Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:19])([CH2:11][CH2:12][CH2:13][CH2:14][S:15]([O-:18])(=[O:17])=[O:16])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:20]([O-:23])(=[O:22])=[O:21])[CH:8]=2)[N:3]=1.[Na+].[Na+].[CH2:26](OS(C1C=CC(C)=CC=1)(=O)=O)[CH3:27].C1S(=O)(=O)CCC1.CO>CCOC(C)=O>[CH2:26]([N+:3]1[C:4]2[C:9](=[CH:8][C:7]([S:20]([O-:23])(=[O:21])=[O:22])=[CH:6][CH:5]=2)[C:10]([CH3:19])([CH2:11][CH2:12][CH2:13][CH2:14][S:15]([OH:18])(=[O:16])=[O:17])[C:2]=1[CH3:1])[CH3:27]
Reactant: CC1=Nc2ccc(S(=O)(=O)[O-])cc2C1(C)CCCCS(=O)(=O)[O-]
Reactant: CCOS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O=S1(=O)CCCC1
Product: CC[N+]1=C(C)C(C)(CCCCS(=O)(=O)O)c2cc(S(=O)(=O)[O-])ccc21
Yield: 41.6 %

Procedure:
Disodium 2,3-dimethyl-3-(4-sulphonatobutyl)-3H-indole-5-sulphonate (1 g), ethyl-p-toluene sulphonate (0.95 ml; 5.56 mmol) and tetramethylenesulphone (10 ml) were heated together at 140° C. for 12 hrs. TLC (silica; 2:1 MeOH; EtOAc) showed the formation of a new product spot (rf=0.8), which turned magenta on standing. The product was precipitated into ethyl acetate and then filtered off and dried in vacuo to give the crude product as a dark purple solid; 1.5 g. The product was purified in multiple shots by HPLC (Vydac protein & peptide C18 (250 mm×25 mm); flow rate 10 ml/min; gradient of 0 to 25% B over 30 mins; eluant A=0.1% TFA in water and eluant B=0.1% TFA in acetonitrile; detection at 220 nm). The fractions containing the desired product were pooled and the solvent removed under reduced pressure. The product was obtained as a pale pink oil (400 mg).
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2([C:24]3[CH:29]=[C:28]([CH3:30])[C:27]([O:31][Si](C(C)(C)C)(C)C)=[C:26]([CH3:39])[CH:25]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:9][C:8]=1[CH3:40])(C)(C)C.[CH3:43][O:44][C:45]1[CH:46]=[C:47](B(O)O)[CH:48]=[CH:49][C:50]=1[O:51][CH3:52].C(N(CC)CC)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>C1COCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(OCC)(=O)C.ClCCl>[CH3:43][O:44][C:45]1[CH:46]=[C:47]([N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14]([C:24]3[CH:25]=[C:26]([CH3:39])[C:27]([OH:31])=[C:28]([CH3:30])[CH:29]=3)([C:10]3[CH:11]=[C:12]([CH3:13])[C:7]([OH:6])=[C:8]([CH3:40])[CH:9]=3)[C:15]2=[O:23])[CH:48]=[CH:49][C:50]=1[O:51][CH3:52]
Reactant: Cc1cc(C2(c3cc(C)c(O[Si](C)(C)C(C)(C)C)c(C)c3)C(=O)Nc3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Reactant: COc1ccc(B(O)O)cc1OC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(N2C(=O)C(c3cc(C)c(O)c(C)c3)(c3cc(C)c(O)c(C)c3)c3ccccc32)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
Combine 3,3-Bis-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-phenyl]-1,3-dihydro-indol-2-one (0.583 g, 0.968 mmol), 3,4-dimethoxybenzeneboronic acid (0.353 g, 1.94 mmol), copper (II) acetate (0.176 g, 0.968 mmol), triethylamine (0.27 mL, 1.94 mmol), 4 angstrom molecular sieves, and dichloromethane (15 mL). Stir at room temperature overnight under ambient atmosphere. Filter the reaction through Celite. Elute through a column of silica gel with 70% dichloromethane in hexanes and concentrate. Dissolve the resulting compound (0.399 g, 0.511 mmol), in THF (4 mL). Add a solution of tetrabutylammonium fluoride (1.0M) in THF (1.35 mL). Stir for 1 h. Add saturated aqueous ammonium chloride(10 mL) water (40 mL) and ethyl acetate (50 mL). Separate the layers and concentrate the organic layer in vacuo. Chromatograph on silica gel eluting with a gradient from 25% to 50% ethyl acetate in hexanes to give 0.153 g (31%) of the title compound: mass spectrum (ion spray): m/z=510(M+1); 1H NMR(DMSO-d6): δ8.23 (s, 2H), 7.31 (d, 1H), 7.21 (td, 1H), 7.11-7.06 (m, 2H), 6.94-6.89 (m, 2H), 6.76-6.74 (m, 5H), 3.80 (s, 3H), 3.75 (s, 3H), 2.07 (s, 12H).
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:15]=2)[N:10]=[C:9]1Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1>C(O)(C)C>[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:15]=2)[N:10]=[C:9]1[NH:39][CH2:38][C:37]1[CH:40]=[CH:41][C:34]([Cl:33])=[CH:35][CH:36]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: COC(=O)c1ccc2c(=O)n(Cc3ccccc3)c(Cl)nc2c1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(=O)n(Cc3ccccc3)c(NCc3ccc(Cl)cc3)nc2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
To a suspension of methyl 3-benzyl-2-chloro-4-oxo-3,4-dihydroquinazoline-7-carboxylate (0.20 g, 0.37 mmol) in isopropyl alcohol (4 mL) was added N,N-diisopropylethylamine (0.13 mL, 0.77 mmol) and p-chlorobenzylamine (0.11 mL, 0.91 mmol). The reaction mixture was heated to 100° C. and stirred for 1 h. The mixture was then cooled to rt and concentrated. The residue was purified by flash silica gel chromatography (0% to 80% EtOAc/hexanes) to afford methyl 3-benzyl-2-[(4-chlorobenzyl)amino]-4-oxo-3,4-dihydroquinazoline-7-carboxylate (0.12 g, 75%). LC-MS: (FA) ES+434.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][C:28]([F:31])([F:30])[F:29])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.O1CCCC1>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][C:28]([F:29])([F:31])[F:30])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: O=CNc1nc(C(=NOCC(F)(F)F)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc(C(=NOCC(F)(F)F)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Yield: 77.9 %

Procedure:
A suspension of 7-[2-(2-formamidothiazol-4-yl)-2-(2,2,2-trifluoroethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.5 g.), conc. hydrochloric acid (1.3 ml.), tetrahydrofuran (10 ml.) and methanol (30 ml.) was treated in a similar manner to that of Example 21-(3) to give 7-[2-(2-aminothiazol-4-yl)-2-(2,2,2-trifluoroethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.1 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:17]=[C:18]([CH:34]=[CH:35][CH:36]=3)[C:19]([N:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)=[O:20])[N:12]3[N:37]=[CH:38][C:39]([CH:40]=[C:41]4[C:45](=[O:46])[NH:44][C:43](=[O:47])[NH:42]4)=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:36]=[CH:35][CH:34]=[C:18]([C:19]([N:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]4)=[O:20])[CH:17]=3)[N:12]3[N:37]=[CH:38][C:39]([CH:40]=[C:41]4[NH:42][C:43](=[O:47])[NH:44][C:45]4=[O:46])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(Nc3cc(Nc4cccc(Cl)c4)nc4c(C=C5NC(=O)NC5=O)cnn34)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC(=O)C(=Cc2cnn3c(Nc4cccc(C(=O)N5CCNCC5)c4)cc(Nc4cccc(Cl)c4)nc23)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
Tert-butyl 4-(3-(5-(3-chlorophenylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)benzoyl)piperazine-1-carboxylate (27 mg, 0.04 mmol) was dissolved in 2 mL of TFA/DCM (1:1) and stirred at room temperature for 1 hour. Excess solvent and TFA were removed by evaporation under a stream of nitrogen. The residue was diluted with water then the mixture was filtered. The recovered solid was washed with water followed by 50% ethanol. The product, 5-((5-(3-chlorophenylamino)-7-(3-(piperazine-1-carbonyl)phenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione, was collected as a solid in 21% yield. LCMS (M+1=558)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8]([C:11](=[O:15])[C:12]([OH:14])=O)=[CH:9][NH:10][C:3]=12.[C:16]1([C:22](=[C:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:23]#[N:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(C(C)C)C(C)C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8]([C:11](=[O:15])[C:12]([N:28]3[CH2:27][CH2:26][C:25](=[C:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:23]#[N:24])[CH2:30][CH2:29]3)=[O:14])=[CH:9][NH:10][C:3]=12
Reactant: N#CC(=C1CCNCC1)c1ccccc1
Reactant: O=C(O)C(=O)c1c[nH]c2c(Cl)ccnc12
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#CC(=C1CCN(C(=O)C(=O)c2c[nH]c3c(Cl)ccnc23)CC1)c1ccccc1
Reaction time: 20 h
Yield: 11 %

Procedure:
To a solution of (7-chloro-1H-pyrrolo[3,2-b]pyridin-3-yl)-oxo-acetic acid (1.5 g, 6.7 mmol) and phenylpiperidine-4-ylidene acetonitrile (1.3 g, 6.7 mmol) in DMF (50 mL) was added DEPBT (3.15 g, 10.5 mmol) and ethyl diisopropylamine (6.1 mL, 35 mmol). The solution was stirred 20 h, concentrated under vacuum and partitioned between 5% Na2CO3(aq) (80 mL) and EtOAc (5×100 mL). The combine organic layers were dried (MgSO4), filtered and concentrated. The residue was purified by Biotage Chromatography (SiO2, 30% EtOAc/Hex to 100% EtOAc) and by preparative HPLC to yield the title compound (300 mg, 0.74 mmol, 11%) as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2=[C:14](OS(C(F)(F)F)(=O)=O)[N:15]([CH:17]([CH3:19])[CH3:18])[N:16]=[C:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2=[C:14]([C:32]3[CH:33]=[CH:34][C:29]([CH3:28])=[CH:30][CH:31]=3)[N:15]([CH:17]([CH3:19])[CH3:18])[N:16]=[C:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(Cc1ccccc1)C2
Product: Cc1ccc(-c2c3c(nn2C(C)C)CN(Cc2ccccc2)CC3)cc1
Yield: 26.1 %

Procedure:
The title compound (67 mg) was prepared according to Example 287 using 300 mg of trifluoro-methanesulfonic acid 6-benzyl-2-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-3-yl ester and 141 mg of 4-methylphenylboronic acid. MS (ESI): exact mass calculated for C23H27N3, 345.22; found, m/z 346.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.60-7.58 (m, 2H), 7.54-7.53 (m, 3H), 7.37-7.35 (m, 2H), 7.28-7.24 (m, 2H), 4.58-4.49 (m, 3H), 4.42-4.33 (m, 2H), 3.81-3.78 (m, 1H), 3.45-3.41 (m, 1H), 2.90-2.82 (m, 2H), 2.41 (s, 3H), 1.42-1.29 (m, 6H).
Reaction SMILES: [CH:1]([N:4]([CH3:35])[C@@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[CH2:15][CH2:14][C@H:13]([NH:16]C(=O)OCC3C=CC=CC=3)[C:12]2=[O:27])[C@H:7]([CH2:28][S:29]([CH:32]([CH3:34])[CH3:33])(=[O:31])=[O:30])[CH2:6]1)([CH3:3])[CH3:2].Br.CC(O)=O>CCOCC>[NH2:16][C@H:13]1[CH2:14][CH2:15][N:11]([C@H:8]2[CH2:9][CH2:10][C@@H:5]([N:4]([CH:1]([CH3:3])[CH3:2])[CH3:35])[CH2:6][C@H:7]2[CH2:28][S:29]([CH:32]([CH3:34])[CH3:33])(=[O:31])=[O:30])[C:12]1=[O:27]
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](CS(=O)(=O)C(C)C)C1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](N)C2=O)[C@H](CS(=O)(=O)C(C)C)C1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 128.5 %

Procedure:
The entirety of benzyl (S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(isopropylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate prepared in Step 2 (250 mg, 0.5 mmol) was charged with 30% HBr/AcOH (5 mL). The reaction vessel warms and a vigorous gas evolution occurs. The mixture was stirred for 25 min at RT and then the flask was placed in a cool water bath before the addition of 20 mL of Et2O. The resulting solid was collected, washed with Et2O twice, and concentrated in vacuo to give (S)-3-amino-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(isopropylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one (240 mg, 91% yield). MS found: (M+H)+=374.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.Cl.Cl.[NH2:12][C:13]1([CH2:18][NH:19][C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[CH2:17][CH2:16][NH:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[NH2:12][C:13]1([CH2:18][NH:19][C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[CH2:17][CH2:16][N:15]([C:7]2[C:2]([Br:1])=[C:3]([NH2:9])[N:4]=[CH:5][N:6]=2)[CH2:14]1
Reactant: Nc1ncnc(Cl)c1Br
Reactant: NC1(CNC(=O)c2ccc(F)cc2F)CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1ncnc(N2CCC(N)(CNC(=O)c3ccc(F)cc3F)C2)c1Br
Temperature: 60 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
A mixture of 5-bromo-6-chloropyrimidin-4-amine (272.7 mg; 1.24 mmol; 1.02 eq.), N-[(3-aminopyrrolidin-3-yl)-methyl]-2,4-difluorobenzamide dihydrochloride (400.0 mg; 1.22 mmol; 1.0 eq.), potassium carbonate (336.8 mg; 2.44 mmol; 2.0 eq.) in DMSO (5.00 ml) was stirred at 60° C. overnight. The reaction mixture was workup and the crude was purified by reverse phase pre-HPLC (Waters, basic condition) to afford the title compound in 76% yield. LC-MS: (M+1=427, obsd.=427).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][CH:9]1[C:14](=[O:26])[NH:15][C:16]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][CH:17]1[CH:19]=[CH2:20])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:24]([O:23][C:21]([C:16]1([NH:15][C:14]([CH:9]2[CH2:10][CH:11]([OH:13])[CH2:12][NH:8]2)=[O:26])[CH2:18][CH:17]1[CH:19]=[CH2:20])=[O:22])[CH3:25]
Reactant: C=CC1CC1(NC(=O)C1CC(O)CN1C(=O)OC(C)(C)C)C(=O)OCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC1CC1(NC(=O)C1CC(O)CN1)C(=O)OCC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Compound 122 (10.5 g, 28.4 mmol) was dissolved in DCM (70 ml) and cooled to 0° C., TFA (35 ml) was added. After appr 1 h the solution was evaporated and neutralized with aqueous sodium carbonate and evaporated on silica. Purification of the crude product by column chromatography on silica (MeOH/DCM: 15/85) gave 9.7 g of still unpure compound title compound. This material was used in the next step.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8]([N:10]([CH3:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=[C:6]([C:18]2[N:22]=[C:21]([N:23]3[CH2:26][CH:25]([OH:27])[CH2:24]3)[O:20][N:19]=2)[N:5]=1.CS(O[CH:33]([CH3:35])[CH3:34])(=O)=O>CN(C=O)C.CCOC(C)=O>[CH:33]([O:27][CH:25]1[CH2:24][N:23]([C:21]2[O:20][N:19]=[C:18]([C:6]3[N:7]=[C:8]([N:10]([CH3:17])[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:9]=[C:4]([NH2:3])[N:5]=3)[N:22]=2)[CH2:26]1)([CH3:35])[CH3:34]
Reactant: CC(C)OS(C)(=O)=O
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(N3CC(O)C3)n2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)OC1CN(c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)C1
Reaction time: 0.17 h
Yield: 26 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 9 mg, 0.22 mmol) was added to a solution of 1-{3-[4-amino-6-(methyl-phenyl-amino)-[1,3,5]triazin-2-yl]-[1,2,4]oxadiazol-5-yl}-azetidin-3-ol (Intermediate 166, 50 mg, 0.147 mol) in anhydrous DMF (0.5 mL) at 0 C under nitrogen and the mixture was stirred for 10 min. A solution of propan-2-yl methanesulfonate (26.7 μL, 0.221 mmol) in anhydrous DMF (0.5 mL) was then added and the mixture was stirred at room temperature for 18 h. Further sodium hydride (60% dispersion in mineral oil, 9 mg, 0.22 mmol) and propan-2-yl methanesulfonate (26.7 μL, 0.221 mmol) were then added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with EtOAc (10 mL) then washed with saturated aq. sodium carbonate (4×5 mL), brine (5 mL) and evaporated under vacuum. The crude residue was purified by flash chromatography (0-2% (7M ammonia in MeOH) in DCM) to afford the title compound as a light yellow glass (22 mg, 39%).
Reaction SMILES: C(N(CC)CC)C.ClC(Cl)(O[C:12](=[O:18])[O:13][C:14](Cl)(Cl)Cl)Cl.[NH2:20][C:21]1[CH:26]=[C:25]([C:27]([CH3:29])=[O:28])[CH:24]=[CH:23]C=1O.Cl>C1COCC1>[CH3:29][C:27]([C:25]1[CH:24]=[CH:23][C:14]2[O:13][C:12](=[O:18])[NH:20][C:21]=2[CH:26]=1)=[O:28]
Reactant: CC(=O)c1ccc(O)c(N)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc2oc(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7.8 ml of triethylamine and 2.75 g (0.0093 mol) of triphosgene are added to a mixture of 4.2 g (0.0277 mol) of 2-amino-4-methylcarbonylphenol in 100 ml of THF, at 0° C. The mixture is stirred at room temperature for 1 hour, poured into 100 ml of a 0.5N HCl solution and extracted with ethyl acetate, the organic phase is dried and the solvent is evaporated off. The compound of the title is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:11][O:12][C:13]([CH:15]1[CH2:20][CH2:19][CH:18]([CH2:21]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:17][CH2:16]1)=[O:14]>CN(C)C=O.C(OCC)(=O)C>[CH3:11][O:12][C:13]([CH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:6]2[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]2)[CH2:17][CH2:16]1)=[O:14]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: COC(=O)C1CCC(COS(=O)(=O)c2ccc(C)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1CCC(Cn2ccc([N+](=O)[O-])n2)CC1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 36.8 %

Procedure:
The 3-Nitro-1H-pyrazole (prepared in example 3, 130 mg, 1.16 mmol) was dissolved in N,N-dimethylformamide (4 mL) and a 60% suspension of sodium hydride in mineral oil (50 mg, 1.25 mmol) was added. After the effervescence ceased and the reaction stirred for an additional 10 min, the 4-(toluene-4-sulfonyloxymethyl)-cyclohexanecarboxylic acid methyl ester (380 mg, 1.16 mmol) was added and the reaction was heated to 80° C. while stirring for 4 h. The reaction continued to stir under nitrogen for 2 h. The solution was diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium bicarbonate solution (35 mL), 1.0 M aqueous hydrochloric acid solution (35 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 5% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) afforded 4-(3-nitro-pyrazol-1-ylmethyl)-cyclohexanecarboxylic acid methyl ester (114 mg, 37%) as a yellow oil: H1-NMR (400 MHz, CDCl3) δ 1.00-1.12 (2H, m), 1.36-1.50 (2H, m), 1.68-1.78 (2H, m), 1.90-2.08 (3H, m), 2.20-2.30 (1H, m), 3.66 (3H, s), 4.03 (2H, d, J=7.2 Hz), 6.88 (2H, d, J=2.4 Hz), 7.40 (2H, d, J=8.4 Hz).
Reaction SMILES: II.[CH:3]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][C:15]([CH:21]=[CH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:16][CH:17]=2)[CH:12]=1)=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[CH:27]1[C:28]2[C:23](=[CH:22][CH:21]=[C:15]3[C:14]=2[C:13]2[C:18](=[CH:19][CH:20]=[C:11]4[C:12]=2[C:6]2[C:5](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:4]=[CH:3]4)[CH:17]=[CH:16]3)[CH:24]=[CH:25][CH:26]=1
Reactant: C(=Cc1ccc2ccc(C=Cc3ccccc3)cc2c1)c1ccccc1
Agent: II
Product: c1ccc2c(c1)ccc1ccc3ccc4ccc5ccccc5c4c3c12

Procedure:
A small amount of iodine was added to a solution of 0.2 g/l of 2,7-bis(styryl)naphthalene, and the solution was irradiated with light from a high-pressure mercury lamp for 2 hr and then subjected to silica gel chromatography, and the separated product was recrystallized from benzene/ethanol as a solvent to obtain hexahelicene.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][C:6]=1[NH:13][C:14](=[O:30])[CH2:15][CH:16]1[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:23][C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(OCC)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=1[NH:13][C:14](=[O:30])[CH2:15][CH:16]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=2[O:23][C:24]2[C:29]1=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CO)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)c1ccc(C=O)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Reaction time: 1.75 h
Yield: 88 %

Procedure:
1.24 g (3.08 mmol) of N-(2-t-butyl-5-hydroxymethylphenyl)-2-(9H-xanthen-9-yl)acetamide (prepared as described in Preparation 14) were added to 12 ml of a methylene chloride suspension containing 1.06 g (4.92 mmol) of pyridinium chlorochromate. The mixture was then stirred for 1.75 hours. At the end of this time, the reaction suspension was diluted with diethyl ether, filtered through a column using 50 ml of Florisil (trade mark) absorbent, and eluted with a 1:1 by volume mixture of methylene chloride and diethyl ether. The solvent was then removed by distillation under reduced pressure. The resulting residue was subjected to column chromatography through 50 g of silica gel. Elution with a 1:9 by volume mixture of diethyl ether and methylene chloride afforded the title compound containing a small amount of impurities. Recrystallization of this from a mixture of ethyl acetate and hexane afforded 442 mg of the title compound as crystals, melting at 172.5°-174° C. (after recrystallization from a mixture of ethyl acetate and hexane). The mother liquors were condensed and subjected to column chromatography through 100 g of silica gel. Elution with a 4:6 by volume mixture of ethyl acetate and hexane afforded a further 643 mg of the title compound. The total yield was 88%.
Reaction SMILES: [C:1]1([C:7]2[C:8]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[C:9]3[C:15]([NH:16][C:17](=[O:24])[C:18]4[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=4)=[CH:14][NH:13][C:10]3=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:31]([O:35][C:36]([NH:38][CH2:39][CH2:40][C:41](O)=[O:42])=[O:37])([CH3:34])([CH3:33])[CH3:32].C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:17]([NH:16][C:15]1[C:9]2[C:10](=[N:11][CH:12]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:8]=2[N:25]2[CH2:26][CH2:27][N:28]([C:41](=[O:42])[CH2:40][CH2:39][NH:38][C:36](=[O:37])[O:35][C:31]([CH3:32])([CH3:33])[CH3:34])[CH2:29][CH2:30]2)[NH:13][CH:14]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: O=C(Nc1c[nH]c2ncc(-c3ccccc3)c(N3CCNCC3)c12)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]cc(NC(=O)c4cccnc4)c23)CC1
Reaction time: 5 h
Yield: 91.3 %

Procedure:
N-(5-Phenyl-4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (0.050 g, 0.125 mmol, see Example 64), 3-(tert-butoxycarbonylamino)propanoic acid (0.0475 g, 0.251 mmol), HOBT-H2O (0.0269 g, 0.176 mmol), and EDCI (0.0313 g, 0.163 mmol) were placed in DCM (5 mL) at room temperature. DIEA (d 0.742; 0.109 mL, 0.627 mmol) was then added, and the reaction was stirred for 5 hours. The reaction was then poured into Na2CO3 and extracted into DCM. The organic fractions were dried, filtered, and concentrated to give the crude product that was purified by column chromatography (500:20 DCM:MeOH) to give tert-butyl 3-(4-(3-(nicotinamido)-5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropylcarbamate (0.065 g, 90.9% yield).
Reaction SMILES: C([O:4][CH2:5][CH2:6][NH:7][C:8]([C@@H:10]1[CH2:14][C:13](=[N:15][O:16][CH3:17])[CH2:12][N:11]1[C:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)=[O:19])=[O:9])(=O)C.[OH-].[Na+].CO>C1COCC1>[C:23]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:22]=[CH:21][C:20]([C:18]([N:11]2[CH2:12][C:13](=[N:15][O:16][CH3:17])[CH2:14][C@H:10]2[C:8]([NH:7][CH2:6][CH2:5][OH:4])=[O:9])=[O:19])=[CH:25][CH:24]=1
Reactant: CON=C1C[C@@H](C(=O)NCCOC(C)=O)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CON=C1C[C@@H](C(=O)NCCO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 7.4 %

Procedure:
A solution was made containing the side-chain protected compound from the previous step, e.g. 2-({[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]carbonyl}amino)ethyl acetate (450 mg, 10.6 mmol) in THF (10 ml). An aqueous solution (10 ml) of sodium hydroxide (75 mg, 19 mmol) with methanol (5 ml) was added and the reaction stirred at room temperature for three hours. The solvent was removed in vacuo and the crude purified by column chromatography using THF (100%) to give the expected final product, e.g. (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(2-hydroxyethyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide (300 mg, 75%) as a white solid.