Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([N:14]1[CH2:18][C@H:17]([S:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][C@H:15]1[C:39](O)=[O:40])(=[O:13])=[O:12].[NH2:42][C@H:43]([C:57]1[N:61]([CH2:62][CH2:63][C:64]#[N:65])[N:60]=[N:59][N:58]=1)[CH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[CH:47][CH:46]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[C:48]1([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:49]=[CH:50][C:45]([CH2:44][C@H:43]([NH:42][C:39]([C@@H:15]2[CH2:16][C@@H:17]([S:19][C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:18][N:14]2[S:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)(=[O:12])=[O:13])=[O:40])[C:57]2[N:61]([CH2:62][CH2:63][C:64]#[N:65])[N:60]=[N:59][N:58]=2)=[CH:46][CH:47]=1
Reactant: N#CCCn1nnnc1[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: N#CCCn1nnnc1[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.7 %

Procedure:
A solution of 520 mg (0.9 mmol) (2S,4R)-1-(Naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carboxylic acid and 315 mg (1 mmol) (1S)-3-[5-(1-Amino-2-biphenyl-4-yl-ethyl)-tetrazol-1-yl]-propionitrile [S. De Lombaert. Preparation of tetrazolylalkylaminomethylphosphonates as neutral endopeptidase inhibitors. U.S., 17 pp. CODEN: USXXAM. U.S. Pat. No. 5,273,990 A 931228] in 5 ml THF was cooled to 0° C. and treated with 206 mg (1.1 mmol) EDCI and 14 mg (0.09 mmol) HOBT. The reaction was stirred for 3 h at RT and partitioned between aqueous 10% KHSO4/ethyl acetate (3×). The organic phases were washed with aqueous saturated NaHCO3 solution and dried over Na2SO4. Purification by flash-chromatography on silicagel (Hexane/EtOAc 1:1) gave 639 mg (81%) (2S,4R)-1-(Naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carboxylic acid [(S)-2-biphenyl-4-yl-1-[1-(2-cyano-ethyl)- 1H-tetrazol-5-yl]-ethyl]-amide, Mp: 122-133 slow dec, MS: 880 (MH+).
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[NH:10]([C:12]1[S:16][N:15]=[C:14]([C:17]([Cl:20])([Cl:19])[Cl:18])[N:13]=1)[NH2:11].Cl.C(O)C>O>[Cl:20][C:17]([Cl:18])([Cl:19])[C:14]1[N:13]=[C:12]([NH:10][N:11]=[CH:1][C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[OH:4])[S:16][N:15]=1
Reactant: NNc1nc(C(Cl)(Cl)Cl)ns1
Reactant: O=Cc1ccccc1O
Agent: Cl
Solvent: CCO
Solvent: O
Product: Oc1ccccc1C=NNc1nc(C(Cl)(Cl)Cl)ns1
Yield: 83 %

Procedure:
A mixture of 1.3 g (0.01 mole) salicylaldehyde, 2.4 g (0.01 mole) 5-hydrazino-3-trichloromethyl-1,2,4-thiadiazole, 1 ml hydrochloric acid (conc.), and 100 ml ethanol was heated 5 hours on a steam bath. Water was added and the solution cooled in a freezer several days. The resulting solid was removed by filtration to give 2.8 g (83% yield) (mp. 204°-205° C.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[N:7]([C:16]1[N:20]([CH3:21])[C:19]2[CH:22]=[CH:23][C:24]([N:26]([C:28]3[CH:33]=[CH:32][N:31]=[C:30](Cl)[N:29]=3)[CH3:27])=[CH:25][C:18]=2[N:17]=1)[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][S:37]([CH2:40][C:41]1[CH:42]=[C:43]([NH2:47])[CH:44]=[CH:45][CH:46]=1)(=[O:39])=[O:38]>>[C:1]([O:5][C:6](=[O:35])[N:7]([C:16]1[N:20]([CH3:21])[C:19]2[CH:22]=[CH:23][C:24]([N:26]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([NH:47][C:43]4[CH:44]=[CH:45][CH:46]=[C:41]([CH2:40][S:37]([CH3:36])(=[O:39])=[O:38])[CH:42]=4)[N:29]=3)[CH3:27])=[CH:25][C:18]=2[N:17]=1)[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cc1cccc(N)c1
Reactant: COc1ccc(N(C(=O)OC(C)(C)C)c2nc3cc(N(C)c4ccnc(Cl)n4)ccc3n2C)cc1
Product: COc1ccc(N(C(=O)OC(C)(C)C)c2nc3cc(N(C)c4ccnc(Nc5cccc(CS(C)(=O)=O)c5)n4)ccc3n2C)cc1

Procedure:
The title compound was prepared following the procedure of example 78 using {5-[(2-Chloro-pyrimidin-4-yl)-methyl-amino]-1-methyl-1H-benzoimidazol-2-yl}-(4-methoxy-phenyl)-carbamic acid tert-butyl ester (100 mg, 0.20 mmol) and 3-methanesulfonylmethyl-phenylamine (37 mg, 0.20 mmol) to give the desired product as a white solid. 1H NMR (300 MHz, d6-DMSO) δ 9.44 (s, 1H), 7.80-7.82 (m, 2H), 7.63-7.70 (M, 2H), 7.56 (d, J=1.5 Hz, 1H), 7.34 (d, J=8.7 Hz, 2H), 7.25 (dd, J=8.6 and 1.2 Hz, 1H), 7.18 (t, J=7.5 Hz, 1H), 6.94 (d, J=9.0 Hz, 2H), 5.75 (d, J=6.0 Hz, 1H), 4.34 (s, 2H), 3.79 (s, 3H), 3.74 (s, 3H), 3.47 (s, 3H), 2.89 (s, 3H), 1.41 (s, 9H). MS (ESI) m/z=644 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:12])[C:10]#[CH:11])=[CH:5][CH:4]=1.C([Mg]Cl)#C.CN(C)C1C=CC(C=O)=CC=1.Br[C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1/[C:32](=[CH:40]/[C:41]1[NH:42][CH:43]=[CH:44][C:45]=1[O:46][CH3:47])/[C:33](=[O:39])[NH:34]2>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:13][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:12])[C:10]#[C:11][C:30]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:31]=2/[C:32](=[CH:40]/[C:41]2[NH:42][CH:43]=[CH:44][C:45]=2[O:46][CH3:47])/[C:33](=[O:39])[NH:34]3)=[CH:5][CH:4]=1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CC(O)c1ccc(N(C)C)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#C[Mg]Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(O)c3ccc(N(C)C)cc3)c21

Procedure:
Using Method D above, 3-(4-dimethylaminophenyl)-3-hydroxy-1-propyne (160 mg, 0.91 mmol) (prepared by the addition of ethynylmagnesium chloride (Aldrich) to 4-dimethylaminobenzaldehyde (Aldrich) according to Method A above) was coupled to (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (108 mg, 0.34 mmol) (Starting Material 1) using (Ph3P)2PdCl2 (30 mg) (Aldrich) and CuI (16 mg) (Aldrich) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 19 h, yielding rac-(Z)-1,3-dihydro-4-[3-(4-dimethylaminophenyl)-3-hydroxy-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 190 mg, 77%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([CH2:19][O:20][CH2:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36].S([O-])(O)(=O)=O.[Na+]>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([CH2:19][O:20][CH2:21][CH:22]3[CH2:27][CH2:26][N:25]([C:35](=[O:37])[CH3:36])[CH2:24][CH2:23]3)[CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1cc(COCC2CCNCC2)cc(-c2cccc(C#N)c2)c1
Reactant: CC(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(COCC2CCN(C(C)=O)CC2)cc(-c2cccc(C#N)c2)c1
Yield: 78 %

Procedure:
In 20 ml of dichloromethane, was dissolved 298 mg of the compound obtained in Example 16. To the resulting solution, was added 3.0 ml of triethylamine. To the obtained mixture, 0.46 ml of acetyl chloride was added under cooling with ice and stirring. The mixture was stirred at 0° C. to room temperature for 18 hours. The obtained mixture was poured into a saturated aqueous solution of sodium hydrogensulfate and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine and subsequently dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to afford 260 mg (78%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[C:17]([CH2:21][OH:22])[CH:18]=[CH:19][CH:20]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1.Cl[CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>CC#N>[CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:16]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(C)c(-c2ccnc(Nc3cccc(CO)c3)n2)s1
Reactant: ClCCN1CCOCC1
Solvent: CC#N
Product: Cc1nc(C)c(-c2ccnc(Nc3cccc(COCCN4CCOCC4)c3)n2)s1

Procedure:
By alkylation of {3-[4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino]-phenyl}-methanol with 4-(2-chloro-ethyl)-morpholine. Yellow solid. Anal. RP-HPLC: tR=8.5 min (10-70% MeCN, purity>95%). 1H-NMR (DMSO-D6) δ: 2.56 (s, 3H, CH3), 2.57 (s, 3H, CH3), 2.63 (m, 2H, CH2), 3.58 (m, 4H, J=4.5 Hz, CH2x2), 4.14 (t, 2H, J=7.5 Hz, CH2), 4.58 (d, 2H, J=5.0 Hz, CH2), 5.28 (t, 1H, J=5.5 Hz, NH), 7.06 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 7.26 (m, 2H, Ph-H), 7.36 (s, 1H, Ph-H), 7.42 (m, 1H, Ph-H), 8.43 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 9.12 (sbr, 1H, Ph-H). MS (ESI+) m/z 426.46 [M+H]+ (C22H27N5O2S requires 425.55).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([CH2:13]O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:15]>CCOCC>[ClH:15].[Cl:15][CH2:13][C:9]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:12]=[CH:11][N:10]=1
Reactant: OCc1cc(-c2ccccc2)ccn1
Agent: Cl
Solvent: CCOCC
Product: ClCc1cc(-c2ccccc2)ccn1
Reaction time: 0.5 h

Procedure:
A solution of 4-phenyl-2-pyridinemethanol (1.57 g) in ether (5 ml) was treated with ethereal hydrogen chloride (ca 5 ml). The resulting solid was filtered off and added to redistilled thionylchloride (7.5 ml) at ca 0°. The brown solution was stirred at ca 0° for 2 h and at 22° for 0.5 h. Ether (100 ml) was added and the resulting solid was filtered off to give the title compound as a solid (1.81 g). T.l.c. Silica (Dichloromethane, ethanol and ammonia 200:8:1) Rf 0.7.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[C:4]([CH3:26])[CH:3]=1.[NH:27]1[C:35]2[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=2[CH:29]=[N:28]1.CN[C@@H]1CCCC[C@H]1NC.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu]I.O.C1(C)C=CC=CC=1>[F:12][C:11]([F:14])([F:13])[CH2:10][CH2:9][CH:8]([NH:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)[C:5]1[CH:6]=[CH:7][C:2]([N:28]2[CH:29]=[C:30]3[C:35]([CH2:34][CH2:33][CH2:32][CH2:31]3)=[N:27]2)=[CH:3][C:4]=1[CH3:26]
Reactant: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(Br)cc2C)cc1
Reactant: c1n[nH]c2c1CCCC2
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(-n3cc4c(n3)CCCC4)cc2C)cc1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
Under a nitrogen atmosphere, a mixture of methyl 4-((1-(4-bromo-2-methylphenyl)-4,4,4-trifluorobutyl)amino)benzoate (optically active form, compound with longer retention time) (3.0 g), 4,5,6,7-tetrahydroindazole (1.278 g), copper(I) iodide (1.594 g), trans-N,N′-dimethylcyclohexane-1,2-diamine (2.64 mL), cesium carbonate (6.82 g) and toluene (17.4 mL) was stirred at 110° C. for 18 hr. To the reaction mixture was added water at room temperature, and the insoluble material was filtered off through celite. The filtrate was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.11 g).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9]C)=[CH:5][C:4]=1[C:11]1[C:12]2[NH:16][C:15]([C:17]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[C:18]3[N:41]=[C:21]([CH:22]=[C:23]4[NH:40][C:26](=[C:27]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:28]5[CH:29]=[CH:30][C:31]=1[N:32]=5)[CH:25]=[CH:24]4)[CH:20]=[CH:19]3)=[CH:14][CH:13]=2.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[C:11]1[C:12]2[NH:16][C:15]([C:17]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[C:18]3[N:41]=[C:21]([CH:22]=[C:23]4[NH:40][C:26](=[C:27]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:28]5[CH:29]=[CH:30][C:31]=1[N:32]=5)[CH:25]=[CH:24]4)[CH:20]=[CH:19]3)=[CH:14][CH:13]=2
Reactant: CCCCCCCc1c2nc(c(-c3cc(OC)ccc3OC)c3ccc([nH]3)c(CCCCCCC)c3nc(cc4ccc1[nH]4)C=C3)C=C2
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCCCCCc1c2nc(c(-c3cc(O)ccc3O)c3ccc([nH]3)c(CCCCCCC)c3nc(cc4ccc1[nH]4)C=C3)C=C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
A starting compound (7)(20.5 mg, 31.9 μmol) was dissolved in 2 mL of chloroform. BBr3 (0.2 mL) was added by using a syringe under a nitrogen atmosphere. After stirred for 3 hours at room temperature, the resultant mixture was diluted by adding chloroform little by little to decompose excessive BBr3. The resultant solution was neutralized with an aqueous solution of sodium bicarbonate and then washed with water. After the solvent was removed, the resultant mixture was dried. As a result, the compound (8) (17.1 mg) was obtained in a yield of 87%.
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[CH2:40]1[O:51][C:50]2[CH:49]=[CH:48][C:44]([C:45](Cl)=[O:46])=[CH:43][C:42]=2[O:41]1>>[CH2:40]1[O:51][C:50]2[CH:49]=[CH:48][C:44]([C:45]([O:1][CH:2]3[CH2:20][CH:19]4[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]5[C:16]([C:22]([NH:24][S:25]([CH:28]6[CH2:30][CH2:29]6)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]4=[O:21])[CH2:15]5)[CH2:3]3)=[O:46])=[CH:43][C:42]=2[O:41]1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)c3ccc4c(c3)OCO4)CN2C1=O
Yield: 35.1 %

Procedure:
Prepared by way of method I using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and 3,4-methylenedioxybenzoyl chloride (65 μL, 0.35 mmol). The final trituration (diethyl ether/hexane) and filtration gave 44 mg (35%) of 18-(3,4-methylenedioxybenzoyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 98.6% pure (HPLC), MS m/z 717 (M+H)+, HRMS: calcd. 717.2806 and found 717.2789 (M+H)+, mp 153-155° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:22][CH3:23])[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16]OS(C)(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-:41].C(OCC)(=O)C>C(#N)C>[F:41][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH:3]([O:22][CH3:23])[O:2][CH3:1]
Reactant: COC(COCCOCCOCCOCCOS(C)(=O)=O)OC
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(COCCOCCOCCOCCF)OC
Temperature: 90 °C
Yield: 93 %

Procedure:
A mixture of the sulfonate (Compound 6) (75 mg, 0.21 mmol) and TBAF (1.1 M in THF, 573 μl, 0.63 mmol) in acetonitrile (8 ml) was heated at 90° C. for 30 minutes. TLC (ethyl acetate) monitoring showed the reaction was completed. After cooling to ambient and evaporation of the solvent the residue was flashed (Ethyl acetate) to afford the product (56 mg, 93%) as colourless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:23])[NH:14][C:15]1[CH:20]=[CH:19][C:18](Br)=[CH:17][C:16]=1[F:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:23])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[S:25][CH3:24])=[CH:17][C:16]=1[F:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1ccc(Br)cc1F
Reactant: CSc1ccccc1B(O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CSc1ccccc1-c1ccc(NC(=O)C2CCCN2C(=O)OC(C)(C)C)c(F)c1

Procedure:
2-(4-Bromo-2-fluoro-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (2 g, 4.8 mmol), 2-(methylthio)benzene boronic acid (0.98 g, 5.8 mmol), and tetrabutylammonium bromide (78 mg, 0.24 mmol) were combined in 30 mL toluene, added 5 mL of a 2M aqueous Na2CO3 solution followed by tetrakistriphenylphosphine palladium(0) (0.28 g, 0.24 mmol). Heated reaction at reflux for 4 hours, cooled, concentrated, redissolved in EtOAc (250 mL), washed with water (3×200 mL), brine (200 mL), dried with MgSO4, filtered, and concentrated in the presence of 4 g coarse silica. Loaded silica onto a silica gel column, eluted with 20% EtOAc in hexanes. Combined and concentrated pure fractions to yield title compound as a yellow foam. (1.84 g, 88%) APCI (AP−): 429.2 (M−H)−.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([CH2:7][C@@:8]2([CH3:29])[N:12]3[C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)[C:9]2=[O:28])=[CH:5][CH:4]=1)#[N:2].CCO[C:35]([CH3:37])=[O:36]>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:1]([C:3]1[CH:31]=[CH:30][C:6]([CH2:7][C@@:8]2([CH3:29])[N:12]3[C:13]([S:16]([NH:12][C@@H:8]([CH3:7])[C:9]([NH:10][CH2:37][CH2:35][OH:36])=[O:28])(=[O:18])=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)[C:9]2=[O:28])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(C)=O
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(S(=O)(=O)Cl)n21
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: C[C@H](NS(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)NCCO
Reaction time: 2 h

Procedure:
To a solution of above amine salt (0.043 g, 0.254 mmol) in anhydrous DMF, was added DMAP (0.037 g, 0.303 mmol). The reaction mixture was stirred at room temperature for 1 h. (R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-sulfonyl chloride (0.036 g, 0.073 mmol) was then added to the reaction mixture and stirred for another 2 h. The reaction mixture was diluted with EtOAc and washed with 1 N HCl and saturated NaHCO3. The organic phase was dried over Na2SO4 and concentrated. The residue was purified by silica gel preparative thin layer chromatography to afford 0.035 g of the title compound as a white foam (M+1, 591.1).
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].[CH2:13]([C@H:16]1[C@H:20]([CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:19][N:18]([C@@H:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH3:31])[C:17]1=O)[CH:14]=[CH2:15].O.O.O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[CH2:13]([C@H:16]1[C@H:20]([CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:27])[CH3:28])([CH3:24])[CH3:25])[CH2:19][N:18]([C@@H:30]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH3:31])[CH2:17]1)[CH:14]=[CH2:15]
Reactant: C=CC[C@@H]1C(=O)N([C@H](C)c2ccccc2)C[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: COCCO[AlH2-]OCCOC
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: C=CC[C@@H]1CN([C@H](C)c2ccccc2)C[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 45 °C
Reaction time: 5 h
Yield: 67.7 %

Procedure:
A 65% solution of Red-Al™ in toluene (788 mL, 2.63 mol) was added dropwise to a solution of (3S,4S)-3-allyl-4-(tert-butyldimethylsilyloxy)methyl-2-oxo-1-[(1R)-1-phenylethyl]pyrrolidine (327 g, 875 mmol) in toluene (1500 mL) in a nitrogen atmosphere over one hour. The reaction solution was stirred at 45° C. for five hours and then cooled to 0° C., and a 20% (+)-potassium sodium tartrate tetrahydrate solution (2.00 L) was added. The reaction solution was poured into a mixture of ethyl acetate and brine, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1→4:1) to give 213 g of the title compound as a colorless syrup.
Reaction SMILES: [Cl:1][C:2]1[C:8]([N:9]2[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH3:17])[CH3:16])[CH2:10]2)=[CH:7][C:5]([NH2:6])=[C:4]([N+:18]([O-])=O)[CH:3]=1>[Ni].CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:18])[C:5]([NH2:6])=[CH:7][C:8]=1[N:9]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH3:16])[CH3:17])[CH2:10]1
Reactant: CN(C)CC1CCN(c2cc(N)c([N+](=O)[O-])cc2Cl)C1
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CN(C)CC1CCN(c2cc(N)c(N)cc2Cl)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-chloro-5-(3-dimethylaminomethyl-pyrrolidin-1-yl)-2-nitroaniline (630 mg, 2.1 mmol), EtOAc (20 mL) and Ra—Ni (150 mg) was stirred for 2 days at rt under a hydrogen atmosphere (3.0 bar). The catalyst was removed by filtration and the filtrate was concentrated. The crude was purified by chromatography to give the sub-title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:3]=1[C:4]([C:6]1[NH:10][C:9]([C:11]([OH:13])=O)=[CH:8][CH:7]=1)=[O:5].ClC1C=CC([N+]([O-])=O)=CC=1C(C1NC(C(Cl)=O)=CC=1)=O.C(Cl)(=O)C(Cl)=O.[NH2:47][C:48]1[CH:49]=[C:50]([OH:54])[CH:51]=[CH:52][CH:53]=1>>[OH:54][C:50]1[CH:49]=[C:48]([NH:47][C:11]([C:9]2[NH:10][C:6]([C:4](=[O:5])[C:3]3[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:2]=3[Cl:1])=[CH:7][CH:8]=2)=[O:13])[CH:53]=[CH:52][CH:51]=1
Reactant: Nc1cccc(O)c1
Reactant: O=C(O)c1ccc(C(=O)c2cc([N+](=O)[O-])ccc2Cl)[nH]1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(Cl)c1ccc(C(=O)c2cc([N+](=O)[O-])ccc2Cl)[nH]1
Product: O=C(Nc1cccc(O)c1)c1ccc(C(=O)c2cc([N+](=O)[O-])ccc2Cl)[nH]1
Yield: 51.6 %

Procedure:
5-(2-Chloro-5-nitro-benzoyl)-1H-pyrrole-2-carboxylic acid (200 mg) (Example 63) was converted to 5-(2-chloro-5-nitro-benzoyl)-1H-pyrrole-2-carbonyl chloride using oxalyl chloride at room temperature for one hour. It was then condensed with 3-amino-phenol (170 mg, 1.7 eq.) and TEA at room temperature for 1.5 hrs to give 135 mg of 5-(2-chloro-5-nitro-benzoyl)-1H-pyrrole-2-carboxylic acid (3-hydroxy-phenyl)-amide.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[N:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[N:3]=1.[N+:25]([O-])([OH:27])=[O:26].O>C(OC(=O)C)(=O)C.C(O)(=O)C>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:14])=[O:15])=[CH:9][CH:8]=2)[N:4]([C:17]2[CH:22]=[CH:21][C:20]([N+:25]([O-:27])=[O:26])=[C:19]([O:23][CH3:24])[CH:18]=2)[N:3]=1
Reactant: COc1cccc(-n2nc(Cl)cc2-c2ccc(S(C)(=O)=O)cc2)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(-n2nc(Cl)cc2-c2ccc(S(C)(=O)=O)cc2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 3-chloro-1-(3-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole (575 mg) in acetic anhydride (10 ml) and acetic acid (1 ml) was added nitric acid (fuming) (500 ml) at 0° C. After being stirred at 0° C. for 2 hours, the reaction mixture was poured into water, and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, and filtered. The filtrate was evaporated in vacuo, and purified by column chromatography using dichloromethane as eluent to give 3-chloro-1-(3-methoxy-4-nitro-phenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole (590 mg).