Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][O-:3].[Na+].C(C(CC)(C([O-])=O)C([O-])=O)C.Cl[C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=1[N+:24]([O-])=O>CN(C)C(=O)C>[I:23][C:20]1[CH:19]=[C:18]2[C:17]([CH2:1][C:2](=[O:3])[NH:24]2)=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1cc(I)ccc1Cl
Reactant: CC[O-]
Agent: CCC(CC)(C(=O)[O-])C(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=C1Cc2ccc(I)cc2N1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 53 %

Procedure:
To a jacketed reactor, N,N-dimethylacetamide (DMAc) (120 mL) and sodium ethylate (NaOEt) powder (12.1 g) is charged at 20° C. Diethylmalonate (28.8 g) is added dropwise into the above mixture while keeping internal temperature at around 10° C. After finishing addition, warm up the mixture to 20° C., and continue to stir for another 10 minutes. Then, 2-chloro-5-iodonitrobenzene (17 g) is added in one portion, and heat the mixture to 78° C. and stir for usually at least 2.5 hours until process monitor shows almost complete conversion. The resulting mixture is cooled down to 20° C., and it is quenched by 2 N cold aq. HCl solution (180 mL). The bottom yellow oil was transferred to a jacket reactor with ethanol (92 mL) in it. Then, to the above solution the first portion of SnCl2.2H2O (30 g) powder is added, and the resulting mixture is heated to 70° C. and stirred for 1 hour. The second portion of SnCl2.2H2O (30 g) is added, the mixture is stirred usually at least 0.5 hour until process monitor shows almost complete conversion. Then, heat the resulting mixture to 80° C. and add 36% aq. HCl solution (60 mL) during 0.5 hour. The mixture is stirred for at least 2.5 hours until process monitor shows almost complete conversion. Then, to the mixture water (90 mL) is added and the resulting mixture is cooled down to 20° C. Collect the solid by filtration and wash the solid with water (250 mL) to afford the crude 6-iodo-2-oxindole. Then, it is purified by crystallization with acetic acid (HOAc) (110 mL), and followed by washing with 3 N aq. HCl solution (80 mL) to afford the 6-iodo-2-oxindole in 53% yield and 99% HPLC purity (Rt=7.45 min).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](I)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.[F-].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(COC)OC.C(O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:28]3[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=3)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(I)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cs+]
Solvent: CCO
Solvent: COCCOC
Product: CC(=O)N1c2ccc(-c3ccc(Cl)cc3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Suzuki cross-coupling of 1-acetyl-6-iodo-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (20 mg), 4-chlorophenylboronic acid (22 mg), cesium fluoride (15 mg), triphenylphosphine (5 mg) and tris(dibenzylideneacetone)dipalladium(0) (4.5 mg) in dimethoxyethane/ethanol 4:1 (v/v) (5 ml) was performed according to the method described in example 13.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15]2([CH2:18][CH:19]=O)[CH2:17][CH2:16]2)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:21]([O:23][C:24]([CH:26]=[C:27]([CH3:33])[CH2:28]P(=O)([O-])[O-])=[O:25])[CH3:22]>>[CH2:21]([O:23][C:24](=[O:25])[CH:26]=[C:27]([CH3:33])[CH:28]=[CH:19][CH2:18][C:15]1([C:7]2[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[CH:6]=2)[CH2:16][CH2:17]1)[CH3:22]
Reactant: CCOC(=O)C=C(C)CP(=O)([O-])[O-]
Reactant: CC(C)(C)c1cc(C(C)(C)C)cc(C2(CC=O)CC2)c1
Product: CCOC(=O)C=C(C)C=CCC1(c2cc(C(C)(C)C)cc(C(C)(C)C)c2)CC1
Yield: 77.5 %

Procedure:
The above cyclopropyl aldehyde 10 (520 mg, 2.4 mmol) and 3-ethoxycarbonyl-2-methylprop-2-enylphosphonate (2.53 g, 9.6 mmol) were condensed as described for Example 1 to give 712 mg of ethyl-6-[1-(3,4-diethylbenzene)-cyclopropyl]-3-methyl-2,4-hexadienoate (11) as a pale yellow oil in 91% yield.
Reaction SMILES: [OH:1][C:2]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[C:15]([CH3:18])([CH3:17])[CH3:16].[NH2:19][C:20]1[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[CH:22][C:21]=1[OH:29]>>[NH2:26][C:24]1[CH:23]=[CH:22][C:21]([OH:29])=[C:20]([NH:19][C:6](=[O:7])[C:5]2[CH:4]=[C:3]([C:15]([CH3:16])([CH3:18])[CH3:17])[C:2]([OH:1])=[C:10]([C:11]([CH3:12])([CH3:14])[CH3:13])[CH:9]=2)[CH:25]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Product: CC(C)(C)c1cc(C(=O)Nc2cc(N)ccc2O)cc(C(C)(C)C)c1O

Procedure:
4-hydroxy-3,5-di(tert.-butyl)benzoic acid and 2-amino-4-nitrophenol are treated in the same manner as described in Preparation 5-(1) and Preparation 1-(2) to give N-(5-amino-2-hydroxyphenyl)-4-hydroxy-3,5-di(tert.-butyl)benzamide are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2].CCN(C(C)C)C(C)C.[CH2:38]([N:40]1[N:44]=[N:43][C:42]([CH2:45][N:46]2[C:51]3[CH:52]=[C:53]([C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)[S:54][C:50]=3[C:49](=[O:61])[N:48]([CH:62]3[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]3)[C:47]2=[O:68])=[N:41]1)[CH3:39]>C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([N:65]4[CH2:66][CH2:67][CH:62]([N:48]5[C:49](=[O:61])[C:50]6[S:54][C:53]([C:55]7[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=7)=[CH:52][C:51]=6[N:46]([CH2:45][C:42]6[N:43]=[N:44][N:40]([CH2:38][CH3:39])[N:41]=6)[C:47]5=[O:68])[CH2:63][CH2:64]4)=[O:22])=[CH:23][CH:24]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: CCn1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5nnn(CC)n5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (160 mg; compound C10) dissolved in DCM (20 ml) HBTU (167 mg) and DIPEA (0.21 ml) are added and the reaction mixture is stirred for 30 min at RT. Subsequently, 1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione (175 mg; compound B39) is added and the reaction mixture is stirred for 24 h at RT. After extraction with a saturated solution of sodium hydrogen carbonate and a saturated solution of sodium chloride the organic phase is separated and dried over Na2SO4. After filtration the solvent is removed under reduced pressure to give the crude title product. After purification by flash column chromatography (silica gel, eluent: EtOAc) the title compound is obtained as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[F:11].[Br:12]Br>C(Cl)(Cl)Cl>[Br:12][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([F:11])[CH:4]=1)=[O:10]
Reactant: CC(=O)c1ccc(Br)c(F)c1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1ccc(Br)c(F)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a 0° C. solution containing 2.4 g of 1-(4-bromo-3-fluorophenyl)ethanone (11.1 mmols) in 56 mL of CHCl3 was added dropwise 0.57 mL of bromine (11.1 mmols). The reaction was stirred at 0° C. for three hours and then allowed to warm to ambient temperature. The reaction mixture was quenched with 10 mL of saturated aqueous Na2S2O3. The layers were separated, and the organics were dried over MgSO4, filtered through a frit, and concentrated to a yellow solid which was used without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[C:8]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][N:22]=2)(=[O:20])=[O:19])[N:7]([CH3:30])[N:6]=1.[H-].[Na+].Cl[C:34]1[N:39]=[CH:38][C:37](S(C)(=O)=O)=[CH:36][N:35]=1>C1COCC1.CC(N(C)C)=O>[CH:27]([C:24]1[CH:25]=[CH:26][C:21]([S:18]([NH:17][C:8]2[N:7]([CH3:30])[N:6]=[C:5]([O:4][CH2:3][CH2:2][O:1][C:34]3[N:35]=[C:36]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:37]=[CH:38][N:39]=3)[C:9]=2[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:19])=[O:20])=[N:22][CH:23]=1)([CH3:28])[CH3:29]
Reactant: Cc1ccc(-c2c(OCCO)nn(C)c2NS(=O)(=O)c2ccc(C(C)C)cn2)cc1
Reactant: CS(=O)(=O)c1cnc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(OCCOc3nccc(S(C)(=O)=O)n3)nn(C)c2NS(=O)(=O)c2ccc(C(C)C)cn2)cc1
Reaction time: 0.08 h
Yield: 40.6 %

Procedure:
To a solution of N-[3-(2-hydroxyethoxy)-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]-5-isopropyl-2-pyridinesulfonamide (Example 40) (112 mg) in anhydrous THF (5 ml) at 0° C. and under an atmosphere of nitrogen was added sodium hydride (60% dispersion in oil, 21.8 mg) and the mixture was stirred for 5 minutes. To the mixture was added 2-chloro-5-(methylsulfonyl)pyrimidine (50 mg) in dimethylacetamide (1 ml). After stirring for 150 min. the reaction mixture was partitioned between ethyl acetate (50 ml) and saturated ammonium chloride solution (50 ml). The ethyl acetate layer was washed with brine (50 ml), dried (MgSO4), filtered and evaporated to dryness. Purification of the residue on a Phenomenex Magellen™ column using a 0.1M NH4OAc:MeCN gradient (95:5 to 60:40) over 5min. and then an isocratic flow (60:40) for 15 minutes gave the title compound as a white solid (31 mg).
Reaction SMILES: [NH2:1][C:2](=[N:33]O)[C:3]1[CH:32]=[CH:31][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:30]=[CH:29][C:24]([C:25]([NH2:28])=[N:26]O)=[CH:23][CH:22]=3)[CH2:13][CH2:12]2)=[CH:5][CH:4]=1.C(OC(=O)C)(=O)C>[C].[Pd].C(O)(=O)C>[NH2:33][C:2](=[NH:1])[C:3]1[CH:32]=[CH:31][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([NH2:28])=[NH:26])=[CH:29][CH:30]=3)[CH2:13][CH2:12]2)=[CH:5][CH:4]=1
Reactant: NC(=NO)c1ccc(OCCCC2CCN(CCCOc3ccc(C(N)=NO)cc3)CC2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: N=C(N)c1ccc(OCCCC2CCN(CCCOc3ccc(C(=N)N)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100.8 %

Procedure:
To an acetic acid (150 mL) suspension of 14.9 g of 4-{3-[4-(3-{4-[amino(hydroxyimino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}-N′-hydroxybenzamidine was added 5.97 mL of acetic anhydride at room temperature, which was then stirred at room temperature for 1 hour and 20 minutes. To this mixture was added 1.50 g of 5% palladium-carbon, which was then stirred under hydrogen atmosphere for 4 hours and 40 minutes. Insoluble matter was filtered off, and 55 mL of 6.0 mol/L hydrochloric acid was then added. The solvent was distilled off under reduced pressure, and ethanol was added to the resultant residue. The solid matter was collected by filtration to provide 14.0 g of 4-{3-[4-(3-{4-[amino(imino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}benzamidine as white solid form.
Reaction SMILES: [F:1][CH:2]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4].[Li]CCCC.CCCCCC.[Br:32][C:33]1[CH:34]=[C:35]2[C:41]([CH:42]([C:44]3[C:49]([Cl:50])=[CH:48][CH:47]=[C:46]([F:51])[C:45]=3[Cl:52])O)=[CH:40][NH:39][C:36]2=[N:37][CH:38]=1.S(Cl)(Cl)=O>C1COCC1.C(Cl)Cl>[C:15]1([S:12]([C:2]([S:3]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)(=[O:5])=[O:4])([F:1])[CH:42]([C:41]2[C:35]3[C:36](=[N:37][CH:38]=[C:33]([Br:32])[CH:34]=3)[NH:39][CH:40]=2)[C:44]2[C:49]([Cl:50])=[CH:48][CH:47]=[C:46]([F:51])[C:45]=2[Cl:52])(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(c1ccccc1)C(F)S(=O)(=O)c1ccccc1
Reactant: OC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(Br)cc12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: O=S(=O)(c1ccccc1)C(F)(C(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(Br)cc12)S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-(fluoro(phenylsulfonyl)methylsulfonyl)benzene (836 mg, 2.66 mmol) in THF (8.0 mL) was added 2.5 M of n-BuLi in Hexane (1.18 mL, 2.95 mmol) at −78° C.; the resulting mixture was stirred for 30 min at −78° C. before use. To a stirred solution of (5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2,6-dichloro-3-fluorophenyl)methanol (250.0 mg, 0.6410 mmol) in THF (5.0 mL, 62 mmol) was added thionyl chloride (0.12 mL, 1.6 mmol) at 0° C. The resulting mixture was stirred for 30 min at rt, then the solvent was removed and the residue was dried under high vacuum. To this residue was added THF (10.0 mL) followed by adding the previously prepared solution (lithiated 1-(fluoro(phenylsulfonyl)methylsulfonyl)benzene) by canula at −78° C. The resulting mixture was allowed to warm up to rt in about 1 hr. Then the solvent was removed under reduced pressure to give a residue, which was diluted by DCM and extracted by DCM (20 mL×3). The organic phase were combined, dried (Na2SO4) and concentrated to give a crude residue, which was purified by silica gel chromatography (eluent: 20% AcOEt in DCM) to give the title compound. MS (ES+): m/z 684.92, 686.92, 688.92 [MH+]. HPLC: tR=1.65 min (polar—3 min, TOF)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C([O:26]CC)C>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][CH2:10][CH2:11][OH:12])=[CH:6][CH:7]=1.[CH3:23][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O-:26])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: CCOCC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: OCCC#Cc1ccc(Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Dissolve 13.3 g (0.0736 mole) of 4-(4-chlorophenyl)-3- butyn-1-ol in 70 ml pyridine and cool to 0° C. Add 16 g (0.0837 mole) of p-toluenesulfonyl chloride and stir in ice bath for one hour. Store in freezer over night. Add 200 ml diethyl ether and then wash with 3×150 ml 1N hydrochloric acid. The organic layer is then washed with 50 ml saturated aqueous sodium bicarbonate solution and then dried over magnesium sulfate. Evaporate solvent to obtain the title compound.
Reaction SMILES: [OH-].[K+].[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[CH3:15][N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1>CO>[C:12]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[NH:3][CH:4]=[C:5]2[C:19]1[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH:18]=1)([OH:14])=[O:13]
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: CN1CCC(=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1CC=C(c2c[nH]c3ccc(C(=O)O)cc23)CC1
Yield: 71 %

Procedure:
To a solution of 5.8 gm (90 mMol) potassium hydroxide in 50 mL methanol were added 4.83 gm (30 mMol) indole 5-carboxylic acid followed by 7.4 mL (60 mMol) 1-methyl-4-piperidone and the resulting solution was heated at reflux for 18 hours. The reaction mixture was then concentrated under reduced pressure and the resulting oil dissolved in 200 mL water. The solution was gradually neutralized by addition of 18 mL 5N hydrochloric acid. The precipitate which formed was isolated by filtration and washed with water to provide 6.09 gm after drying. This solid was dissolved in 100 mL 0.5N sodium hydroxide, filtered and the filtrate treated with 50 mL 1N hydrochloric acid. The solid which formed was filtered and dried under reduced pressure to provide 5.46 gm (71%) of the title compound.
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]([C:10]1[N:11]=[C:12]([C:15]([NH:17][C:18]2[C:23]([CH3:24])=[C:22]([O:25][CH3:26])[CH:21]=[CH:20][C:19]=2[C:27](=[O:29])[CH3:28])=O)[S:13][CH:14]=1)([CH3:9])[CH3:8].O.Cl>C(O)(C)(C)C.CCOCC>[OH:29][C:27]1[C:19]2[C:18](=[C:23]([CH3:24])[C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[N:17]=[C:15]([C:12]2[S:13][CH:14]=[C:10]([CH:7]([CH3:9])[CH3:8])[N:11]=2)[CH:28]=1
Reactant: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1C
Temperature: 100 °C
Yield: 89.2 %

Procedure:
Potassium tert-butoxide (21.8 g, 195 mmol) was added to a suspension of 2′-[[(4-iso-propylthiazole-2-yl)(oxo)methyl]amino]-4′-methoxy-3′-methylacetophenone (35, 30.8 g, 92.7 mmol) in tert-butanol. The resulting reaction mixtures was heated at 100° C. overnight. Then, the reaction mixture was cooled at room temperature and diluted with ether (100 mL). The precipitate was filtered off and washed with Et2O to give a powder (fraction A). The mother liquor was concentrated in vacuo, triturated in ether, filtered off, and washed with ether to give a powder (fraction 2). Fractions 1 and 2 were mixed and poured into water (250 mL). The pH of the resulting solution was adjusted to 6-7 (control with pH paper) with HCl 1N. The precipitate was filtered off, washed with water and dried. Then, the solid was triturated in diisopropyl ether, filtered off and dried to give 26 g (88%) of the title product 36 as a brownish solid: m/z=315 (M+H)+.
Reaction SMILES: C(OC(N1CCC(NC(C2SC=CC=2NC2C=CN=C3NC=CC=23)=O)C1)=O)(C)(C)C.[CH2:31]([NH:38][CH2:39][CH2:40][NH2:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[NH:42]1[C:46]2=[N:47][CH:48]=[CH:49][C:50]([NH:51][C:52]3[C:53]4[CH:63]=[CH:62][CH:61]=[CH:60][C:54]=4[S:55][C:56]=3[C:57](O)=[O:58])=[C:45]2[CH:44]=[CH:43]1>>[CH2:31]([NH:38][CH2:39][CH2:40][NH:41][C:57]([C:56]1[S:55][C:54]2[CH:60]=[CH:61][CH:62]=[CH:63][C:53]=2[C:52]=1[NH:51][C:50]1[CH:49]=[CH:48][N:47]=[C:46]2[NH:42][CH:43]=[CH:44][C:45]=12)=[O:58])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NCCNCc1ccccc1
Reactant: O=C(O)c1sc2ccccc2c1Nc1ccnc2[nH]ccc12
Agent: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: O=C(NCCNCc1ccccc1)c1sc2ccccc2c1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using N-benzylethylenediamine instead of 1-BOC-3-aminopyrrolidine and 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-benzo[b]thiophene-2-carboxylic acid instead of 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid. LCMS (ESI) 393 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.42 (1H, br. s.) 8.89 (1H, s) 8.23 (1H, t, J=5.37 Hz) 8.04 (1H, dt, J=8.07, 0.92 Hz) 7.82 (1H, d, J=5.37 Hz) 7.50 (2H, dddd, J=6.92, 5.94, 0.78, 0.61 Hz) 7.26-7.41 (3H, m) 7.08-7.25 (7H, m) 6.48 (1H, d, J=2.34 Hz) 6.03 (1H, d, J=5.42 Hz) 3.46 (2H, s) 2.46 (2H, t, J=6.20 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14][C@H:15]1[O:20][C@:16]1([CH3:19])[CH2:17][OH:18]>CO.O.[Ni]>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14][CH2:15][C@:16]([CH3:19])([OH:20])[CH2:17][OH:18]
Reactant: COc1c(C)c(C)c(OC)c(C[C@H]2O[C@]2(C)CO)c1C
Agent: [Ni]
Solvent: O
Solvent: CO
Product: COc1c(C)c(C)c(OC)c(CC[C@](C)(O)CO)c1C
Yield: 86.4 %

Procedure:
185 mg of (2R,3R)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2,3-epoxy-2-methylbutanol were dissolved in 5 ml of methanol and the solution was subsequently diluted with 5 ml of water. Thereupon, Raney-nickel was added and the mixture was heated at reflux for 2 hours under hydrogen. After completion of the hydrogen uptake, the mixture was filtered, washed with methanol and methylene chloride and concentrated on a rotary evaporator. Residual water was distilled off azeotropically by the addition of methylene chloride. The oil obtained was recrystallized from hexane/ether and there were obtained 161 mg of 55% (S)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-methyl-1,2-butanediol (48% yield; analysis of the acetonide by gas chromatography). Data of the pure substance: m.p. 86°-87° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:12]=[C:13]([C:15](=[O:17])[CH3:16])[CH:14]=1)=[O:8])[CH3:5].CO[C:27](OC)([N:29]([CH3:31])[CH3:30])C>>[CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:12]=[C:13]([C:15](=[O:17])[CH:16]=[CH:27][N:29]([CH3:31])[CH3:30])[CH:14]=1)=[O:8])[CH3:5]
Reactant: COC(C)(OC)N(C)C
Reactant: COCC(C)NC(=O)c1cc(C(C)=O)cc(-c2ccc(C)cc2)c1
Product: COCC(C)NC(=O)c1cc(C(=O)C=CN(C)C)cc(-c2ccc(C)cc2)c1

Procedure:
A solution of 5-acetyl-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide (648 mg, 2 mmol) in N,N-dimethylacetamide dimethyl acetal (0.8 mL) was heated to reflux for 18 hours. The reaction mixture was cooled and volatiles were removed in vacuo. The resulting 188 mg of crude 5-(3-dimethylamino-acryloyl)-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide was used directly in the next step without further purification.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[C:5]1([P:11]([CH2:14]O)[CH2:12]O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[C:5]1([P:11]([CH2:14][NH:4][CH:1]([CH3:3])[CH3:2])[CH2:12][NH:4][CH:1]([CH3:3])[CH3:2])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: OCP(CO)c1ccccc1
Reactant: CC(C)N
Product: CC(C)NCP(CNC(C)C)c1ccccc1
Reaction time: 8 h

Procedure:
Degassed isopropyl amine (1 ml, 11.6 mmol) of was added to 491 mg (2.886 mmol) of (phenylphosphinediyl)dimethanol (PhP(CH2OH)2) and the mixture was stirred overnight. The excess amine was removed in vacuo to afford the product as a viscous colorless oil. 1H NMR (400 Mhz, C6D6): δ 7.55 (m, 2H); 7.09 (m, 3H); 3.11 (m, 4H); 2.68 (m, 2H); 0.89 (m, 12H). 31P NMR (162 Mhz, C6D6): −29.5.
Reaction SMILES: [OH-].[Li+].[CH2:3]([O:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH2:18][C@H:19]([N:24]2[CH2:29][CH2:28][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:26][CH2:25]2)[C:20]([O:22]C)=[O:21])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[C:4]#[C:5][CH3:6]>O1CCCC1>[CH2:3]([O:7][C:8]1[CH:9]=[CH:10][C:11]([S:14]([NH:17][CH2:18][C@H:19]([N:24]2[CH2:25][CH2:26][N:27]([S:30]([CH3:33])(=[O:31])=[O:32])[CH2:28][CH2:29]2)[C:20]([OH:22])=[O:21])(=[O:16])=[O:15])=[CH:12][CH:13]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC[C@@H](C(=O)OC)N2CCN(S(C)(=O)=O)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)NC[C@@H](C(=O)O)N2CCN(S(C)(=O)=O)CC2)cc1
Temperature: 0 °C
Reaction time: 20 h
Yield: 92.5 %

Procedure:
1.3 ml (1.3 mmol) of an aqueous solution of lithium hydroxide having a concentration of 1M are added to a solution of 400 mg (0.8 mmol) of methyl (S)-3-(4-but-2-ynyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoate diluted in 10 ml of tetrahydrofuran cooled beforehand to 0° C. The reaction medium is stirred at ambient temperature for 20 h. After evaporation to dryness, 1.5 ml of an aqueous solution of acetic acid having a concentration of 1M are added so as to obtain a pH=6. The product precipitates, and is filtered off, rinsed with water and then with diethyl ether and dried under vacuum. 340 mg (89%) of (S)-3-(4-but-2-ynyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoic acid are obtained in the form of a white solid.