Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.[Cl:7][S:8](O)(=[O:10])=[O:9].N#N.S(Cl)(Cl)=O>O>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([S:8]([Cl:7])(=[O:10])=[O:9])=[N:3]1
Reactant: O=S(=O)(O)Cl
Reactant: Cn1cccn1
Agent: N#N
Solvent: O=S(Cl)Cl
Solvent: O
Product: Cn1ccc(S(=O)(=O)Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The N-methylpyrazole sulfonyl chloride was prepared by adding N-methylpyrazole to chilled (0° C.) chlorosulfonic acid. The reaction mixture was allowed to warm to room temperature and then heated to 100° C. overnight under a stream of N2. The reaction mixture was then cooled to room temperature and chilled to 0° C. To this solution was added thionyl chloride (2.5 eq.) and the reaction was stirred at room temperature for 30 min., then warmed to 70° C. for two hours. The reaction was cooled to room temperature and then chilled in an ice bath. Water and ice were slowly added to the reaction mixture to precipitate a white solid which was collected by filtration. The desired sulfonyl chloride was washed with cold water and hexane.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:20](O)[CH3:21].C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:21]12[CH2:20][CH:3]([CH2:4][CH2:5]1)[CH:2]=[C:12]2[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2C2=CC3CCC2C3)C1
Temperature: 95 °C
Reaction time: 12 h
Yield: 45.6 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (594 mg, 1.81 mmol), bicyclo[2.2.1]-2-hepten-2-ylboronic acid (250 mg, 1.81 mmol), ethanol (2 ml), 2N aqueous sodium carbonate solution (10 ml), and tetrakis(triphenylphosphine)palladium(0) (253 mg, 0.219 mmol) in toluene (20 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (282 mg, 45.6%) as an oil.
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19][CH2:20][CH2:21][CH3:22])=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[CH2:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:25]#[CH:26].C(N(C(C)C)CC)(C)C>O1CCCC1.[Cu]I>[CH2:24]([C:25]1[N:3]=[N:2][N:1]([CH:4]2[CH2:23][N:8]3[C:9]4[C:14]([C:15]([CH2:16][C:17]([O:19][CH2:20][CH2:21][CH3:22])=[O:18])=[C:7]3[CH2:6][CH2:5]2)=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH:26]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Reactant: C#CCc1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCOC(=O)Cc1c2n(c3ccccc13)CC(n1cc(Cc3ccccc3)nn1)CC2
Reaction time: 8 h

Procedure:
To a stirred solution of propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate (1 eq) (Synthesis described in WO07019675 A1) and prop-2-yn-1-ylbenzene (2 eq) in tetrahydrofuran (THF) (0.1M) at room temperature was added diisopropyl ethylamine (DIPEA) (5 eq) and CuI (5 eq). The reaction mixture was stirred overnight then quenched with NH4Cl sat and extracted with ethyl acetate (EA), washed with brine, dried over Na2SO4 and evaporated. Purification by combi-flash EA/Hex 0-100% afforded the desired compound which was used directly for next step.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>>[NH:10]([C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1)[NH2:11]
Reactant: Clc1ccc(Cl)nc1
Reactant: NN
Solvent: O
Product: NNc1ccc(Cl)cn1

Procedure:
5 g of 2,5-dichloropyridine were reacted in the manner described in Example 22 with 2.2 ml of hydrazine hydrate. 1.6 g of 2-hydrazino-5-chloropyridine were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][CH:7]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:32][O:33][C:34](=[O:38])[CH2:35][CH2:36][NH2:37].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:32][O:33][C:34](=[O:38])[CH2:35][CH2:36][NH:37][C:18](=[O:20])[C:17]1[CH:16]=[CH:15][C:14]([CH:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:24][CH:23]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:22][CH:21]=1
Reactant: CCCCCCC(Oc1ccc(Br)cc1)c1ccc(C(=O)O)cc1
Reactant: COC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCC(Oc1ccc(Br)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a mixture of 4-[1-(4-bromo-phenoxyl)-heptyl]-benzoic acid (1700 mg, 4.35 mmol) in methylene chloride (43 mL) are added triethyl amine (1.82 mL, 13.4 mmol), DMAP (5.0 mg), 3-amino-propionic acid methyl ester (910 mg, 6.52 mmol) and EDCI (2507 mg, 13.04 mmol) at room temperature. The reaction mixture is stirred at room temperature overnight, loaded on silica gel, eluted with eluted with hexanes with a gradient from 0% of ethyl acetate to 100% of ethyl acetate giving racemic 3-{4-[1-(4-bromo-phenoxyl)-heptyl]-benzoylamino}-propionic acid methyl ester (1660 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]2=[N:12][CH:13]=[N:14][C:15]([O:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)=[C:10]2[CH:9]=[N:8]1.C1(C)C=CC=CC=1.[C:31]1([CH2:37][C:38]([N:40]=[C:41]=[S:42])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(O)C>[C:31]1([CH2:37][C:38]([NH:40][C:41]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][C:15]3[N:14]=[CH:13][N:12]=[C:11]4[N:7]([CH:2]5[CH2:3][CH2:4][CH2:5][CH2:6][O:1]5)[N:8]=[CH:9][C:10]=34)=[CH:18][CH:19]=2)=[S:42])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: Nc1ccc(Oc2ncnc3c2cnn3C2CCCCO2)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ncnc3c2cnn3C2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 4-[1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-phenylamine (0.199 g, 0.63 mmol, 1.0 eq.), toluene (10 ml), ethanol (10 ml) and phenyl-acetyl isothiocyanate (0.33 g, 2.0 mmol, 3.0 eq). The reaction mixture was stirred at room temperature overnight. After removal of solvent in vacuo, the product was separated by flash chromatography using a 3:1 hexane/ethyl acetate solution as the eluent to give 2-phenyl-N-{[(4-{[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]oxy}phenyl)amino]carbonothioyl}acetamide (0.17 g, 54% yield). 1H NMR (400 MHz, DMSO): 12.39 (s, 1H), 11.78 (s, 1H), 8.59 (s, 1H), 8.20 (s, 1H), 7.71 (d, 2H), 7.53 (t, 1H), 7.34 (m, 5H), 7.26 (m, 1H), 5.97 (d, 1H), 3.94 (d, 1H), 3.73 (s, 2H), 3.72 (m 1H), 3.40 (s, 2H), 2.05 (m, 1H), 1.93 (m, 1H), 1.77 (m, 1H), 1.58 (m, 1H); MS (ESI) for C25H24N6O3S: 489 (MH+).
Reaction SMILES: [Si]([O:8][C@@H:9]1[C:24]([CH3:26])([CH3:25])[C:23](=[O:27])[C@H:22]([CH3:28])[C@@H:21]([O:29][Si](C(C)(C)C)(C)C)[C@@H:20]([CH3:37])[CH2:19][CH2:18][CH2:17][CH:16]=[CH:15][CH2:14][C@@H:13](/[C:38](/[CH3:46])=[CH:39]/[C:40]2[N:41]=[C:42]([CH3:45])[S:43][CH:44]=2)[O:12][C:11](=[O:47])[CH2:10]1)(C(C)(C)C)(C)C>C1COCC1.C(Cl)Cl>[CH3:45][C:42]1[S:43][CH:44]=[C:40](/[CH:39]=[C:38](/[C@H:13]2[O:12][C:11](=[O:47])[CH2:10][C@H:9]([OH:8])[C:24]([CH3:26])([CH3:25])[C:23](=[O:27])[C@H:22]([CH3:28])[C@@H:21]([OH:29])[C@@H:20]([CH3:37])[CH2:19][CH2:18][CH2:17][CH:16]=[CH:15][CH2:14]2)\[CH3:46])[N:41]=1
Reactant: C/C(=C\c1csc(C)n1)[C@@H]1CC=CCCC[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C(=O)C(C)(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Agent: C/C(=C\c1csc(C)n1)[C@@H]1C/C=C\CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Agent: C/C(=C\c1csc(C)n1)[C@@H]1C/C=C\CCC[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C(=O)C(C)(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Solvent: ClCCl
Solvent: C1CCOC1
Product: C/C(=C\c1csc(C)n1)[C@@H]1CC=CCCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Temperature: 22 °C
Reaction time: 36 h

Procedure:
A solution of (4S,7R,8S,9S,16S,Z)-4,8-Bis((tert-butyldimethylsilyl)oxy)-5,5,7,9-tetramethyl-16-((E)-1-(2-methylthiazol-4-yl)prop-1-en-2-yl)oxacyclohexadec-13-ene-2,6-dione (26.2 mg, 37.1 μmol) in THF (3.6 ml) in a plastic vial was treated with HF-pyridine complex (70% HF, 1.09 mL). The reaction mixture was stirred at 22° C. for 36 h, diluted with DCM and quenched by NaHCO3 (sat.). The aqueous layer was extracted with DCM (2×). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. Purification on SiO2 (hexanes: diethyl ether 2:1 to 1:1) afforded 15.2 mg (81%, Z:E=95:5) of epothilone C as a colorless solid together with 2.6 mg of mono-desilylated product.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](OS(C2C=CC(C)=CC=2)(=O)=O)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]1([C:34]#[CH:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CCCCCCC.C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:35]#[C:34][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Oc2nn(Cc3ccccc3)c3ccccc23)cc1
Solvent: CCCCCCC
Solvent: ClCCl
Product: C(#Cc1nn(Cc2ccccc2)c2ccccc12)c1ccccc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 1-benzyl-1H-indazol-3-yl ester and phenylacetylene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/DCM 1:1; yield (9.25 mg, 6%); 1H NMR δ (CDCl3): 7.92 (d, J=7.92 Hz, 1H), 7.4-7.17 (m, 13H), 5.5 (s, 2H); LCMS m/z: 308.
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>CN(C=O)C>[F:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: Cc1c(F)c(F)cc(C(=O)O)c1F
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1c(F)c(F)cc(C(=O)Cl)c1F

Procedure:
A mixture of 2,4,5-trifluoro-3-methylbenzoic acid (6.0 g), thionyl chloride (26 ml) and DMF (0.01 ml) was refluxed for 4 hours. Then excess thionyl chloride was removed under reduced pressure, the resulting residue was distilled under reduced pressure to give the title compound (4.51 g) as pale yellow liquid, bp 90°-92° C./40 mmHg.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.[H-].[Na+].[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:12]=1[C:13](Cl)=[O:14]>CN(C=O)C>[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:12]=1[C:13]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1)=[O:14]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: Nc1ccncn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccncn1)c1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 9.9 %

Procedure:
4-aminopyrimidine (0.16 g, 1.72 mmol) was added to a cooled (0° C.) mixture of NaH (0.17 g, 4.25 mmol, 60% in mineral oil) in DMF (5 mL). The resulting mixture was stirred for 20 minutes under N2 at 0° C. and then 2,6-dichlorobenzoyl chloride (0.3 g, 1.43 mmol) was added dropwise. After one hour the reaction was poured into the ice-water (20 mL). The mixture was extracted with EtOAc (2×50 mL) and the combined organic extracts were concentrated under reduced pressue. The residue was purified by silica gel column chromatography (EtOAc/hexanes=1:1) to afford the desired product (38 mg, yield 10%). 1HNMR: (DMSO-d6, 400 MHz): 611.73 (s, 1H), 8.91 (s, 1H), 8.74 (d, J=5.6 Hz, 1H), 8.17 (d, J=5.6 Hz, 1H), 7.55-7.47 (m, 3H). LCMS (ESI) m/z: 267.8 [M+H+]
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH2:14][OH:15])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2].[C:16](OC(=O)C)(=[O:18])[CH3:17].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.C(OCC)(=O)C>[C:16]([O:15][CH2:14][CH2:13][N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CCN(CCO)c1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCN(CCOC(C)=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
To a flask containing 2-(ethyl-4-nitroanilino)-1-ethanol (4.2 g) and 4-dimethylaminopyridine (0.12 g) in pyridine (20 mL) at 0° C. under a drying tube is added acetic anhydride (5.0 mL) dropwise. The reaction mixture is allowed to warm to room temperature overnight. The reaction mixture is diluted with ethyl acetate and partioned against saturated aqueous sodium carbonate. The layers are separated and the aqueous phase extracted with two additional portions of ethyl acetate. The combined organic phases are washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue is azeotroped three times with toluene to remove residual pyridine. The residue is adsorbed onto silica and chromatographed on silica eluting with 50% ethyl acetate in heptane. The product-containing fractions are evaporated to give 4.9 g of 2-(ethyl-4-nitroanilino)ethyl acetate as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][N:6]1[C:11]2[NH:12][N:13]=[C:14]([NH:15][CH3:16])[C:10]=2[C:9](=[O:17])[N:8]([CH2:18][CH2:19][CH3:20])[C:7]1=[O:21].C(N(CC)CC)C.Cl[C:33]([O:35][CH3:36])=[O:34]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][N:6]1[C:11]2=[N:12][N:13]([C:33]([O:35][CH3:36])=[O:34])[C:14]([NH:15][CH3:16])=[C:10]2[C:9](=[O:17])[N:8]([CH2:18][CH2:19][CH3:20])[C:7]1=[O:21]
Reactant: CCCn1c(=O)c2c(NC)n[nH]c2n(Cc2cccc(Cl)c2)c1=O
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCCn1c(=O)c2c(NC)n(C(=O)OC)nc2n(Cc2cccc(Cl)c2)c1=O
Reaction time: 20 h
Yield: 86 %

Procedure:
To a mixture of 7-(3-chlorobenzyl)-3-methylamino-5-propylpyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (1.0 g, 2.9 mM) and triethylamine (1.2 ml, 8.6 mM) in dioxane (50 ml) was added dropwise methyl chloroformate (0.66 ml, 8.5 mM) at room temperature and the mixture was allowed to stir at the same temperature for 20 hours. The mixture was concentrated to dryness and the residue was triturated with water (10 ml). Recrystallization from chloroform/methanol gave colorless crystals (1.0 g, 86%), m.p. 164°-166° C.
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3C[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])[CH:5]=1.C1(C2C3C=CC=CC=3N(CC(C3CCCC3)=O)C(=O)N(CC(O)=O)N=2)CCCCC1.NC1C=C(N(C)[C:78]2[N:79]=[N:80][N:81]([CH2:83][O:84][C:85](=[O:90])[C:86]([CH3:89])([CH3:88])[CH3:87])[N:82]=2)C=CC=1.C1(C2C3C=CC=CC=3N(CC(=O)C(C)(C)C)C(=O)N(CC(O)=O)N=2)CCCCC1.COC(=O)C1C=CC=C(N)C=1>>[CH:20]1([C:18]2[C:17]3[CH:16]=[CH:29][CH:28]=[CH:27][C:26]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:33])([CH3:35])[CH3:34])[C:14](=[O:37])[N:13]([CH2:12][C:11]([NH:10][C:6]3[CH:5]=[C:4]([C:78]4[N:79]=[N:80][N:81]([CH2:83][O:84][C:85](=[O:90])[C:86]([CH3:88])([CH3:87])[CH3:89])[N:82]=4)[CH:9]=[CH:8][CH:7]=3)=[O:38])[N:19]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Reactant: CN(c1cccc(N)c1)c1nnn(COC(=O)C(C)(C)C)n1
Agent: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(C2CCCCC2)c2ccccc21
Agent: COC(=O)c1cccc(N)c1
Agent: O=C(O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C2CCCC2)C1=O
Product: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)Nc2cccc(-c3nnn(COC(=O)C(C)(C)C)n3)c2)N=C(C2CCCC2)c2ccccc21

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1), except that [5-cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 22, step a) and 2,2-dimethyl-propionic acid 5-[(3-amino-phenyl)-methyl-amino]-tetrazol-2-ylmethyl ester were used in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 1, step d) and 3-amino-benzoic acid methyl ester respectively in step e, followed by reaction of the product obtained, in place of 2,2-dimethyl-propionic acid 5-(3-{2-[5-cyclopentyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-phenyl)-tetrazol-2-ylmethyl ester (Example 10, step a), according to the method of Example 10, step b. 1H NMR (DMSO-d6) 9.85 (1H, s), 7.56-7.48 (3H, m), 7.30-7.20 (3H, m), 7.15 (1H, d), 7.06 (1H, d), 7.00 (1H, br m), 6.65 (1H, br m), 4.65 (2H, br m), 4.25 (1H, br d), 3.95 (1H, br d), 3.40 (3H, s), 3.05-2.85 (2H, m), 1.90-1.40 (9H, m), 1.40-0.95 (9H, m). The compound was further characterised as the N-methyl-D-glucamine salt. Found: C, 56.42; H, 7.05; N, 16.27%; C31H37N9O3.C7H17NO5.1.5CH3CO2H requires C, 56.67; H, 6.96; N, 16.12%.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH3:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4][N:3]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][N:26]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:24][C:25]1[N:26]=[CH:27][C:28]([S:31]([N:15]([CH3:16])[C:12]2[CH:13]=[CH:14][C:9]([CH2:8][N:6]3[CH2:5][CH2:4][N:3]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[C@@H:2]([CH3:1])[CH2:7]3)=[CH:10][CH:11]=2)(=[O:33])=[O:32])=[CH:29][CH:30]=1
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1CN(Cc2ccc(N(C)S(=O)(=O)c3ccc(Cl)nc3)cc2)CCN1C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
D3 (500 mg, 1.57 mmol) and 2-chloro-pyridine-5-sulfonyl chloride (330 mg, 1.57 mmol) were combined in DCM (10 mL) under Ar. Triethylamine (0.44 mL, 3.13 mmol) was added and the solution stirred overnight. The solution was diluted with DCM and washed with water. The water layer was re-extracted with DCM. The combined organic layers were washed with brine, dried and concentrated. The crude product was purified by column chromatography. Elution with 0-50% Et2O/petroleum ether yielded the product as a white foam (685 mg), δH (CDCl3, 400 MHz): 1.24 (3H, d), 1.46 (9H, s), 2.01 (1H, m), 2.16 (1H, m), 2.56 (1H, d), 2.73 (1H, d), 3.10 (1H, m), 3.22 (3H, s), 3.40-3.50 (2H, AB), 3.81 (1H, d), 4.20 (1H, br.s), 7.05 (2H, d), 7.31 (2H, d), 7.42 (1H, d), 7.74 (1H, dd), 8.54 (1H, d). MS (ES+): MH+ 495.1/497.1
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][NH2:13])[N:7]=1)=[O:5].C(N(CC)CC)C.C[O:22][C:23](=O)[N:24]=[C:25](SC)[C:26]([C:40]1[CH:45]=[C:44]([O:46][CH3:47])[CH:43]=[C:42]([O:48][CH2:49][CH2:50][F:51])[C:41]=1[F:52])=[N:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[N:38]=[C:37]([CH3:39])[O:36][N:35]=2)=[CH:30][CH:29]=1>CN(C=O)C>[CH3:2][O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]2[C:23](=[O:22])[NH:24][C:25]([CH:26]([C:40]3[CH:45]=[C:44]([O:46][CH3:47])[CH:43]=[C:42]([O:48][CH2:49][CH2:50][F:51])[C:41]=3[F:52])[NH:27][C:28]3[CH:29]=[CH:30][C:31]([C:34]4[N:38]=[C:37]([CH3:39])[O:36][N:35]=4)=[CH:32][CH:33]=3)=[N:13]2)[N:7]=1)=[O:5]
Reactant: COC(=O)c1cccc(NN)n1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(OCCF)c1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(-n2nc(C(Nc3ccc(-c4noc(C)n4)cc3)c3cc(OC)cc(OCCF)c3F)[nH]c2=O)n1
Temperature: 85 °C
Reaction time: 24 h

Procedure:
After adding 149 mg of 6-hydrazinopyridine-2-carboxylic acid methyl ester hydrochloride and 92 μl of triethylamine to a solution of 255 mg of {2-[2-fluoro-3-(2-fluoroethoxy)-5-methoxyphenyl]-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (Example (3e)) in 5 ml of DMF, the mixture was stirred at 85° C. for 24 hours under a nitrogen atmosphere.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].[C:12](Cl)([Cl:14])=[O:13].C(N(CC)C1C=CC=CC=1)C>C(OCC)(=O)C>[C:12]([Cl:14])(=[O:13])[O:11][C:8]1[CH:9]=[CH:10][C:5]([NH:1][C:2](=[O:3])[CH3:4])=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: CC(=O)Nc1ccc(O)cc1
Solvent: CCN(CC)c1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(OC(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
A solution of 4-acetominophenol (75.0 g), phosgene solution (450 mL, 20% in toluene), and ethyl acetate (1875 mL) was cooled to 0° C. N,N-Diethylaniline (94.7 mL) was added dropwise and the reaction was stirred at 0° C. for two hours. The reaction was then allowed to warm to room temperature. An aliquot for NMR analysis was taken four hours post addition. The reaction remained incomplete and was stirred at room temperature overnight. An-aliquot for NMR analysis after overnight stirring indicated no change had occurred in the reaction since the previous aliquot. The reaction was heated to 40° C. until phosgene gas evolution ceased (approximately 30 minutes). The reaction was cooled to room temperature and was then filtered. The filter cake was washed with ethyl acetate. NMR analysis of the filtered solid indicated it was N,N-diethylaniline related material. The filtrate was washed was washed with 0.1N HCl (375 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford a pale yellow solid. The solid was triturated using ether (375 mL) for twenty minutes at room temperature. The solid was filtered and washed with ether. NMR analysis indicated product with residual ether remaining. The solid was dried overnight in a vacuum oven at ambient temperature to afford 77.55 g (73.3% yield). NMR and MS analysis indicated product. 1H NMR (300 MHz, CDCl3+DMSO-d6): δ 9.18 (s, 1H), 7.62 (d, 2H), 7.15 (d, 2H), 2.18 (s, 3H); MS m/z: 214 (M+H)+.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([CH3:6])=[O:5].[F:7][C:8]1[CH:17]=[CH:16][C:11]([CH:12]=[CH:13][CH:14]=O)=[CH:10][CH:9]=1.Cl>O.C(O)C>[F:7][C:8]1[CH:17]=[CH:16][C:11]([CH:12]=[CH:13][CH:14]=[CH:3][C:4](=[O:5])[CH3:6])=[CH:10][CH:9]=1
Reactant: CC(C)=O
Reactant: O=CC=Cc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)C=CC=Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.3 %

Procedure:
Sodium hydroxide (2 g) in water (35 ml) was added to a stirred mixture of acetone (9.7 g) and ethanol (20 ml) cooled in a water bath. 4-Fluorocinnamaldehyde (5 g) was added dropwise to the stirred solution such that the temperature did not exceed 25°. The mixture was stirred at room temperature for 5 min, diluted with water (250 ml), adjusted to pH 1 with 5 M hydrochloric acid and extracted with ethyl acetate (3×100 ml). The combined extracts were washed with brine (1×100 ml), dried (MgSO4) and evaporated to give an orange oil (6.1 g) which was used crude in the next stage.