Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:7]=[C:8]([C:24]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=2)=[O:25])[C:9](=[O:23])[N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:11]=1[CH3:12])(=[O:5])[CH3:4]>C1COCC1>[Br:1][CH2:4][C:3]([C:6]1[CH:7]=[C:8]([C:24]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=2)=[O:25])[C:9](=[O:23])[N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:11]=1[CH3:12])=[O:5]
Reactant: BrBr
Reactant: CC(=O)c1cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n(-c2cccc(C(F)(F)F)c2)c1C
Solvent: C1CCOC1
Product: Cc1c(C(=O)CBr)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 40.7 %

Procedure:
Bromine (34 μl, 0.66 mmol) in THF (5 ml) was added to a solution of 5-acetyl-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (320 mg, 0.63 mmol) in TBF (10 ml). After 2 h, the yellow colour had disappeared. The reaction mixture was partitioned between water and ethyl acetate, the organic phase was separated, evaporated, and the residue was chromatographed on silica using ethyl acetate/heptane (1/1, 2/1, 4/1) as eluent. Fractions containing the product were combined and evaporated to give the title compound (150 mg, 41%).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:27]=[CH:26][C:13]3/[C:14](=[CH:23]/[C:24]#[N:25])/[C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:7]2[CH:28]=[CH:29][CH:30]=[CH:31][C:6]=2[N:5]=1)[CH2:2][CH3:3].C[Si]([N:36]=[N+:37]=[N-:38])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:27]=[CH:26][C:13]3/[C:14](=[CH:23]/[C:24]4[NH:38][N:37]=[N:36][N:25]=4)/[C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:7]2[CH:28]=[CH:29][CH:30]=[CH:31][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCCc1nc2ccccc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CCCc1nc2ccccc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\c1nnn[nH]1
Temperature: 90 °C
Reaction time: 24 h
Yield: 50.1 %

Procedure:
(E)-[2-(2-Propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (200 mg, 0.496 mmol) obtained in Example 1 was dissolved in toluene (5 mL), trimethylsilylazide (1.3 mL, 9.92 mmol) and dibutyltin oxide (123 mg, 0.496 mmol) were added, and the mixture was stirred at 90° C. for 24 hr. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=99/1) to give the title compound (compound 4) (111 mg, 50%).
Reaction SMILES: [N:1]([C:4]([C:7]1[CH:8]=[CH:9][C:10]2[C:14]([CH3:16])([CH3:15])[O:13][B:12]([OH:17])[C:11]=2[CH:18]=1)([CH3:6])[CH3:5])=[N+]=[N-]>CO>[NH2:1][C:4]([C:7]1[CH:8]=[CH:9][C:10]2[C:14]([CH3:16])([CH3:15])[O:13][B:12]([OH:17])[C:11]=2[CH:18]=1)([CH3:6])[CH3:5]
Reactant: CC(C)(N=[N+]=[N-])c1ccc2c(c1)B(O)OC2(C)C
Solvent: CO
Product: CC(C)(N)c1ccc2c(c1)B(O)OC2(C)C
Yield: 111.9 %

Procedure:
The solution of 6-(2-azidopropan-2-yl)-3,3-dimethylbenzo[c][1,2]-oxaborol-1(3H)-ol (100 mg) in MeOH (6 mL) was hydrogenated under H2 using 10% Pd/C (15 mg) as catalyst at atmospheric pressure for 5 h. The catalyst was removed by filtration, and the solvent was evaporated at reduced pressure to give crude product 6-(2-aminopropan-2-yl)-3,3-dimethylbenzo[c][1,2]oxa-borol-1(3H)-ol (100 mg) as colorless oil. It was used without further purification in the next step.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:26])=[CH:7][CH:6]=1.[CH:27]([NH:30][CH3:31])([CH3:29])[CH3:28].CN(C=O)C>O>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][N:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:30]([CH:27]([CH3:29])[CH3:28])[CH3:31])=[CH:6][CH:7]=3)[C:12](=[O:26])[CH:13]=2)=[N:20][CH:21]=1
Reactant: O=c1cc(OCc2ccc(Cl)cn2)ccn1-c1ccc(OCCBr)cc1
Reactant: CNC(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N(C)CCOc1ccc(-n2ccc(OCc3ccc(Cl)cn3)cc2=O)cc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 98.9 %

Procedure:
A mixture of 1-[4-(2-bromoethoxy)phenyl]-4-[(5-chloro-2-pyridinyl)methoxy]-1H-pyridin-2-one (1.1 g, 2.6 mmols, Step (1) of Example 109), isopropyl(methyl)amine (0.811 mL, 7.8 mmols) and DMF (2.6 mL) was stirred at 60° C. for 2 days. Water was added to the reaction liquid and filtered. So obtained crude title compound was purified on silica gel column chromatography (KP-Sil FLASH 25+M, chloroform:methanol=1:0→5:1) to provide the title compound (1.1 g, 99%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@H:13]2[C@H:12]([NH:20][C:21]2[CH:26]=[C:25](I)[N:24]=[CH:23][N:22]=2)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(CC)CC.[C:35]1([C:41]#[CH:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Si:1]([O:8][CH2:9][C@@H:10]1[C@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@H:13]2[C@H:12]([NH:20][C:21]2[CH:26]=[C:25]([C:42]#[C:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:24]=[CH:23][N:22]=2)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(C)O[C@@H]2[C@@H](CO[Si](C)(C)C(C)(C)C)C[C@@H](Nc3cc(I)ncn3)[C@@H]2O1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)O[C@@H]2[C@@H](CO[Si](C)(C)C(C)(C)C)C[C@@H](Nc3cc(C#Cc4ccccc4)ncn3)[C@@H]2O1
Reaction time: 1 h
Yield: 83.5 %

Procedure:
To a solution of N-[(3aS,4R,6R,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-6-iodopyrimidin-4-amine (0.300 g, 0.594 mmol) in DMF (2.46 mL) was added CuI (0.0113 g, 0.0594 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.0292 g, 0.0415 mmol). The tube was sealed and flushed with argon. Et3N (0.165 mL, 1.19 mol) was added and the reaction was stirred for 1 h. Phenylacetylene (0.216 mL, 1.96 mmol) was added and the reaction was stirred overnight. The suspension was filtered and the filtrate was concentrated in vacuo. The crude mixture was purified by flash chromatography (10 to 40% EtOAc/hexanes) to afford the title compound as a yellow oil (0.238 g, 84%). LC/MS: Rt=2.47 min, ES+ 480 (FA standard).
Reaction SMILES: [CH:1]([C:4]1[N:8]([C:9]2[CH:10]=[C:11]([C:22]([OH:24])=O)[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[CH:14]=2)[N:7]=[N:6][CH:5]=1)([CH3:3])[CH3:2].[N:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[CH:31]([NH2:33])[CH3:32]>>[N:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[CH:31]([NH:33][C:22]([C:11]1[CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[CH:14]=[C:9]([N:8]2[C:4]([CH:1]([CH3:2])[CH3:3])=[CH:5][N:6]=[N:7]2)[CH:10]=1)=[O:24])[CH3:32]
Reactant: CC(N)c1cnccn1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-n3nncc3C(C)C)c2)cc1
Product: Cc1ccc(-c2cc(C(=O)NC(C)c3cnccn3)cc(-n3nncc3C(C)C)c2)cc1

Procedure:
5-(5-Isopropyl-[1,2,3]triazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid was subject to the amide coupling reaction described in step 4 of Example 6, but replacing 2-amino-propan-1-ol with 1-pyrazin-2-yl-ethylamine, to give 5-(5-isopropyl-[1,2,3]triazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide, MS (M+H)=427.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[C:18]2[C:5]([C@@:6]3([CH3:25])[C@H:15]([CH2:16][S:17]2(=[O:21])=[O:20])[C@:14]2([CH3:22])[C@H:9]([C:10]([CH3:24])([CH3:23])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]3)=[C:4]([C:26]([NH:28][CH2:29][C:30]([O:32]C)=[O:31])=[O:27])[CH:3]=1.O[Li].O>CO.O>[OH:1][C:2]1[CH:19]=[C:18]2[C:5]([C@@:6]3([CH3:25])[C@H:15]([CH2:16][S:17]2(=[O:21])=[O:20])[C@:14]2([CH3:22])[C@H:9]([C:10]([CH3:23])([CH3:24])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]3)=[C:4]([C:26]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:27])[CH:3]=1
Reactant: COC(=O)CNC(=O)c1cc(O)cc2c1[C@]1(C)CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CS2(=O)=O
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CC1(C)CCC[C@]2(C)[C@H]3CS(=O)(=O)c4cc(O)cc(C(=O)NCC(=O)O)c4[C@]3(C)CC[C@@H]12
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.9 %

Procedure:
A mixture of methyl 2-{[(1R,10R,11S,16S)-5-hydroxy-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-3-yl]formamido}acetate (90) (0.13 g, 0.27 mmol) and LiOH.H2O (0.07 g, 2 mmol) in MeOH (10 mL) and water (10 mL) was stirred at room temperature for 18 h. The mixture was concentrated under reduced pressure and the aqueous residue was acidified with 1 M HCl. The resulting solid was collected by filtration to give 2-{[(1R,10R,11S,16S)-5-hydroxy-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-3-yl]formamido}acetic acid (91) (0.09 g, 72%) as a brown solid. 1H NMR (CD3OD): δ 8.82 (m, 1H), 7.24 (d, 1H), 7.03 (d, 1H), 4.06 (m, 2H), 3.47 (m 2H), 2.76 (d, 1H), 2.11 (d, 1H), 1.88-1.38 (m, 10H), 1.20 (m, 1H), 1.00 (m, 5H), 0.89 (s, 3H), 0.86 (s, 3H). MS m/z 464 (C24H33NO6S+H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:17][C:16]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@@H:22]4[NH:27][S:28]([CH:31]=[CH2:32])(=[O:30])=[O:29])=[N:15][N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[NH:33]1[CH2:37][CH2:36][C@@H:35]([OH:38])[CH2:34]1>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:17][C:16]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@@H:22]4[NH:27][S:28]([CH2:31][CH2:32][N:33]3[CH2:37][CH2:36][C@@H:35]([OH:38])[CH2:34]3)(=[O:29])=[O:30])=[N:15][N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: O[C@@H]1CCNC1
Reactant: C=CS(=O)(=O)N[C@H]1CCc2c(-c3nnc(-c4ccc(OC(C)C)c(C#N)c4)s3)cccc21
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4NS(=O)(=O)CCN3CC[C@@H](O)C3)s2)cc1C#N
Temperature: 80 °C
Yield: 25.8 %

Procedure:
Prepared using General Procedure 13. To a solution of (S)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)ethenesulfonamide (40 mg, 0.5 mmol) in DMF (0.5 mL) was added (R)-pyrrolidin-3-ol (18.7 mg, 0.21 mmol) and the reaction was heated to 80° C. for 18 h. The product was purified by preparative HPLC to give 30 mg (56%) of N-((S)-4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-2-((R)-3-hydroxypyrrolidin-1-yl)ethanesulfonamide 37 as an off-white solid. LCMS-ESI (m/z) calculated for C27H31N5O4S2: 553.2; found 554.2 [M+H]+, tR=2.52 min.
Reaction SMILES: C([O:8][C:9]([C@@H:11]1[CH2:14][CH2:13][N:12]1[C:15](=[O:31])[C@@H:16]([CH2:27][CH:28]([CH3:30])[CH3:29])[NH:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])=[O:10])C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[C:21]1([S:18]([NH:17][C@@H:16]([C:15]([N:12]2[CH2:13][CH2:14][C@H:11]2[C:9]([OH:10])=[O:8])=[O:31])[CH2:27][CH:28]([CH3:30])[CH3:29])(=[O:20])=[O:19])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: [H][H]
Reactant: CC(C)C[C@@H](NS(=O)(=O)c1ccccc1)C(=O)N1CC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@@H](NS(=O)(=O)c1ccccc1)C(=O)N1CC[C@H]1C(=O)O
Yield: 97.8 %

Procedure:
N-benzenesulfonyl-D-leucyl-(S)-azetidine-2-carboxylic acid benzyl ester (667 mg) was dissolved in methanol (10 ml), and 10% palladium-carbon (80 mg) was added. The resulting mixture aerated with hydrogen was allowed to react at room temperature for 3 h, filtered and concentrated under reduced pressure to remove the solvent to give a white foam-like solid (520 mg, 99%), which was directly used for the next reaction.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][N:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH:6]2[CH2:5][CH2:4]1.[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O.O.CC(C)=O>[CH2:13]([O:20][C:21]([N:10]1[CH2:9][CH2:8][N:7]2[CH2:12][CH:3]([CH2:2][OH:1])[CH2:4][CH2:5][CH:6]2[CH2:11]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCC1CCC2CNCCN2C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(OCc1ccccc1)N1CCN2CC(CO)CCC2C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30.6 %

Procedure:
To a solution of the title product of Example 6 (640 mg, 3.76 mmol)in acetone/water (6.3 ml and 2.2 ml, respectively), a solution of benzylchloroformate (0.61 ml, 729 mg, 4.27 mmol) in acetone (2,0 ml) was added dropwise over several minutes while maintaining the pH of the mixture at 9.5 by intermittent dropwise addition of saturated aqueous sodium carbonate. After completing the addition, the reaction was stirred for 5 minutes at ambient temperature. The acetone solvent was removed in vacuo, ethyl acetate (60 ml) and water (30 ml) were added, and the pH of the well-stirred mixture was adjusted to 9.5 (sodium carbonate). The separated organic phase was dried (anhydrous sodium sulfate)and concentrated in vacuo to an oil (940 mg). Rash chromatography of the entire sample [10 g, silica gel, 32-63 mesh, eluting initially with ethyl acetate (100 mg), followed by ethyl acetate/methanol (100 ml, 97:3 in volume) and finally ethyl acetate/methanol (200 ml, 90:10 in volume)]afforded the present title compound as a colorless oil, 350 mg (30.6% yield). TLC Rf (ethyl acetate/methanol/concentrated aqueous ammonia=9:2:0.2 in volume): 0.63.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[C:9]([CH2:28][CH3:29])[CH:8]=1)C.[OH-].[Na+]>C(O)C>[CH2:28]([C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[O:13][CH2:14][CH2:15][C:16]1[N:17]=[C:18]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[O:19][C:20]=1[CH3:21])[O:6][CH2:5][C:4]([OH:30])=[O:3])[CH3:29]
Reactant: CCOC(=O)COc1ccc(OCCc2nc(-c3ccccc3)oc2C)c(CC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cc(OCC(=O)O)ccc1OCCc1nc(-c2ccccc2)oc1C
Temperature: 55 °C
Yield: 82.8 %

Procedure:
A solution of {3-ethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}acetic acid ethyl ester (0.23 g, 0.57 mmol) in ethanol (10 mL) was treated with 2.5 N aqueous NaOH (1.1 mL), and heated at 55° C. for 2 h. The reaction was cooled to ambient temperature and concentrated down to near dryness. The residue was then diluted with EtOAc (40 mL) and water (20 mL) and acidified to pH=1 with 1N aqueous HCl. The organic layer was washed with brine (20 mL), dried (Na2SO4) and concentrated in vacuo to give a white solid (0.18 g, 81%). 1H NMR (400 MHz, CDCl3) δ 7.98 (dd, J=7.8, 2.9 Hz, 2H), 7.46-7.40 (m, 3H), 6.79 (d, J=2.9 Hz, 1H), 6.70 (d, J=8.8 Hz, 1H), 6.63 (dd, J=8.8, 2.9 Hz, 1H), 4.58 (s, 2H), 4.14 (t, J=6.4 Hz, 2H), 3.01 (t, J=6.4 Hz, 2H), 2.56 (q, J=7.5 Hz, 2H), 2.39 (s, 3H), 1.11 (t, J=7.6 Hz, 3H); MS (ES) m/e 382 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:21][CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[C:5]([O:7][CH3:8])=[O:6].[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:31][O:32][C:33]1[CH:34]=[CH:35][C:36]([S:39]([NH:1][C:2]2[CH:3]=[C:4]([CH:9]=[C:10]([O:21][CH2:22][CH2:23][O:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)[C:11]=2[O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:5]([O:7][CH3:8])=[O:6])(=[O:41])=[O:40])=[CH:37][CH:38]=1
Reactant: COC(=O)c1cc(N)c(Oc2ccccc2OC)c(OCCOC2CCCCO2)c1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(NS(=O)(=O)c2ccc(OC)cc2)c(Oc2ccccc2OC)c(OCCOC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2.14 g of methyl 3-amino-4-(2-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate were dissolved in in pyridine (30 ml), treated dropwise while cooling with ice with a solution of 1.488 g of 4-methoxybenzenesulphonyl chloride in toluene (10 ml) and subsequently stirred at RT for 20 hours. The reaction mixture was poured on to ice/3M HCl, the product was extracted with ethyl acetate and the organic phase was dried over magnesium sulphate. After removing the solvent there was obtained methyl 3-(4-methoxy-benzenesulphonylamino)-4-(2-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate as a resin.
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][NH:10][C:11](=[O:23])[C:12]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([Br:20])[C:13]=1[O:21]C)[CH2:2][CH3:3].[ClH:24].CC(C)=O>CCO>[ClH:24].[CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][NH:10][C:11](=[O:23])[C:12]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([Br:20])[C:13]=1[OH:21])[CH2:2][CH3:3]
Reactant: CCCN1CCCC1CNC(=O)c1c(OC)ccc(Br)c1OC
Agent: Cl
Solvent: CCO
Solvent: CC(C)=O
Product: CCCN1CCCC1CNC(=O)c1c(OC)ccc(Br)c1O
Yield: 48 %

Procedure:
The title compound was prepared from (-)-N-n-propyl-2-(3-bromo-2,6-dimethoxybenzamidomethyl)pyrrolidine by dealkylation in the same manner as described in Example 2. Yield 48%. M.p. (HCl) 140°-141° C. (acetone). [α]D25 =-78° C. (c=0.80, EtOH) base.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:12]([C:13](=[O:30])[CH2:14][NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][C:26]([O:28]C)=[O:27])[CH:20]=2)=[O:17])[CH:11]([C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:32])[CH2:10][CH:9]1[S:39]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)(=[O:41])=[O:40].[OH-].[K+]>O.CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:12]([C:13](=[O:30])[CH2:14][NH:15][C:16](=[O:17])[NH:18][C:19]2[CH:20]=[C:21]([CH2:25][C:26]([OH:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:11]([C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:32])[CH2:10][CH:9]1[S:39]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)(=[O:41])=[O:40]
Reactant: COC(=O)Cc1cccc(NC(=O)NCC(=O)N2C(C(=O)N3CCOCC3)CC(S(=O)(=O)c3ccccc3)C2c2ccccc2F)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cc1cccc(NC(=O)NCC(=O)N2C(C(=O)N3CCOCC3)CC(S(=O)(=O)c3ccccc3)C2c2ccccc2F)c1
Yield: 71.5 %

Procedure:
A The reaction is carried out in a way analogous to that described in Example 3, but from 3.5 g of (2RS,4SR,5RS)-5-(2-fluorophenyl)-1-{2-[3-(3-(methoxycarbonylmethyl)phenyl)ureido]acetyl}-2-morpholinocarbonyl-4-(phenylsulphonyl)pyrrolidine and 0.3 g of potassium hydroxide in a mixture of 30 cm3 of distilled water and 50 cm3 of methanol. After treatment, there are obtained 2.45 g of (2RS,4SR,5RS)-3-{3-[2-(5-(2-fluorophenyl)-2-morpholinocarbonyl-4-phenylsulphonyl-1-pyrrolidinyl)-2-oxoethyl]ureido}phenylacetic acid [Rf =0.64; eluent: methylene chloride/methanol (80/20)].
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:14]2[S:15][C:16]([N:19]([CH:27]([CH3:29])[CH3:28])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:17][N:18]=2)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[CH2:31][CH:32]=O>CCO>[CH:27]([N:19]([C:16]1[S:15][C:14]([C:5]2[N:6]=[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]3[N:3]([CH:31]=[CH:32][N:1]=3)[CH:4]=2)=[N:18][CH:17]=1)[C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:29])[CH3:28]
Reactant: CC(C)N(C(=O)OC(C)(C)C)c1cnc(-c2cnc(N)c(-c3ccccc3)n2)s1
Reactant: O=CCCl
Solvent: CCO
Product: CC(C)N(C(=O)OC(C)(C)C)c1cnc(-c2cn3ccnc3c(-c3ccccc3)n2)s1
Temperature: 60 °C

Procedure:
A solution of tert-butyl 2-(5-amino-6-phenylpyrazin-2-yl)thiazol-5-yl(isopropyl)carbamate (23.7 mg, 0.06 mmol) in EtOH (0.25 mL) was added chloroacetaldehyde (11.8 μL, 50% in water) and the reaction mixture was then heated to 60° C. for 24 h and then concentrated to dryness. The crude product was dried under high vacuum and used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[BH3-]C#N.[Na+]>CO.C(O)(=O)C.C([O-])(O)=O.[Na+]>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C=O)cc1
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc(CN2CCOCC2)cc1
Reaction time: 1 h

Procedure:
(4-Formyl-benzyl)-carbamic acid tert-butyl ester Compound 15a (555 mg, 2.37 mmol, prepared as described in Far A R, Cho Y L, Rang A, Rudkewich D M, Rebek J, Tetrahedron, 2002, 58(4), 741-756) was added to a solution of morpholine (207 μL, 2.37 mmol) in MeOH (5 mL) and acetic acid (0.20 mL). The mixture was stirred for 1 hr and then 95% NaBH3CN (198 mg, 3.0 mmol) was added. The reaction was diluted after 2 hr with saturated NaHCO3 and extracted with EtOAc to provide (4-morpholin-4-ylmethyl-benzyl)-carbamic acid tert-butyl ester Compound 15b (230 mg), isolated by flash chromatography as a white solid. MS 307 (MH+). Compound 15b (230 mg, 0.752 mmol) was deprotected with 20% TFA in DCM (10 mL) to provide 4-morpholin-4-ylmethyl-benzylamine Compound 15c (63 mg) upon work-up. MS 207 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]C)=O)=[C:10]([N:17]=[CH:18][N:19]([CH3:21])C)[CH:9]=2)=[CH:4][CH:3]=1.NC1[CH:37]=[CH:36][C:26]([O:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[C:25]([O:38][CH3:39])[CH:24]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[C:13](=[O:15])[N:19]([C:21]4[CH:37]=[CH:36][C:26]([O:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])=[C:25]([O:38][CH3:39])[CH:24]=4)[CH:18]=[N:17][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N=CN(C)C
Reactant: COc1cc(N)ccc1OCC(=O)OC(C)(C)C
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC(=O)OC(C)(C)C
Yield: 34 %

Procedure:
Condensation of methyl 5-(4-chlorophenyl)-3-((dimethylamino)methylene-amino)-thiophene-2-carboxylate (740 mg) and tert-butyl 2-(4-amino-2-methoxy-phenoxy)acetate Part C (581 mg) as described in Example 1 yielded the title compound 388 mg (34%). 1H NMR (CDCl3) δ 1.50 (s, 9H), 3.92 (s, 3H), 4.65 (s, 2H), 6.91 (br s, 2H), 6.99 (br s, 1H), 7.44 (d, J=8.24 Hz, 2H), 7.53 (s, 1H), 7.65 (d, J=8.25 Hz, 2H), 8.14 (s, 1H); 13C NMR (CDCl3) δ 28.04, 56.21, 66.57, 82.58, 111.28, 113.76, 118.98, 120.86, 123.21, 127.65, 129.45, 130.85, 131.52, 135.68, 148.12, 150.00, 151.66, 156.73, 157.36, 167.51; HPLC (Method #1): 3.89 min retention time; MS (ES): m/z 499 [M+H]+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][CH:26]([N:28]1[C:32]([C:33]([OH:35])=O)=[CH:31][CH:30]=[N:29]1)[CH3:27].CCN(C(C)C)C(C)C.[NH:45]1[C:53]2[C:48](=[C:49]([C:54]3[CH:55]=[C:56]([NH2:63])[C:57]4[CH:58]=[N:59][NH:60][C:61]=4[CH:62]=3)[CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46]1>CN(C=O)C>[NH:45]1[C:53]2[C:48](=[C:49]([C:54]3[CH:62]=[C:61]4[C:57]([CH:58]=[N:59][NH:60]4)=[C:56]([NH:63][C:33]([C:32]4[N:28]([CH:26]([CH3:25])[CH3:27])[N:29]=[CH:30][CH:31]=4)=[O:35])[CH:55]=3)[CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: CC(C)n1nccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1nccc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reaction time: 0.17 h

Procedure:
To a solution of HATU (0.253 g) in DMF (3 ml) was added 1-(1-methylethyl)-1H-pyrazole-5-carboxylic acid (0.102 g) and DIPEA (0.211 ml) and the mixture was left to stand for 10 min. 6-(1H-Indol-4-yl)-1H-indazol-4-amine (0.075 g) dissolved in DMF (3 ml) was added and the solution was left to stand at RT for 18 h. DMF was removed by blow down (not to dryness) and the residue was dissolved in chloroform (1 ml) and loaded onto an aminopropyl SPE (2 g) (pre-conditioned with methanol (6 ml) and chloroform (6 ml)). The mixture was left on the column for 2 h then eluted with ethyl acetate:methanol (1:1, 10 ml). The solvent was blown down to dryness and the residue was dissolved in DMSO:methanol (1 ml, 1:1) and purified by MDAP (method K). The solvent was removed in vacuo and dried in an vacuum oven (50° C.) overnight to give title compound, 18 mg.