min to a clear colourless stirred solution of CuOTf-ligand complex (15.0 mg, 0.020 mmol, 0.10 eq.) in Et2O (2.0 mL) under an argon atmosphere. The resulting dark mixture was allowed to stir for an additional 10 min before 3-methyl-2-cyclohexenone (0.023 mL, 0.20 mmol, 1.0 eq.) and then TMSCl (0.13 mL, 1.0 mmol, 5.0 eq.) were added dropwise via syringe. The reaction was stirred until complete (TLC control (EtOAc/Petrol 1:9)). The reaction was quenched by the addition of Et2O (ca 3 mL) and then NH4Cl (1 M. aq., ca 1.5 mL). The mixture was partitioned between water and Et2O and the aqueous phase extracted with Et2O (3×10 mL). The combined organic phase was washed with NaHCO3 (aq. sat., ca 10 mL), dried (Na2SO4), filtered and concentrated in vacuo to give an oil. Flash column chromatography of the residue (EtOAc/petrol; SiO2) gave (−)-3-methyl-3-(4-phenylbutyl)cyclohexenone (21.9 mg, 0.09 mmol, 45%) as a yellow oil. HPLC analysis indicated an enantiomeric excess of 60% [Chiralpak® IA; flow 1 ml/min; hexane/i-PrOH: 99:1; λ=210 nm; minor enantiomer (+)-3-methyl-3-(4-phenylbutyl)cyclohexenone, tR=14.90 min; major enantiomer (−)-3-methyl-3-(4-phenylbutyl)cyclohexenone, tR=15.70 min].
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1)=[O:4]>CO.Cl.[Pd]>[CH3:1][C:2]([CH3:17])([CH3:16])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][NH2:13])=[CH:14][CH:15]=1)=[O:4]
Reactant: CC(C)(C)C(=O)NCCc1ccc(C#N)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(C)C(=O)NCCc1ccc(CN)cc1

Procedure:
Bubble nitrogen for 15 min into a solution of 4-[2-(2,2-dimethyl-propionylamino)-ethyl]-benzonitrile (175 mg, 0.76 mmol) in methanol (31 mL) with concentrated HCl (3 drops). Add 10% Pd/C (Degussa type E101, 18 mg) and submit the mixture to hydrogenation at atmospheric pressure for 64 h. Filter the catalyst through Celite® and concentrate in vacuo to obtain the hydrochloride salt of the title compound. Add saturated aqueous NaHCO3 and extract twice with EtOAc. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo to obtain the title compound as a yellow oil (110 mg, 62%). MS (ES+) m/z: 235 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[C:9]([N+:14]([O-])=O)[CH:8]=1)[CH3:2].[H][H]>[Pd].CO>[NH2:11][C:10]1[CH:12]=[CH:13][C:7]([O:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])=[CH:8][C:9]=1[NH2:14]
Reactant: [H][H]
Reactant: CCOCCOc1ccc(N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CCOCCOc1ccc(N)c(N)c1

Procedure:
A mixture of 1.8 g. of 4-(2-ethoxyethoxy)-2-nitroaniline and 0.3 g. of 5% palladium-on-charcoal catalyst in 200 ml. of methanol is hydrogenated under ambient conditions. After the uptake of hydrogen is complete, the mixture is filtered and 1,2-diamino-4-(2-ethoxyethoxy) benzene is isolated from the filtrate by evaporation.
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([N:19]3[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]3)[CH:10]=2)=[O:7])=[CH:4][C:3]=1[NH:27][C:28]1[N:33]=[C:32]([C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[CH:31]=[CH:30][N:29]=1.C1([S:46](O)(=[O:48])=[O:47])C=CC=CC=1>C(OCC)(=O)C>[CH2:6]([O:7][SH:46](=[O:48])=[O:47])[C:5]1[CH:25]=[CH:26][CH:2]=[CH:3][CH:4]=1.[CH3:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=[C:11]([N:19]3[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]3)[CH:10]=2)=[O:7])=[CH:4][C:3]=1[NH:27][C:28]1[N:33]=[C:32]([C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[CH:31]=[CH:30][N:29]=1
Reactant: O=S(=O)(O)c1ccccc1
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Solvent: CCOC(C)=O
Product: O=[SH](=O)OCc1ccccc1
Temperature: 76 °C
Reaction time: 0.67 h

Procedure:
To a 1 L round-bottom flask equipped with a mechanical stirrer, a thermometer, and a condenser, 4 g of 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide free base and 500 mL of ethyl acetate were charged. The slurry was stirred and heated to 76° C. (reflux) and held at that temperature for 40 minutes. To the resulting clear solution, 7.5 mL of 1 M benzene sulfonic acid solution (in ethyl acetate) was added. The mixture was stirred at 76° C. for 5 hours, cooled down to room temperature by natural cooling (cooling rate ˜0.5° C./min) and held at room temperature for ˜1 hour. The solid was collected by filtration and was dried at 50-55° C./10-20 torr for 8-16 hours to obtain 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide mono benzyl sulfonate salt as a yellowish solid. Melting point=˜260° C.; x-ray diffraction pattern showing maxima at 2θ=6.5°, 7.8°, 9.4°, 10.4°, 13.7°, 17.0°, 17.5°, 17.9°, 18.8°, 21.2°.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][C:27]([C:32]([O:34][CH3:35])=[O:33])([CH2:30][CH3:31])[CH2:28][CH3:29])/[C:9]1=[O:36])=O)(C)(C)C.[F:37][C:38]1[CH:39]=[CH:40][C:41]([CH3:53])=[C:42]([CH:44]=[N:45][C:46]([O:48][Si](C)(C)C)=[CH2:47])[CH:43]=1>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:36])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=4[O:26][C:27]([CH2:28][CH3:29])([C:32]([O:34][CH3:35])=[O:33])[CH2:30][CH3:31])[CH2:47][C:46](=[O:48])[NH:45][CH:44]3[C:42]3[CH:43]=[C:38]([F:37])[CH:39]=[CH:40][C:41]=3[CH3:53])[C:11]2=[CH:12][CH:13]=1
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Reactant: CCC(CC)(Oc1ccc(Cl)cc1/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21)C(=O)OC
Solvent: Cc1ccccc1
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)OC
Temperature: 60 °C
Reaction time: 3 h
Yield: 23.9 %

Procedure:
A mixture of E/Z-3-[5-chloro-2-(1-methoxycarbonyl-1-ethyl-propoxy)-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (7.6 g, 15 mmol) and 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (60 mmol) prepared in Example 4 in toluene (60 mL) was heated at 60° C. for 3 h, and concentrated in vacuo. To the residue was added DCM (50 mL) and TFA (20 mL), and the resulting solution was stirred at room temperature for 3 h, then concentrated in vacuo, partitioned between ethyl acetate and diluted aqueous NaOH solution. The organic layer was washed with water, dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash column chromatography to give the title compound as white solid (2.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1.[O:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:10](=[O:12])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(CC(=O)O)c1
Reactant: c1ccoc1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1cccc(CC(=O)c2ccco2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
3-Methoxyphenylacetic acid (20 g, 120.35 mmol) was dissolved in CH2Cl2 (200 mL), and furan (24.6 g, 361.39 mmol) and trifluoroacetic anhydride (37.8 g, 180 mmol) were added to the solution. The reaction was kept being stirred overnight at room temperature. The reaction was quenched with saturated NaHCO3 to pH=6.9, and the organic reagent in the mixture was evaporated. The residue was extracted with EtOAc, and the organic layer was washed with brine, dried over MgSO4, and evaporated. The resulting residue was purified by chromatography on a silica gel column using hexane-EtOAc as eluent to give 1-(furan-2-yl)-2-(3-methoxyphenyl)ethan-1-one as yellow oil: 20 g (yield: 77%)
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[C:6]([OH:13])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=[O:9].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[CH2:14]([O:13][C:6]1[CH:5]=[C:4]([I:3])[CH:12]=[CH:11][C:7]=1[C:8]([O:10][CH2:8][C:7]1[CH:11]=[CH:12][CH:4]=[CH:5][CH:6]=1)=[O:9])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccc(I)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc(I)cc1OCc1ccccc1
Temperature: 60 °C
Yield: 109.6 %

Procedure:
Sodium hydride (4.7 g, 60% dispersion in mineral oil) is added portionwise over 15 minutes to a solution of 4-iodosalicylic acid (15.4 g) in dry dimethylformamide (150 mL). After stirring for 40 minutes benzyl bromide (19.9 g) is added and the mixture heated at 60° C. for 1.5 hours. The reaction mixture is evaporated and the residue partitioned between chloroform and water. The organic phase is dried over magnesium sulphate, evaporated and the residue triturated with ether to give benzyl 2-benzyloxy-4-iodobenzoate (14.2 g) as a cream coloured solid.
Reaction SMILES: O1[CH:6]2[CH:2]1[C:3](=[O:34])[CH:4]([CH:23]([OH:33])[C:24]#[C:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:5]2[CH:7]=[CH:8][CH:9]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.C(N(CC)CC)C.[OH:42][CH:43]([CH2:46][OH:47])[CH2:44][SH:45].S([O-])(O)(=O)=O.[K+]>CO>[OH:42][CH:43]([CH2:46][OH:47])[CH2:44][S:45][C:2]1[C:3](=[O:34])[CH:4]([CH:23]([OH:33])[C:24]#[C:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:5]([CH:7]=[CH:8][CH:9]([O:15][Si:16]([C:19]([CH3:22])([CH3:20])[CH3:21])([CH3:18])[CH3:17])[CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=1
Reactant: COC(=O)CCCC#CC(O)C1C(=O)C2OC2C1C=CC(O[Si](C)(C)C(C)(C)C)C1CCCC1
Reactant: OCC(O)CS
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)CCCC#CC(O)C1C(=O)C(SCC(O)CO)=CC1C=CC(O[Si](C)(C)C(C)(C)C)C1CCCC1
Reaction time: 2 h
Yield: 62 %

Procedure:
A 49 mg amount of 2,3-epoxy-5-(1-hydroxy-6-methoxycarbonyl-2-hexynyl}-4-(3-t-butyldimethylsilyloxy-3-cyclopentyl-1-propenyl)cyclopentanone was dissolved in 1 ml of methanol and 21 μl of triethylamine was added. Then, 12 mg of 2,3-dihydroxypropanethiol was added thereto, followed by stirring for 2 hours. The reaction mixture was poured on an aqueous saturated solution of potassium hydrogen sulfate, followed by extracting with ethyl acetate. The extracted solution was washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering and concentrating, the concentrate was subjected to silica gel chromatography to give 36 mg (yield 62%) of 2-(2,3-dihydroxypropylthio)-5-(1-hydroxy-6-methoxycarbonyl-2-hexynyl)-4-(3-t-butyldimethylsilyloxy-3-cyclopentyl-1-propenyl)-2-cyclopentenone.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1.ClCCl>[CH3:1][O:2][C:3](=[O:20])[C@@H:4]1[CH2:8][C@@H:7]([O:9][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The product from Example 11 (50.0 g; 178 mmol) is dissolved in anhydrous pyridine (910 ml). Methanesulphonyl chloride (18.6 ml; 241 mmol) is added dropwise while cooling in ice. Subsequently, the solution is stirred for 2.5 h during which it is allowed to warm to room temperature. The solution is then diluted with dichloromethane (3.6 l) and extracted twice by shaking with a 10% solution of sodium hydrogen carbonate (1.1 l on each occasion). The organic phase is dried (magnesium sulphate), concentrated and the residue subsequently distilled repeatedly with toluene. Yield: 64.0 g (quantitative).
Reaction SMILES: C[C:2]1[CH:6]=C(C)[N:4]([C:8](=[NH:20])[NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[N:3]=1.CS(O)(=O)=O.NN1CC[O:30][CH2:29][CH2:28]1>>[NH2:20][C:8]([NH:4][N:3]1[CH2:2][CH2:6][O:30][CH2:29][CH2:28]1)=[N:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1)(=[O:11])=[O:12]
Reactant: Cc1cc(C)n(C(=N)NS(=O)(=O)c2ccc(Cl)cc2)n1
Reactant: NN1CCOCC1
Agent: CS(=O)(=O)O
Product: NC(=NS(=O)(=O)c1ccc(Cl)cc1)NN1CCOCC1

Procedure:
The compound of Example 28 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-chlorobenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of N-aminomorpholine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 318.78; found mol. wt. (M+H) 319.3; 637.0 (Dimer)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]([OH:12])=O.S(Cl)(Cl)=O.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:30](=[O:31])[CH2:29][C:28](=[O:32])[NH:27][C:26]3[C:33]4[C:38]([CH:39]=[CH:40][C:25]2=3)=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:20][CH:19]=1>>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][C:10]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:30](=[O:31])[CH2:29][C:28](=[O:32])[NH:27][C:26]3[C:33]4[C:38]([CH:39]=[CH:40][C:25]2=3)=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:20][CH:19]=1)=[O:12]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=C(O)Cc1c(Cl)cccc1Cl
Solvent: O=S(Cl)Cl
Product: O=C(Cc1c(Cl)cccc1Cl)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 31.7 %

Procedure:
2,6-Dichlorophenylacetic acid (62 mg, 0.3 mmol) was treated with thionyl chloride in the same manner as that of Example 13, and then by using the resultant together with 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (63 mg, 0.2 mmol) obtained in Example 1, (3), the title compound (32 mg, yield 32%) was obtained as pale brown crystals in the same manner as that of Example 1, (4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15](S(C)=O)[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[NH2:31][CH:32]1[CH2:36][CH2:35][N:34]([CH3:37])[C:33]1=[O:38].C[O-].[Na+]>CC(N(C)C)=O.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:31][CH:32]4[CH2:36][CH2:35][N:34]([CH3:37])[C:33]4=[O:38])[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CN1CCC(N)C1=O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(Cl)cnc32)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)N(C)C
Product: CN1CCC(Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1=O
Temperature: 140 °C

Procedure:
A solution of 5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine, 15a, (0.060 g, 0.129 mmol) in DMA (0.5 mL) was treated with 3-amino-1-methylpyrrolidin-2-one (0.030 g, 0.258 mmol) and the reaction was heated at 140° C. for 20 minutes. The reaction mixture was cooled to room temperature and then treated with 0.5 mL of 25% NaOMe in MeOH and heated at 50° C. for 15 min. The mixture was then partitioned between aqueous saturated Na2CO3 solution and EtOAc. The aqueous layer was extracted with EtOAc twice more and the combined organic phases were concentrated in vacuo. The crude material was purified by preparative HPLC. The isolated product was filtered through basic resin to remove residual TFA and provide the desired product.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:19]([C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)([CH3:21])[CH3:20]>>[CH:19]([C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)=[CH:24][CH:23]=1)([CH3:21])[CH3:20]
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Reactant: CC(C)c1ccc(N)cc1
Product: CC(C)c1ccc(NC(=O)c2cccc(S(=O)(=O)N3CCCCC3)c2)cc1

Procedure:
The entitled compound was produced according to the method of Example 73 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 4-isopropylaniline as the starting materials.
Reaction SMILES: [CH2:1]([C:4]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)([CH2:9][CH:10]=[CH2:11])[C:5]([O:7][CH3:8])=[O:6])[CH:2]=[CH2:3].C(C(C1C=CC=CC=1)(CC=C)C(OC)=O)C=C>>[F:18][C:15]1[CH:14]=[CH:13][C:12]([C:4]([CH2:9][CH2:10][CH3:11])([CH2:1][CH2:2][CH3:3])[C:5]([O:7][CH3:8])=[O:6])=[CH:17][CH:16]=1
Reactant: C=CCC(CC=C)(C(=O)OC)c1ccc(F)cc1
Agent: C=CCC(CC=C)(C(=O)OC)c1ccccc1
Product: CCCC(CCC)(C(=O)OC)c1ccc(F)cc1

Procedure:
The title compound was prepared according to the procedure of Example 1B, substituting the compound of Example 14B for the compound of Example 1A. 1H NMR (300 MHz, CDCl3): δ 0.89 (t, J=6.99 Hz, 6 H) 1.07 (m, 4 H) 1.95 (m, 4 H) 3.63 (s, 3 H) 6.99 (t, J=8.64 Hz, 2 H) 7.22 (m, 2 H).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:16][CH:15]=1.[C:25]([N:32]1[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>C1COCC1.O.C(OCC)C>[C:28]([O:27][C:25]([N:32]1[CH2:37][CH2:36][C:35]([CH:21]([C:22]([OH:24])=[O:23])[CH2:20][C:17]2[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=2)([OH:38])[CH2:34][CH2:33]1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=C(O)CCc1ccc(F)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N1CCC(O)(C(Cc2ccc(F)cc2)C(=O)O)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (1.6 M in hexane, 8.8 mL, 14.0 mmol) was added dropwise under stirring over 5 min to a cooled solution of N,N-diisopropylamine (2.0 mL, 14.0 mmol) in THF (10 mL) at −40° C. The solution was warmed to 0° C. and a solution of 3-(4-fluoro-phenyl)propionic acid (1.18 g, 7.0 mmol) in THF (8 mL) was added. The mixture was stirred for 30 min at rt, cooled to −78° C. and N-BOC-4-piperidone (1.68 g, 8.4 mmol) in THF (7 mL) added dropwise over 15 min. The solution was allowed to warm to rt and poured into a stirred mixture of diethylether (100 mL) and water (50 mL). The organic layer was discarded, the aqueous layer extracted with another portion of diethylether. The aqueous layer was acidified with 2 M aq. HCl to pH 3.5 and extracted with dichloromethane (3×1100 mL). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo, giving 69NLS56 as a yellow solid, which is used without further purification.