Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:15]/[C:16]1[NH:20][CH:19]=[N:18][C:17]=1[CH3:21])/[C:5](=[O:14])[NH:6]2.C[Si](C)(C)N[Si](C)(C)C.[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CN(C=O)C>[CH3:21][C:17]1[N:18]=[CH:19][NH:20][C:16]=1/[CH:15]=[C:4]1\[C:5](=[O:14])[NH:6][C:7]2[C:3]\1=[C:2]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=2
Reactant: OB(O)c1ccccc1
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(Br)c21
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COCCOC
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(-c3ccccc3)c21
Yield: 9 %

Procedure:
Using Method S above, (Z)-4-bromo-1,3-dihydro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-5-nitro-2H-indol-2-one (100 mg, 0.29 mmol) (Starting Material 9 above) was first treated with 1,1,1,3,3,3-hexamethyidisilazane (1.53 g, 9.5 mmol) (Aldrich) then coupled with phenyl boronic acid (52.4 mg, 0.43 mmol) (Aldrich) using DPPFPdCl2 (11.7 mg) (Aldrich) as catalyst in aqueous 2M Na2CO3 (0.29 mL, 0.58 mmol), DMF (3 mL) and DME (3 mL) at reflux for 1 day to yield (Z)-1,3-dihydro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-5-nitro-4-phenyl-2H-indol-2-one (yield 9 mg, 9%).
Reaction SMILES: C(O[C:6](=[O:33])[NH:7][C@H:8]([C:12](=[O:32])[NH:13][C@H:14]([B:19]1[O:27][C@H:26]2[C@:21]([CH3:31])([C@H:22]3[CH2:28][C@@H:24]([CH2:25]2)[C:23]3([CH3:30])[CH3:29])[O:20]1)[CH2:15][CH:16]([CH3:18])[CH3:17])[CH:9]([CH3:11])[CH3:10])(C)(C)C.C(O[C:39]([NH:41][C@@H:42]([CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[C:49]([O:55][CH3:56])[C:48]=1[O:57][CH3:58])C(O)=O)=[O:40])(C)(C)C.[O:59]([C:66]1[CH:67]=[C:68]([CH2:72]C(O)=O)[CH:69]=[CH:70][CH:71]=1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>>[CH3:10][CH:9]([CH3:11])[C@H:8]([NH:7][C:6](=[O:33])[C@@H:42]([NH:41][C:39](=[O:40])[CH2:72][C:68]1[CH:69]=[CH:70][CH:71]=[C:66]([O:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH:67]=1)[CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[C:49]([O:55][CH3:56])[C:48]=1[O:57][CH3:58])[C:12]([NH:13][C@H:14]([B:19]1[O:27][C@H:26]2[C@:21]([CH3:31])([C@H:22]3[CH2:28][C@@H:24]([CH2:25]2)[C:23]3([CH3:30])[CH3:29])[O:20]1)[CH2:15][CH:16]([CH3:17])[CH3:18])=[O:32]
Reactant: O=C(O)Cc1cccc(Oc2ccccc2)c1
Reactant: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Reactant: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)c(OC)c1OC
Product: COc1ccc(C[C@H](NC(=O)Cc2cccc(Oc3ccccc3)c2)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)B2O[C@@H]3C[C@@H]4C[C@@H](C4(C)C)[C@]3(C)O2)C(C)C)c(OC)c1OC

Procedure:
The title compound is prepared from {(S)-2-Methyl-1-[(R)-3-methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-butylcarbamoyl]-propyl}-carbamic acid tert-butyl ester ((A) in Synthetic Scheme 2) by reiteration of the 2-step (deprotection/coupling) procedure described in example 1 but using (S)-2-tert-Butoxycarbonylamino-3-(2,3,4-trimethoxy-phenyl)-propionic acid ((D) in Synthetic Scheme 2) and (3-Phenoxy-phenyl)-acetic acid ((F) in Synthetic Scheme 2) (Trans World Chemicals, Inc.; Rockville, Md., USA) as the partners in each coupling reaction (step B, example 1), respectively. The title compound is obtained as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:8]([O:17][CH3:18])=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].[OH-].[K+]>C1COCC1.CCOCC>[CH3:18][O:17][C:8]1[C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1cc(-c2ccccc2)c(OC)c(-c2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1c(-c2ccccc2)cc(C(=O)O)cc1-c1ccccc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
At ambient temperature, to a stirred solution of 2′-methoxy-[1,1′;3′,1″]terphenyl-5′-carboxylic acid methyl ester (1.148 g, 3.606 mmol) in THF (36.06 mL) was added 1N KOH (36.06 mL) and the reaction was stirred for 16 h. The reaction was heated at 100° C. for an additional 24 h. The reaction was cooled to ambient temperature, diluted with ether (100 mL) and extracted with 0.1N NaOH. The aqueous extracts were washed with ether (3×), acidified with 6N HCl and extracted with EtOAc. The organic extracts were dried (MgSO4) and concentrated to give 1.043 g (95%) of the tide compound. 1H NMR (DMSO-d6) δ3.15 (s, 3 H), 7.40-7.52 (m, 6 H), 7.58-7.60 (m, 4 H), 7.88 (s, 2 H), 13.04 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]#[C:29][CH:30]([OH:32])[CH3:31])[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.ClC1C=CC2OCCC3C=C(C4N(C5C=CC(F)=CC=5F)N=CN=4)SC=3C=2N=1.CC(O)C#C>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([CH2:28][CH2:29][CH:30]([OH:32])[CH3:31])[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: CC(O)C#Cc1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Agent: C#CC(C)O
Agent: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Product: CC(O)CCc1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Yield: 38 %

Procedure:
Following the procedures for 246, 4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-but-3-yn-2-ol was prepared (Yield: 93%. 1H NMR (DMSO-d6, 400 MHz): δ8.32 (s, 1H), 7.93 (dd, J=5.6, 8.4 Hz, 1H), 7.74-7.69 (m, 1H), 7.45-7.40 (m, 2H), 7.33 (d, J=8.0 Hz, 1H), 6.95 (s, 1H), 5.59 (d, J=5.2 Hz, 1H), 4.64 (q, J=5.6, 6.8 Hz, 1H), 4.32 (t, J=4.0 Hz, 2H), 3.13 (t, J=4.4 Hz, 2H), 1.42 (d, J=6.4 Hz, 3H), ESI-MS: (m/z)=451 [M+H]+) from 9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene and but-3-yn-2-ol, and hydrogenated to give 244 Yield: 38%. 1H NMR (DMSO-d6, 400 MHz): δ8.26 (s, 1H), 7.89-7.84 (m, 1H), 7.70-7.65 (m, 1H), 7.40 (t, J=8.0 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 7.00 (s, 1H), 4.44 (s, 1H), 4.23 (t, =4.8 Hz, 2H), 3.58-3.56 (m, 1H), 3.13 (t, J=4.8 Hz, 2H), 2.71-2.63 (m, 2H), 1.69-1.61 (m, 2H), 1.05 (d, J=6.4 Hz, 3H). LC-MS (ESI): m/z=455 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH:8][CH3:9])=[N:6][CH:7]=1.CC(O[CH2:20][CH3:21])(OCC)OCC>CC(O)=O>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:20]([CH3:21])[N:8]([CH3:9])[C:5]2=[N:6][CH:7]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: CNc1ncc(Br)cc1N
Solvent: CC(=O)O
Product: Cc1nc2cc(Br)cnc2n1C
Temperature: 80 °C

Procedure:
To a suspension of 5-bromo-N2-methylpyridine-2,3-diamine (510 mg, 2.51 mmol) in AcOH (20 mL) was added MeC(OEt)3 (1 mL) and the solution was warmed to 80° C. for 2 hours. The reaction mixture was allowed to cool to room temperature and was concentrated in vacuo. The crude residue was purified by silica gel column chromatography (0-25% THF/CH2Cl2 gradient) to afford the desired product. 1H NMR (400 MHz, CDCl3) δ 8.36 (d, J=1.8 Hz, 1H), 8.06 (d, J=1.9 Hz, 1H), 3.80 (s, 3H), 2.65 (s, 3H).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=4)[N:21]=3)[CH:19]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([C:22]2[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[N:25]=[C:20]([N:18]3[CH:19]=[C:15]([C:12]4[CH:13]=[CH:14][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:10][CH:11]=4)[N:16]=[CH:17]3)[N:21]=2)=[CH:35][CH:34]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)cn2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)cn2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 31.4 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-4-{1-[6-(4-chloro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (0.26 g) in dichloromethane (6 mL) was added TFA 1. (6 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (3 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried to yield the title compound as an off-white solid (0.073 g, 10%). MS (ISN) 478.0 [(M−H)−]; mp 324° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:10]2[C:13]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[CH2:30]([S:33](Cl)(=[O:35])=[O:34])[CH2:31][CH3:32]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:30]([S:33]([NH:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:10]2[C:13]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:14][CH2:15][CH2:16]2)=[CH:5][CH:4]=1)(=[O:35])=[O:34])[CH2:31][CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(CN)cc2C1C1(c2ccccn2)CCC1
Reactant: CCCS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCS(=O)(=O)NCc1ccc2c(c1)C(C1(c3ccccn3)CCC1)N(C(=O)OC(C)(C)C)CC2

Procedure:
tert-Butyl 7-(aminomethyl)-1-[1-(pyridin-2-yl)cyclobutyl]-3,4-dihydroisoquinoline-2(1H)-carboxylate (33 mg, 0.084 mmol) was dissolved in dichloromethane. 4-Dimethylaminopyridine (30.7 mg, 0.252 mmol) was added. After stirring for 5 min propane-1-sulfonyl chloride (12 mg, 0.084 mmol) was added and stirring was continued over night. The reaction mixture was diluted with dichloromethane (30 ml) and washed with aqueous ammonium chloride solution. The organic layer was washed with water, dried (MgSO4) and concentrated in vacuo. The crude product was used for the next step without further purification. Yield: 37 mg.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:21]3[C:13](=[N:14][C:15]4[N:16]=[CH:17][N:18]=[CH:19][C:20]=43)[NH:12][C:11]([CH3:22])=[C:10]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:5][CH:4]=1)#[N:2].[F:28][C:29]([F:40])([F:39])[C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.N1C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:21]3[C:13](=[N:14][C:15]4[N:16]=[CH:17][N:18]=[CH:19][C:20]=43)[N:12]([C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([C:29]([F:40])([F:39])[F:28])[CH:35]=3)[C:11]([CH3:22])=[C:10]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:5][CH:4]=1)#[N:2]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C1=C(C)Nc2nc3ncncc3n2C1c1ccc(C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nc3ncncc3n2C1c1ccc(C#N)cc1
Reaction time: 12 h

Procedure:
(rac)-Ethyl 6-(4-cyanophenyl)-8-methyl-6,9-dihydropyrimido[2,1-f]purine-7-carboxylate (30 mg, 0.08 mmol), 3-(trifluoromethyl)phenylboronic acid (31 mg, 0.17 mmol, 2 eq.), anhydrous copper-(II) acetate (30 mg, 0.17 mmol, 2 eq.) and molecular sieve (100 mg, 4 Å) were initially charged. Under an atmosphere of argon, abs. dichloromethane (5 ml), pyridine (27 μl, 0.33 mmol, 4 eq.) and triethylamine (23 μl, 0.17 mmol, 2 eq.) were added. After 12 h of stirring, the mixture was filtered over kieselguhr and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (5.6 mg, 13% of theory).
Reaction SMILES: C1([OH:7])C=CC=CC=1.[CH:8](Cl)(Cl)[CH:9](Cl)Cl.[CH:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[C:17]([OH:27])=[CH:16][CH:15]=1>>[CH:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[C:17]([OH:27])=[CH:16][CH:15]=1.[OH:7][C:23]1[CH:22]=[CH:21][C:20]([CH2:18][CH2:19][C:14]2[CH:15]=[CH:16][C:17]([OH:27])=[CH:9][CH:8]=2)=[CH:25][CH:24]=1
Reactant: Oc1ccccc1
Reactant: ClC(Cl)C(Cl)Cl
Agent: Oc1cccc(-c2ccccc2O)c1
Product: Oc1ccc(CCc2ccc(O)cc2)cc1

Procedure:
The inherent viscosity of the polyesters determined at 30° C., in a solvent combination of 60 parts by weight phenol and 40 parts by weight sym-tetrachloroethane at a concentration of 0.5 g per dl., is at least about 0.5 and is preferably at least about 0.7. The selection of acid and diphenol components is made so that the polyester preferably has a glass transition temperature of at least 100° C., a viscosity at 320° C. determined in a capillary rheometer at a shear rate of 100 sec-1 of less than 105 poise and a melting point less than about 350° C. An especially preferred group of polyarylene esters comprises those polyesters obtained by condensation of a diphenol comprising at least 90 mol percent 1,2-bis(4-hydroxyphenyl)ethane and a dicarboxylic acid comprising at least 67 mol percent isophthalic acid. Of this preferred group, one of the more preferred combinations is obtained from 1,2-bis(4-hydroxyphenyl)ethane and isophthalic acid without additional components. The preferences are based on the availability and cost of the acid as well as on the desirable glass transition and melting points of the resulting polyesters. Since molding cycles are preferably rapid, it is desirable that a crystalline polyester crystallize in the short period during which the polymer is cooling in the mold. Thus a molding material for uses where high temperature dimensional stability is important, needs to have a rapid rate of crystallization. The glass transition temperature, the melting point and the rate of crystallization can be determined by means of differential scanning calorimetry as described in copending application Ser. No. 709,469, filed July 28, 1976, now U.S. Pat. No. 4,102,864, which methods are hereby incorporated by reference.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[N:5]([CH2:9][C@@H:10]2[C@H:13]([NH:14][C:15](=[O:31])/[C:16](=[N:23]\[O:24][C:25]3([C:28]([OH:30])=[O:29])[CH2:27][CH2:26]3)/[C:17]3[N:18]=[C:19]([NH2:22])[S:20][CH:21]=3)[C:12](=[O:32])[N:11]2[S:33]([OH:36])(=[O:35])=[O:34])[CH2:4]1.Cl.[N:38]1([C:43](N)=[NH:44])C=CC=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:22][C:19]1[S:20][CH:21]=[C:17](/[C:16](=[N:23]/[O:24][C:25]2([C:28]([OH:30])=[O:29])[CH2:26][CH2:27]2)/[C:15]([NH:14][C@@H:13]2[C:12](=[O:32])[N:11]([S:33]([OH:36])(=[O:34])=[O:35])[C@@H:10]2[CH2:9][N:5]2[CH2:4][C@@H:3]([CH2:2][NH:1][C:43]([NH2:44])=[NH:38])[O:7][C:6]2=[O:8])=[O:31])[N:18]=1
Reactant: N=C(N)n1cccn1
Reactant: NC[C@@H]1CN(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)C(=O)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N=C(N)NC[C@@H]1CN(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)C(=O)O1
Temperature: 25 °C
Reaction time: 19 h
Yield: 37.8 %

Procedure:
To a solution of 1-(((Z)-(2-(((2R,3S)-2-(((R)-5-(aminomethyl)-2-oxooxazolidin-3-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)cyclopropane-carboxylic acid (0.795 mmol) and Pyrazole-1-carboxamidine hydrochloride (234.8 mg, 1.602 mmol) in DMF (7.0 mL) was added DIPEA (1.20 mL, 8.06 mmol). After 19 h of stirring at rt, the solution was concd in vacuo and purified by reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (177 mg, 37%) as a white powder. LCMS: Rt=0.47 min, m/z=590.1 (M+H) Method 2m_acidic_polar; 1H NMR (400 MHz, DMSO-d6) δ 9.15 (d, J=8.9 Hz, 1H), 7.62 (br s, 1H), 7.24 (s, 3H), 6.81 (s, 1H), 5.23 (dd, J=8.9, 5.9 Hz, 1H), 4.60-4.51 (m, 1H), 4.23 (ddd, J=9.0, 5.8, 3.7 Hz, 1H), 3.70 (t, J=8.8 Hz, 1H), 3.52 (dd, J=8.8, 5.4 Hz, 1H), 3.49-3.44 (m, 1H), 3.43-3.34 (m, 3H), 1.38-1.24 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[S:5][CH:6]=[C:7]2[C:11](=[O:12])[N:10]([CH:13]3[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]3=[O:20])[C:9](=[O:21])[C:8]=12)([O-])=O.C(O)(=O)C>C(O)C.O.[Fe]>[NH2:1][C:4]1[S:5][CH:6]=[C:7]2[C:11](=[O:12])[N:10]([CH:13]3[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]3=[O:20])[C:9](=[O:21])[C:8]=12
Reactant: O=C1CCC(N2C(=O)c3csc([N+](=O)[O-])c3C2=O)C(=O)N1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Nc1scc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 34 %

Procedure:
0.309 g of 1-nitryl-5-(2,6-dioxopiperidin-3-yl)-5H-thieno(3,4-c)pyrrole-4,6-dione was suspended in 20 mL of ethanol and 20 mL of water, and 0.7 g freshly-activated iron powder (washed with water after hydrochloric acid treatment) and 5 mL acetic acid were added and refluxed for 2 h. The reaction mixture was cooled and filtered. The filtered solution was evaporated to dryness; and the remaining residue was dissolved in 150 mL of ethyl acetate, washed with 40 mL of water and 40 mL of brine, dried over anhydrous MgSO4, filtered, and evaporated to dryness. The remaining residue was purified on silica gel column chromatography to obtain a solid (0.095 g).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[O:14][CH:13]=[C:12]([C:15]#[N:16])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:17][OH:18].O>C(O)C.CCOCC>[Si:1]([O:8][CH2:9][C:10]1[O:14][CH:13]=[C:12]([C:15](=[N:17][OH:18])[NH2:16])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(C#N)co1
Reactant: NO
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cc(C(N)=NO)co1
Yield: 97 %

Procedure:
To a solution of 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-3-furonitrile (1.8 g, 7.6 mmol) that was obtained in Example 1 (1c) in ethanol (10 ml) was added a 40% aqueous solution of hydroxylamine (1.0 ml) with stirring, and the resulting mixture was stirred at 60° C. for 1 hour. After evaporating the reaction mixture in vacuo, the residue obtained was diluted with ether, poured into water (40 ml) and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:1) as the eluent to afford the title compound (2.0 g) in a yield of 97% as a white crystalline solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3][CH2:2]1.[C:22]([BH3-])#N.[Na+].C=O.CC(O)=O.C([O-])(O)=O.[Na+]>CO>[CH3:22][N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3][CH2:2]1
Reactant: c1ccc(-c2[nH]c3ccccc3c2C2CCNCC2)cc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN1CCC(c2c(-c3ccccc3)[nH]c3ccccc23)CC1
Reaction time: 2 h
Yield: 24.1 %

Procedure:
3-(Piperidin-4-yl)-2-phenyl-1H-indole (200 mg, 0.7 mmol), sodium cyanoborohydride (51 mg, 0.8 mmol), formaldehyde (60 μl, 40% in H2O, 0.8 mmol) and AcOH (97 μl, 1.7 mmol) were stirred in MeOH (5 ml) at 0° C. for 1 h, then room temperature for 2 h. The solution was poured into saturated NaHCO3 solution and extracted with EtOAc. The organic layer was washed with water and brine, dried, and evaporated in vacuo to give white crystals (49 mg, 23%), mp 245-246° C. (from EtOH); δH (360 MHz, d6-DMSO) 1.88 (2H, d, J 13, NCH2CHAHB), 2.60-2.80 (2H, m, NCH2CHAHB), 2.76 (3H, s, CH3), 3.00-3.20 (3H, m, CH2CH and NCHAHB), 3.44 (2H, d, J 12, NCHAHB), 6.99 (1H, t, J 7, indole-H), 7.09 (1H, t, J 7, indole-H), 7.20-7.50 (6H, m, ArH), 7.98 (1H, d, J 7, ArH), 11.20 (1H, br s, indole NH); m/z (ES+) 291 (M++H).
Reaction SMILES: C(NC(C1C=C(S([O:16][CH2:17][C@:18]([OH:68])([CH3:67])[C:19](=[O:66])[C@H:20]([CH2:62][CH:63]([CH3:65])[CH3:64])[NH:21][C:22](=[O:61])[C@H:23]([CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[NH:24][C:25](=[O:53])[C@H:26]([CH2:49][CH:50]([CH3:52])[CH3:51])[NH:27][C:28](=[O:48])[C@H:29]([CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[NH:30][C:31](=[O:39])[CH2:32][N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)(=O)=O)C=CC=1)=O)C#C.[CH2:69]([O:72][C:73]1[CH:78]=[C:77]([O:79][CH3:80])[C:76]([S:81](Cl)(=[O:83])=[O:82])=[C:75]([O:85][CH3:86])[CH:74]=1)[C:70]#[CH:71].C(N)(=O)CCCC>>[CH3:80][O:79][C:77]1[CH:78]=[C:73]([O:72][CH2:69][C:70]#[CH:71])[CH:74]=[C:75]([O:85][CH3:86])[C:76]=1[S:81]([O:16][CH2:17][C:18]([OH:68])([CH3:67])[C:19](=[O:66])[C@H:20]([CH2:62][CH:63]([CH3:64])[CH3:65])[NH:21][C:22](=[O:61])[C@H:23]([CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[NH:24][C:25](=[O:53])[C@H:26]([CH2:49][CH:50]([CH3:52])[CH3:51])[NH:27][C:28](=[O:48])[C@H:29]([CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[NH:30][C:31](=[O:39])[CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)(=[O:83])=[O:82]
Reactant: C#CCNC(=O)c1cccc(S(=O)(=O)OC[C@@](C)(O)C(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCc2ccccc2)NC(=O)CN2CCOCC2)c1
Reactant: C#CCOc1cc(OC)c(S(=O)(=O)Cl)c(OC)c1
Agent: CCCCC(N)=O
Product: C#CCOc1cc(OC)c(S(=O)(=O)OCC(C)(O)C(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCc2ccccc2)NC(=O)CN2CCOCC2)c(OC)c1

Procedure:
Prepared in a similar manner to compound 13, except from 4-(propargyloxy)-2,6-dimethoxybenzene-1-sulfonyl chloride and (S)—N—((S)-1-(((2R,4S)-1,2-dihydroxy-2,6-dimethyl-3-oxoheptan-4-yl)amino)-1-oxo-3-phenylpropan-2-yl)-4-methyl-2-((S)-242-morpholinoacetamido)-4-phenylbutanamido)pentanamide.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([OH:13])=O)=[C:4]([OH:14])[CH:3]=1.[N:15]1([CH:21]2[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([N:18]2[CH2:19][CH2:20][N:15]([CH:21]3[CH2:22][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24]3)[CH2:16][CH2:17]2)=[O:13])=[C:4]([OH:14])[CH:3]=1
Reactant: O=C(O)CNc1cc(Cl)c(Cl)cc1O
Reactant: CC(C)(C)OC(=O)N1CC(N2CCNCC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(N2CCN(C(=O)CNc3cc(Cl)c(Cl)cc3O)CC2)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 30.8 %

Procedure:
A mixture of 2-(4,5-dichloro-2-hydroxyphenylamino)acetic acid (500 mg, 2.12 mmol), tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate (565 mg, 2.34 mmol), EDCI.HCl (488 mg, 2.54 mmol), HOBt (343 mg, 2.54 mmol), Et3N (428 mg, 4.24 mmol) in DMF (20 mL) was stirred at room temperature for 15 h. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed withed saturated aqueous NaHCO3 solution and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (DCM/MeOH=30:1) to afford the desired product (300 mg, 31% yield). ESI-MS m/z: 457.4 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([CH2:13][N:14]2[CH2:19][CH2:18][N:17](S(C3C=CC=CC=3)(=O)=O)[C@@H:16]([CH2:29][CH3:30])[CH2:15]2)[CH:3]=1.[C:31]1([CH2:37][C:38](Cl)=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:38](=[O:39])[CH2:37][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@@H:16]([CH2:29][CH3:30])[CH2:15]2)[CH:3]=1
Reactant: CC[C@H]1CN(Cc2cc(Cl)ccc2OCC(=O)O)CCN1S(=O)(=O)c1ccccc1
Reactant: O=C(Cl)Cc1ccccc1
Product: CC[C@H]1CN(Cc2cc(Cl)ccc2OCC(=O)O)CCN1C(=O)Cc1ccccc1

Procedure:
Prepared from the product from example 69 part f) and phenylacetyl chloride according to the procedure described in example 69 part g) to give the title compound as a white solid (30 mg).