Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][CH2:8][O:9][C:10]([CH2:12][C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:14])=[O:11].[C:21](=S)=[S:22].CI.[CH3:26][S:27]([CH3:29])=O>>[CH2:19]([O:18][C:16](=[O:17])[C:15](=[C:26]([S:22][CH3:21])[S:27][CH3:29])[C:13](=[O:14])[CH2:12][C:10]([O:9][CH2:8][CH3:7])=[O:11])[CH3:20]
Reactant: CS(C)=O
Reactant: S=C=S
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: CCOC(=O)CC(=O)C(C(=O)OCC)=C(SC)SC
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
Potassium carbonate (34.15 g, 247 mmol) was slowly added to a solution of diethyl 1,3-acetone dicarboxylate (50 g, 247 mmol) in anhydrous DMSO (64 mL) at room temperature The reaction mixture was stirred for 30 minutes and was cooled to 5° C. Carbon disulfide (14.92 mL, 247 mmol) was added dropwise over 30 minutes at 5-10° C., followed by stirring at 0° C. for 1 h. Methyl iodide (30.8 mL, 494 mmol) was then added dropwise at 10° C. and the reaction mixture was stirred at this temperature for 1 h. After quenching the reaction with water, it was extracted with DCM. The combined organics extracts were dried (MgSO4) and concentrated under reduced pressure. Purification by silica gel (1:7 EtOAc/hexanes) gave 20.2 g (26%) of the title compound as a yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 4.18 (q, 2H), 4.08 (q, 2H), 3.71 (s, 2H), 2.45 (s, 6H), 1.23 (t, 3H), 1.18 (t, 3H). MS (ES) [m+H] calc'd for C11H8F4O3, 307; found 307.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])(C)(C)C.C([O:18][C:19](=[O:38])[C@H:20]([CH2:34][CH:35]([CH3:37])[CH3:36])[NH:21]C(OC1C=CC([N+]([O-])=O)=CC=1)=O)(C)(C)C>CN(C=O)C>[N:8]1([C:6]([NH:21][C@H:20]([C:19]([OH:38])=[O:18])[CH2:34][CH:35]([CH3:37])[CH3:36])=[O:7])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)C[C@H](NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)N1CCNCC1)C(=O)O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 1-(tert-butoxycarbonyl)piperazine (60 mg, 0.036 mmol) and N-(4-nitrophenoxycarbonyl)-L-leucine tert-butyl ester (128 mg, 0.36 mmol) in DMF was stirred at 60° C. for 1 h. concentrated in vacuo and the residue treated with 4 M HCl in dioxane (5 ml) for 16 h. The mixture was concentrated in vacuo, azeotroped with toluene and treated with 4 M HCl in dioxane (5 ml) for 16 h. The mixture was concentrated in vacuo to afford the title compound.
Reaction SMILES: [NH2:1][CH:2]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[CH:3]([C:5]1[CH:9]=[CH:8][O:7][CH:6]=1)[OH:4].[C:21]1([CH2:27][CH2:28][C:29](Cl)=[O:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[O:7]1[CH:8]=[CH:9][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:29](=[O:30])[CH2:28][CH2:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][CH:12]=2)=[CH:6]1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccoc1
Reactant: O=C(Cl)CCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CCc1ccccc1)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccoc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(3-furanyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (500 mg, 1.75 mmol) in ethyl acetate (20 ml) were added 3-phenylpropionyl chloride (390 ml, 2.63 mmol) and saturated aqueous sodium hydrogen carbonate (20 ml) and the mixture was stirred overnight-at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated-brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (650 mg, 89%).
Reaction SMILES: [C-:1]#[N:2].[K+].[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH:9]2[CH2:23]OS(C)(=O)=O.O>CS(C)=O>[C:1]([CH2:23][CH:9]1[C:8]2[C:13](=[CH:14][CH:15]=[C:6]([O:5][CH3:4])[CH:7]=2)[CH2:12][N:11]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:10]1)#[N:2]
Reactant: [C-]#N
Reactant: COc1ccc2c(c1)C(COS(C)(=O)=O)CN(C(=O)OC(C)(C)C)C2
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc2c(c1)C(CC#N)CN(C(=O)OC(C)(C)C)C2
Temperature: 80 °C

Procedure:
Potassium cyanide (5.52 g; 85 mmol) is suspended in 50 ml of DMSO and the solution is heated to 80° C. The compound obtained in Step H (6.3 g; 17 mmol), dissolved beforehand in 50 ml of DMSO, is progressively added to the preceding solution, and then the reaction mixture is heated again at 80° C. for 30 minutes. The solution is poured into 150 ml of water and extracted three times with dichloromethane. The organic phase is then dried over magnesium sulphate, filtered and evaporated. The dark red oil obtained is purified by chromatography on silica gel (eluant:cyclohexane with the progressive addition of ethyl acetate until the proportions 8/2 are reached) and the solid obtained is recrystallised from cyclohexane to yield the title product in the form of a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17][CH2:18][CH2:19][NH:20]C(OC(C)(C)C)=O)([CH3:4])([CH3:3])[CH3:2].[ClH:29]>CCOC(C)=O>[Cl-:29].[C:1]([O:5][C:6]([CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17][CH2:18][CH2:19][NH3+:20])=[O:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cl
Reactant: CC(C)(C)OC(=O)Cn1c(SCCNC(=O)OC(C)(C)C)nc2ccccc21
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Cn1c(SCC[NH3+])nc2ccccc21
Product: [Cl-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-butyl[2-(2-tert-butoxycarbonylamino-ethylsulfanyl)-benzoimidazol-1-yl]-acetate (Precursor V-02b) is dissolved in 3M HCl in AcOEt and stirred for 1 h at rt. Evaporation of the solvent in vacuo yields 2-(1-tert-butoxycarbonylmethyl-1H-benzoimidazol-2-ylsulfanyl)-ethyl-ammonium chloride as a colourless solid. To a solution of n-butylchloroformate (14.9 mg, 14 μl, 0.11 mmol) in dry THF (0.5 ml) cooled to 0° C. is added a solution of HOBt (17.3 mg, 0.11 mmol) and DIPEA (18 mg, 23.8 μl, 0.14 mmol) in dry THF (0.5 ml). The resulting mixture is stirred for 10 min. It is then added dropwise at 0° C. onto a solution of 2-(1-tert-butoxycarbonylmethyl-1H-benzoimidazol-2-ylsulfanyl)-ethyl-ammonium chloride (30 mg, 0.09 mmol) and DIPEA (11.2 mg, 14.9 μl, 0.09 mmol) in dry THF (0.7 ml). The resulting mixture is stirred for 1 h at rt. Then tris-(2-aminoethyl)amine polystyrene (3.4 mmol/g, 25.6 mg) is added and the resulting slurry is allowed to stir for 2 h at rt and then filtered. The solvent is removed in vacuo and the residue is diluted with dichloromethane (5 ml). This organic phase is washed once with a saturated aqueous NaHCO3 solution and a saturated aqueous KH2PO4 solution. Evaporation of the solvent in vacuo yields the title compound (17.1 mg) in 48% as a colourless oil: tR=2.35 min (LC-2), ESI-MS (pos.): m/z 408.29 [M+H]+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:30][O:29][C@@:5]2([O:9][C@H:8]3[CH2:10][C@H:11]4[C@@H:16]5[CH2:17][CH2:18][C:19]6[C@@:25]([CH3:26])([C@H:15]5[CH2:14][CH2:13][C@:12]4([CH3:27])[C@H:7]3[C@@H:6]2[CH3:28])[CH2:24][CH2:23][C:21](=[O:22])[CH:20]=6)[CH2:4][CH2:3]1.[H][H]>O1CCCC1.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH3:1][C@H:2]1[CH2:30][O:29][C@@:5]2([O:9][C@H:8]3[CH2:10][C@H:11]4[C@@H:16]5[CH2:17][CH2:18][C@@H:19]6[CH2:20][C:21](=[O:22])[CH2:23][CH2:24][C@:25]6([CH3:26])[C@H:15]5[CH2:14][CH2:13][C@:12]4([CH3:27])[C@H:7]3[C@@H:6]2[CH3:28])[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CCC5=CC(=O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: C1CCOC1
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@@H]5CC(=O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Yield: 89.6 %

Procedure:
Diosgenone (700 g) was dissolved in tetrahydrofuran (THF) (4500 ml) and inerted with nitrogen. The mixture was treated with activated carbon (35 g) and hydrogenated over 5% Pd—BaSO4 (reduced) (35 g) at 25° C. and 2.5 barg hydrogen. The catalyst was removed by filtration and the mixture concentrated to ca. quarter volume. Water (3000 ml) was added over ca. 30 minutes and the resultant solid filtered. The solid was washed with methanol (560 ml) and dried under vacuum at 40-50° C. to afford smilagenone (630 g, 90%).
Reaction SMILES: [CH2:1]([N:8]1[C@H:12](O)[C@H:11]([C:14](=[O:23])NC(C2SC=CC=2)C)[N:10]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:9]1=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[O:37]1CCOC[CH2:38]1>>[CH2:1]([N:8]1[C@H:12]2[CH2:38][O:37][C:14](=[O:23])[C@H:11]2[N:10]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:9]1=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(NC(=O)[C@H]1[C@@H](O)N(Cc2ccccc2)C(=O)N1Cc1ccccc1)c1cccs1
Reactant: C1COCCO1
Agent: O=S(=O)(O)O
Product: O=C1OC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Reaction time: 1 h
Yield: 95 %

Procedure:
A mixture of the amide-alcohol (2.0 g) prepared in Example 15, dioxane (50 ml) and 20 % sulfuric acid (30.0 g) is refluxed with stirring at 88° to 89° C for 1 hour. The reaction mixture is concentrated to one third of the original volume, diluted with water (50 ml) and cooled in an ice bath. The precipitate is collected by filtration to yield cis-1,3-dibenzyl-hexahyrofuro[3,4-d]imidazole-2,4-dione (1.36 g, 95 %). M.P. 100° to 103° C. [α]D20 + 16.4° (C = 2 in CHCl3). The infrared spectrum of the sample is identified with that of the authentic sample.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:7]([CH2:40]C)[C:8](=[O:39])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C@@H:19]1[CH2:36][C:35]2[CH:34]=C(O)C=[CH:31][C:30]=2[C@@H:29]2[C@@H:20]1[C@H:21]1[C@@:25]([CH2:27][CH2:28]2)([CH3:26])[C@@H:24]([OH:38])[CH2:23][CH2:22]1)[CH2:4][CH2:5][CH3:6].[C:42](Cl)(=O)[CH2:43]CC.[C:48]([O:51][CH2:52][CH3:53])(=[O:50])[CH3:49]>O1CCCC1>[CH2:3]([N:7]([CH3:40])[C:8](=[O:39])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C@@H:19]1[CH2:36][C:35]2[CH:34]=[C:52]([O:51][C:48](=[O:50])[CH2:49][CH2:42][CH3:43])[CH:53]=[CH:31][C:30]=2[C@@H:29]2[C@@H:20]1[C@H:21]1[C@@:25]([CH2:27][CH2:28]2)([CH3:26])[C@@H:24]([OH:38])[CH2:23][CH2:22]1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCN(CC)C(=O)CCCCCCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Reactant: CCOC(C)=O
Reactant: CCCC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCN(C)C(=O)CCCCCCCCCC[C@@H]1Cc2cc(OC(=O)CCC)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Reaction time: 3.5 h

Procedure:
Sodium hydride (0.005 g. of a 50% dispersion in mineral oil) was added to a stirred solution of N-n-butyl-11-(3,17β-dihydroxyoestra-1,3,5(10)-trien-7α-yl)-N-ethylundecanamide (Example 2; 0.052 g.) in tetrahydrofuran (2 ml.) and the mixture was stirred at laboratory temperature for 3.5 hours. Butyryl chloride (0.014 ml.) was added and the mixture was stirred at laboratory temperature for 16 hours, diluted with ethyl acetate (30 ml.) and filtered. The filtrate was washed with water, dried and evaporated to dryness. The residue was purified by chromatography on a silica gel column using a 1:1 v/v mixture of ethyl acetate and toluene as eluant. There was thus obtained as an oil N-n-butyl-11-(3-butyryloxy-17β-hydroxyoestra-1,3,5(10)-trien-7α-yl)-N-methylundecanamide, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH3:13][N:14]1C(=O)CCC1.CN.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:13][NH:14][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: CN1CCCC1=O
Reactant: FC(F)(F)Sc1ccc(Cl)nc1
Agent: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CNc1ccc(SC(F)(F)F)cn1
Temperature: 60 °C

Procedure:
To a mixture of 2-chloro-5-trifluoromethylsulfanylpyridine (1.71 g) and NMP (16 ml), 40% of aqueous methylamine solution (1.86 g) was added dropwise, and then the mixture was heated to 60° C., and stirred with heating for 2 hours. After the mixture was cooled to room temperature, potassium carbonate (1.66 g) was added thereto, and 40% of aqueous methylamine solution (1.86 g) was added dropwise. The mixture was heated to 60° C., and stirred with heating for further 2 hours. After the mixture was cooled to room temperature, water was poured, and extracted with ethyl acetate. The combined organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 1.52 g of methyl-(5-trifluoromethylsulfanylpyridine-2-yl)-amine.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Cl.[CH3:25][C:26]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:31][C:26]5([CH3:25])[CH2:30][CH2:29][CH2:28][CH2:27]5)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Reactant: CC1(N)CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4(C)CCCC4)c3n2)c2ccc(F)cc21
Reaction time: 0.15 h
Yield: 22.9 %

Procedure:
A solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (62 mg, 0.20 mmol), 1-methylcyclopentanamine hydrochloride (35 mg, 0.26 mmol), HATU (98 mmol, 0.26 mmol) and DIEA (42 mg, 0.33 mmol) in 6 mL of DMF was stirred at room temperature for 16 hours. The solvent was evaporated at 70° C. under reduced pressure to give a crude product, which was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 55% acetonitrile/45% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 80% acetonitrile/20% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-N-(1-methylcyclopentyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (18 mg, 22.9%) as an off-white solid. MS: (M+H)+=393; 1H NMR (300 MHz, DMSO): δ 12.84 (s, 1H), 9.09 (s, 1H), 8.49-8.44 (m, 1H), 8.41 (s, 1H), 8.01 (s, 1H), 7.72 (d, 1H, J=7.8 Hz), 7.17 (t, 1H, J=8.1 Hz), 4.17 (s, 3H), 2.19 (brs, 2H), 1.79-1.76 (m, 6H), 1.57 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[S:10][C:11]=1[CH3:12].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:15])[S:10][C:11]=1[CH3:12]
Reactant: N[C@@H](Cc1cccc(F)c1)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1sc(C(=O)O)cc1-c1c(Cl)cnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1sc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (187 mg, 0.73 mmol) [prepared according to the procedure of Example 158], 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (233 mg, 0.70 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-fluoro-L-phenylalanine (5.03 g, 17.8 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (412 mg, 0.88 mmol) in Chloroform (9 mL). DIEA (640 μL, 3.66 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (180 mg, 0.30 mmol, 42%): LC-MS (ES) m/z=537 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[CH:6][CH:5]=[N:4][NH:3]1.[C:20](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[CH3:20][N:3]1[C:2](=[O:1])[C:7]([CH2:8][N:9]2[C:10](=[O:19])[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]2=[O:18])=[CH:6][CH:5]=[N:4]1
Reactant: O=C([O-])[O-]
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccn[nH]c1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: Cn1nccc(CN2C(=O)c3ccccc3C2=O)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
2-[(3-Oxo-2,3-dihydropyridazin-4-yl)methyl]isoindoline-1,3-dione (255 mg, 1.00 mmol) in dimethylformamide (3 mL) was heated with potassium carbonate (145 mg, 1.05 mmol) and methyl iodide (426 mg, 3.00 mmol) at 70° C. for 2 hours. After completion of the reaction, the solvent was removed by vacuum distillation, and the resulting residue was stirred with 4 M hydrogen chloride/1,4-dioxane (10 mL) at room temperature for 2 hours. After completion of the reaction, the reaction solution was mixed with water and extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate) to give the desired product (233 mg, 86% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([NH:13][C:14]([O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[O:15])[CH:10]([C:23](O)=[O:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.CCN(C(C)C)C(C)C.[F:50][C:51]1[CH:52]=[C:53]([NH2:57])[CH:54]=[CH:55][CH:56]=1>ClCCCl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([NH:13][C:14]([O:16][CH2:17][CH2:18][Si:19]([CH3:20])([CH3:22])[CH3:21])=[O:15])[CH:10]([C:23](=[O:24])[NH:57][C:53]2[CH:54]=[CH:55][CH:56]=[C:51]([F:50])[CH:52]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)OCC[Si](C)(C)C)C(C(=O)O)C1
Reactant: Nc1cccc(F)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC(NC(=O)OCC[Si](C)(C)C)C(C(=O)Nc2cccc(F)c2)C1
Reaction time: 0.25 h
Yield: 42.6 %

Procedure:
To a solution of 4-(2-trimethylsilanyl-ethoxycarbonylamino)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (3200.00 mg; 8.54 mmol; 1.00 eq.) in DCE (40.0 ml), bis(2-oxo-1,3-oxazolidin-3-yl)phosphinic chloride (2392.68 mg; 9.40 mmol; 1.10 eq.) was added. After stirring for 15 mins. DIEA (1.69 ml; 9.40 mmol; 1.10 eq.) and 3-fluoro-phenylamine (1044.40 mg; 9.40 mmol; 1.10 eq) were added. The reaction mixture was stirred overnight at 45° C. The reaction solution was diluted with EtOAc, washed, dried and concentrated to give the crude product, which was subjected for SNAP (100 g) column for purification (eluted with 20-50% EtOAc in hexane) to afford the title compound (1700 mg, 42.5%).
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[CH2:7][C:6](=[O:8])[C:5](=[CH:9][CH2:10][NH:11][CH2:12][CH:13]([NH:17]C(OCC2C3CC4C(=CC=CC=4)C=3C=CC=2)=O)[C:14]([OH:16])=[O:15])[C:4](=[O:35])[CH2:3]1.N1CCCCC1>CN(C=O)C>[NH2:17][CH:13]([CH2:12][NH:11][CH2:10][CH:9]=[C:5]1[C:4](=[O:35])[CH2:3][C:2]([CH3:1])([CH3:36])[CH2:7][C:6]1=[O:8])[C:14]([OH:16])=[O:15]
Reactant: CC1(C)CC(=O)C(=CCNCC(NC(=O)OCc2cccc3c2Cc2ccccc2-3)C(=O)O)C(=O)C1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CC1(C)CC(=O)C(=CCNCC(N)C(=O)O)C(=O)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The resin prepared according to example 1 (7.085 g) in DMF was treated with 20% piperidine in DMF (40 mL) for 10 min and filtered. Another 40 mL portion of 20% piperidine in DMF was added to the resin and shaken at room temperature for 20 min. The resin was filtered and washed with DMF (3×40 mL), MeOH (3×40 mL) and DCM (3×40 mL). The resin was dried in vacuo.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([S:12]([F:17])([F:16])([F:15])([F:14])[F:13])[CH:11]=1)[C:6](O)=[O:7])=[O:2].[CH3:18]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.C[C:52]1[C:58]([N:59]2[C:66]3[N:62]([N:63]=[C:64]([C:67]4[CH:68]=[N:69][CH:70]=[CH:71][CH:72]=4)[CH:65]=3)[CH:61]=[CH:60]2)=[C:57]([CH3:73])[CH:56]=[CH:55][C:53]=1[NH2:54]>CN(C=O)C.O>[CH3:18][C:55]1[CH:56]=[C:57]([CH3:73])[C:58]([N:59]2[C:66]3[N:62]([N:63]=[C:64]([C:67]4[CH:68]=[N:69][CH:70]=[CH:71][CH:72]=4)[CH:65]=3)[CH:61]=[CH:60]2)=[CH:52][C:53]=1[NH:54][C:6](=[O:7])[C:5]1[CH:9]=[C:10]([S:12]([F:17])([F:16])([F:15])([F:14])[F:13])[CH:11]=[C:3]([CH:1]=[O:2])[CH:4]=1
Reactant: Cc1ccc(N)c(C)c1-n1ccn2nc(-c3cccnc3)cc12
Reactant: O=Cc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(-n2ccn3nc(-c4cccnc4)cc23)cc1NC(=O)c1cc(C=O)cc(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
214 mg (0.659 mmol, 85% pure) of the compound from Example 36A and 301 mg (0.791 mmol) of HATU were dissolved in 2.3 ml of anhydrous DMF, and 140 μl (0.791 mmol) of N,N-diisopropylethylamine were added. After 30 min, 200 mg (0.659 mmol) of the compound of Example 11A were added. After the reaction mixture had been stirred at RT for 1.5 h, about 50 ml of water were added and the mixture was extracted three times with in each case about 50 ml of ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulphate, filtered and freed from the solvent on a rotary evaporator. The crude product obtained in this manner was purified by MPLC (30 g of silica gel, mobile phase gradient cyclohexane/ethyl acetate 1:1→1:5). Evaporation of the product fractions and drying of the residue under high vacuum gave 160 mg (36% of theory, 85% pure) of the title compound.
Reaction SMILES: [C:1]1([CH3:19])[C:2]([S:7]([NH:10][C:11]2[CH:15]=[CH:14][S:13][C:12]=2[C:16]([OH:18])=[O:17])(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.OS(O)(=O)=O>O1CCOCC1.C(Cl)(Cl)Cl>[C:1]([O:17][C:16]([C:12]1[S:13][CH:14]=[CH:15][C:11]=1[NH:10][S:7]([C:2]1[C:1]([CH3:19])=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:9])=[O:8])=[O:18])([CH3:19])([CH3:2])[CH3:6]
Reactant: Cc1ccccc1S(=O)(=O)Nc1ccsc1C(=O)O
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: Cc1ccccc1S(=O)(=O)Nc1ccsc1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 146.8 %

Procedure:
To a cold (−40° C.) mixture of 3-(Toluene-2-sulfonylamino)-thiophene-2-carboxylic acid (1.5 g, 5.05 mmol) in 1,4-dioxane/CHCl3 (1:2, 12 mL) was bubbled 2-methyl-2-propene gas (15 mL) in a sealed tube. To this was added Conc. H2SO4 (0.070 mL, 1.3 mmol) and slowly warmed up to room temperature. The resultant reaction mixture was heated at 70° C. for 2.5 days in a sealed tube, cooled to −40° C., stopper was removed. The reaction mixture was slowly brought up to room temperature and stirred until the excess gas is released. The mixture was extracted with EtOAc, washed with aq. NaHCO3 solution, brine and dried. Evaporation of the solvent and purification of the residue on silica gel using EtOAc/hexane (1:10) as an eluent furnished 3-(Toluene-2-sulfonylamino)-thiophene-2-carboxylic acid tert-butyl ester (1.31 g 73.5% based on 90% conversion). 1H NMR (CDCl3, 300 MHz) 9.89 (s, 1H), 8.01 (d, J=7.9 Hz, 1H), 7.43 (dt, J=7.5 Hz, 1.5 Hz, 1H), 7.3-7.25 (m, 3H), 7.2 (d, J=5.4 Hz, 1H), 2.69 (s, 3H), 1.56 (s, 9H).