Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[N:21]([CH3:46])[C:22]4[C:27]([N:28]=3)=[C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:25]=[C:24]([N:35]3[C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=5[N:37]=[C:36]3[CH2:44][CH3:45])[N:23]=4)[C:15]([CH3:48])([CH3:47])[CH2:14]2)=[O:12])[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1([C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[N:21]([CH3:46])[C:22]4[C:27]([N:28]=3)=[C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:25]=[C:24]([N:35]3[C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=5[N:37]=[C:36]3[CH2:44][CH3:45])[N:23]=4)[C:15]([CH3:47])([CH3:48])[CH2:14]2)=[O:12])[CH2:9][CH2:10]1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(=O)C4(NC(=O)OC(C)(C)C)CC4)CC3(C)C)n(C)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(=O)C4(N)CC4)CC3(C)C)n(C)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a solution of (1-{4-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]-3,3-dimethylpiperazine-1-carbonyl}cyclopropyl)carbamic acid tert-butyl ester in DCM (3 mL) was added TFA (2 mL) and the resulting mixture stirred at r.t. for 30 min then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, MeOH:DCM, 0-10%) affording 780 as a white foam (99 mg, 60%). LCMS (method I): RT 2.67 min, [M+H]+ 573.3. 1H NMR (CDCl3, 400 MHz): δ 8.02-8.01 (1 H, m), 7.76-7.75 (1 H, m), 7.32-7.22 (2 H, m), 4.34 (4 H, s), 3.93 (3 H, s), 3.88-3.86 (6 H, m), 3.65 (2 H, s), 3.48 (2 H, s), 3.36 (2 H, q, J=7.48 Hz), 2.57 (2 H, t, J=5.16 Hz), 1.85-1.75 (2 H, brd s), 1.45 (3 H, t, J=7.46 Hz), 1.23 (6 H, s), 1.05-0.99 (2 H, m), 0.81-0.80 (2 H, m)
Reaction SMILES: [C:1]1([NH2:8])[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([O:19]C)=[C:14]([CH:18]=1)[C:15](O)=O.[OH-].[K+]>>[NH:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=[C:15]1[C:14]1[CH:18]=[C:10]([Cl:9])[CH:11]=[CH:12][C:13]=1[OH:19]
Reactant: COc1ccc(Cl)cc1C(=O)O
Reactant: Nc1ccccc1N
Agent: [K+]
Agent: [OH-]
Product: Oc1ccc(Cl)cc1-c1nc2ccccc2[nH]1
Temperature: 200 °C
Reaction time: 5 h
Yield: 26.7 %

Procedure:
A mixture of benzene-1,2-diamine (500 mg, 4.6 mmol), 5-chloro-2-methoxy-benzoic acid (1.3 g, 6.9 mmol) in PPA (30 mL) was allowed to stir at 200° C. for 5 hours. The mixture was poured to ice and neutralized with KOH. The mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over Na2SO4. The organic phase was concentrated to provide 2-(1H-benzo[d]imidazol-2-yl)-4-chlorophenol (300 mg, yield: 27%). 1H-NMR (DMSO-d6, 400 MHz) δ 8.20 (d, J=2.5 Hz, 1H), 7.73˜7.70 (m, 2H), 7.44 (dd, J=8.8, 2.6 Hz, 1H), 7.34˜7.32 (m, 2H), 7.10 (d, J=8.8 Hz, 1H). MS (M+H)+: 245.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][CH:22]=[C:21]([C:24](O)=[O:25])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([NH:40][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[CH:8]=[C:9]([O:13][CH3:14])[C:10]([F:12])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:16]=3[NH:23][CH:22]=2)=[O:25])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1cc(-c2ncnc3c(C(=O)O)c[nH]c23)c(OCC2CC2)cc1F
Product: COc1cc(-c2ncnc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-(2-Cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A79) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: O=[C:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[CH2:8]([C:10]1([CH2:16][CH3:17])[CH2:12][CH:11]1[C:13]([NH2:15])=[O:14])[CH3:9].C1(C)C=CC=CC=1>O>[CH2:8]([C:10]1([CH2:16][CH3:17])[CH2:12][CH:11]1[C:13]([NH:15]/[C:2](=[CH:6]\[CH3:7])/[C:3]([OH:5])=[O:4])=[O:14])[CH3:9]
Reactant: CCC1(CC)CC1C(N)=O
Reactant: CCC(=O)C(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: C/C=C(\NC(=O)C1CC1(CC)CC)C(=O)O
Yield: 9.7 %

Procedure:
A mixture of 2.3 g of 2-ketobutyric acid, 2.0 g of 2,2-diethylcyclopropanecarboxamide, and 25 ml of toluene was heated under reflux for 16 hrs with removal of H2O by a modified Dean-Stark trap containing molecular sieves (4A). No product precipitated upon cooling. Ether (25 ml) was added and the mixture was extracted with saturated NaHCO3 (3 times). The combined extracts were acidified with concentrated HCl. The gummy precipitate crystallized when triturated with water. Recrystallization from ethyl acetate gave 0.31 g of product, m.p. 129°-30°. The NMR spectrum was consistent with the desired structure.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH2:11][CH2:12][CH:13]=O)=[CH:8][CH:9]=2)[CH2:4][O:3]1.[CH3:15][NH:16][CH2:17][CH2:18][OH:19]>>[OH:19][CH2:18][CH2:17][N:16]([CH3:15])[CH2:13][CH2:12][CH2:11][C:7]1[N:6]=[C:5]2[CH2:4][O:3][C:2](=[O:1])[C:10]2=[CH:9][CH:8]=1
Reactant: CNCCO
Reactant: O=CCCc1ccc2c(n1)COC2=O
Product: CN(CCO)CCCc1ccc2c(n1)COC2=O
Yield: 60.9 %

Procedure:
In a process similar to that described in Preparation 8, 3-(5-Oxo-5,7-dihydro-furo[3,4-b]pyridin-2-yl)-propionaldehyde (76 mg, 0.4 mmol) and 2-(methylamino)ethanol (32 μL, 0.4 mmol) are reacted to provide the title compound as an oil (61 mg, 61%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.[Cl:39][C:40]1[C:41]([C:50]([F:53])([F:52])[F:51])=[N:42][N:43]([CH2:46][C:47](O)=[O:48])[C:44]=1[CH3:45]>>[Cl:39][C:40]1[C:41]([C:50]([F:52])([F:51])[F:53])=[N:42][N:43]([CH2:46][C:47]([N:36]2[CH2:35][CH2:34][N:33]([C:27]3[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:26]=3[Cl:25])[CH2:38][CH2:37]2)=[O:48])[C:44]=1[CH3:45]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: Clc1ccc(N2CCNCC2)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(Cl)cc2Cl)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(2,4-Dichlorophenyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.56 (s, 1H), 7.36 (d, 1H), 7.15 (d, 1H), 5.37 (s, 2H), 3.61 (m, 4H), 3.01 (m, 2H), 2.94 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) M+H expect 455.0, found=454.9.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:11])([CH2:9][CH3:10])[C:4](=[O:8])[CH:5](Cl)[Cl:6].C.C(O)C>C(OCC)(=O)C.[Pd]>[ClH:6].[NH2:2][C:3]([CH3:11])([CH2:9][CH3:10])[C:4](=[O:8])[CH2:5][Cl:6]
Reactant: CCC(C)(N)C(=O)C(Cl)Cl
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCC(C)(N)C(=O)CCl
Reaction time: 3 h
Yield: 196.6 %

Procedure:
In a 2 L Parr bottle were placed 41 g of 3-amino-1,1-dichloro-3-methyl-2-pentanone hydrochloride, 0.8 g of 10% palladium over charcoal and 400 ml of ethanol (200 proof). The resulting mixture was shaken in a Parr apparatus at 50 psi for 3 hours. The crude reaction mixture was filtered through Celite™ filter agent and evaporated in vacuo. A viscous oil resulted, which was taken up in approximately 400 ml of ethyl acetate and stirred at room temperature for several hours. The expected 3-amino-1-chloro-3-methyl-2-pentanone hydrochloride crystallized as a white solid. To the resulting suspension were added 300 ml of hexane. Filtration yielded 34 g (98%) of the expected 3-amino-1-chloro-3-methyl-2-pentanone hydrochloride (Compound 14).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH:13]1[CH2:25]O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)(Cl)(Cl)Cl>[CH2:5]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH:13]1[CH2:25][Cl:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: ClCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 77 °C
Reaction time: 2 h

Procedure:
To the solution of thionyl chloride (1.63 ml, 22.4 mmol) in CCl4 (30 ml) was added the solution of (1,4-dibenzylpiperazin-2-yl)-methanol (2.74 g, 9.25 mmol) in CCl4 dropwise in 10 minutes. The produced suspension was stirred for 2 hours at 77° C. After cooled to room temperature, 20 ml of ice water was added and the aqueous layer was separated from the organic solvent. The PH of aqueous layer was adjusted to 12 with 4N NaOH aq., and extracted with CHCl3 three times. The combined organic layer was dried over MgSO4, and concentrated to give brownish oil which was purified by column chromatography on silica gel (CH2Cl2/MeOH=30/1) to give 1,4-dibenzyl-2-chloromethyl-piperazine in crude form (3.08 g, 95%, ca. 90% purity from HPLC analysis). The compound was used for next reaction without further purification: HPLC-MS (ESI): Calcd for C19H23ClN2[M+H]+ 315, found: 315.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[N:15]=[C:14]([OH:16])[C:13]([C:17]([OH:19])=O)=[CH:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1([CH:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[NH2:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:26]([NH:27][C:17]([C:13]1[C:14]([OH:16])=[N:15][C:10]([CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:11][CH:12]=1)=[O:19])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)c1cnc(COCc2ccccc2)nc1O
Reactant: NC(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NC(c1ccccc1)c1ccccc1)c1cnc(COCc2ccccc2)nc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
A mixture of step D product (2-e) (20.0 g, 76.9 mmol), diphenylmethanamine (15.5 g, 84.6 mmol), HATU (43.8 g, 115.0 mmol), and TEA (23.3 g, 230 mmol) in DMF (100 mL) were combined and stirred at the ambient temperature overnight. Ice-water (40 mL) was added to the reaction mixture and extracted with DCM (30 mL×2). The organic phase was concentrated to give a residue, which was purified by silica gel chromatography (eluented with PE/EA=3:1˜1:1) to a afford the product, 2-f, (31.0 g, 96%). 1H NMR (300 MHz, CD3OD): δ4.29 (s, 2H), 4.52 (s, 2H), 6.22 (s, 1H), 7.21-7.23 (m, 15H), 8.60 (s, 1H). LC-MS: (M+H)+ 426.
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.C(O)C.O.[NH2:23]N>C(O)(=O)C>[NH:1]([C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1)[NH2:23]
Reactant: NN
Reactant: NC1=Nc2ccccc2C(c2ccccc2)=NC1
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: NNC1=Nc2ccccc2C(c2ccccc2)=NC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2.35 parts of 2-amino-5-phenyl-3H-1,4-benzodiazepine, 50 parts by volume of ethanol and 1.2 parts by volume of glacial acetic acid is added 1.5 parts by volume of 100% hydrazine hydrate and the mixture is stirred for 1 hour at room temperature. Treatment of the mixture in a similar manner to Example 2 yields 2-hydrazino-5-phenyl-3H-1,4-benzodiazepine as white crystals. Recrystallization from a mixture of methylene chloride and benzene yields white crystals melting at 116° to 118° C. (effervescence).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][N:6]1[CH:11]=[CH:10][NH:9][C:8](=O)[C:7]1=[O:13])[CH3:2].P(Br)(Br)([Br:17])=O.C([O-])([O-])=O.[Na+].[Na+]>ClCCCl.O.ClCCl>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][N:6]1[CH:11]=[CH:10][N:9]=[C:8]([Br:17])[C:7]1=[O:13])[CH3:2]
Reactant: O=P(Br)(Br)Br
Reactant: CCOC(=O)Cn1cc[nH]c(=O)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O
Product: CCOC(=O)Cn1ccnc(Br)c1=O
Reaction time: 1 h

Procedure:
A solution of (2,3-dioxo-3,4-dihydro-2H-pyrazin-1-yl)-acetic acid ethyl ester (25.0 g, 126 mmol) and phosphorous oxybromide (37.9 g, 132 mmol) in 1,2-dichloroethane (250 mL) was heated to reflux. After 8 h the reaction mixture was treated with sat. aq. Na2CO3 (250 mL) and stirred for 1 h. The mixture was diluted with water (100 mL) and dichloromethane (100 mL), the layers were separated and the aqueous layer was backwashed with EtOAc (3×200 mL). The combined organics were dried (MgSO4), and concentrated to give an oil which was stored on a high vacuum line overnight to afford a brown solid. 1H NMR (CDCl3) δ 7.17 (d, 1H, 4.2 Hz), 7.07 (d, 1H, 4.2 Hz), 4.65 (s, 2H), 4.27 (q, 2H, 7.2 Hz), 1.31 (t, 3H, 7.2 Hz).
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[C:8]2[CH:9]=[C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17](O)=[O:18])[CH:11]=[CH:12][C:7]=2[NH:6][CH2:5][CH2:4][NH:3]1.F[B-](F)(F)F.[N:29]1(OC(N(C)C)=[N+](C)C)[C:33]2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CN.C1COCC1.Cl>ClCCl>[O:1]=[S:2]1(=[O:23])[C:8]2[CH:9]=[C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([NH:29][CH3:33])=[O:18])[CH:11]=[CH:12][C:7]=2[NH:6][CH2:5][CH2:4][NH:3]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1cccc(Oc2ccc3c(c2)S(=O)(=O)NCCN3)c1
Agent: CN
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)c1cccc(Oc2ccc3c(c2)S(=O)(=O)NCCN3)c1

Procedure:
The acid of Example 11 (0.66 mmol) is stirred overnight at ambient temperature in 50 ml of dichloromethane in the presence of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium tetrafluoroborate (0.80 mmol), diisopropylethylamine (0.80 mmol) and 2M methylamine solution in THF (1.32 mmol). The reaction mixture is then neutralised with 1N HCl solution, extracted with ethyl acetate, washed (saturated NaCl solution), dried (MgSO4), filtered and then evaporated under reduced pressure to yield, after triturating the residue in a dichloromethane/methanol mixture and filtering, the title product.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH2:8][C:9]([NH:11][C@H:12]([C:16]([NH:18][C@H:19]([C@H:79]([OH:81])[CH3:80])[CH2:20][NH:21][C@H:22]([C:26]([NH:28][C@@H:29]1[C:57](=[O:58])[NH:56][C@@H:55]([CH2:59][CH2:60][NH2:61])[C:53](=[O:54])[NH:52][C@H:51]([CH2:62][CH:63]([CH3:65])[CH3:64])[C:49](=[O:50])[NH:48][C@@H:47]([CH2:66][CH:67]([CH3:69])[CH3:68])[C:45](=[O:46])[NH:44][C@@H:43]([CH2:70][CH2:71][NH2:72])[C:41](=[O:42])[NH:40][C@@H:39]([CH2:73][CH2:74][NH2:75])[C:37](=[O:38])[NH:36][C@@H:35]([C@H:76]([OH:78])[CH3:77])[C:33](=[O:34])[NH:32][CH2:31][CH2:30]1)=[O:27])[CH2:23][CH2:24][NH2:25])=[O:17])[CH2:13][CH2:14][NH2:15])=[O:10])[CH3:4].C[C@@H](O)[C@@H]1NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC(=O)[C@@H](NC([C@@H](NC[C@H](NC([C@@H](NC(CCCCC(C)C)=O)CCN)=O)[C@H](O)C)CCN)=O)CCNC1=[O:86].C([O-])(=O)C.N>>[CH3:1][CH2:2][C@H:3]([CH2:5][CH2:6][CH2:7][CH2:8][C:9]([NH:11][C@H:12]([C:16]([NH:18][C@H:19]([C:20]([NH:21][C@H:22]([C:26]([NH:28][C@@H:29]1[C:57](=[O:58])[NH:56][C@@H:55]([CH2:59][CH2:60][NH2:61])[C:53](=[O:54])[NH:52][C@H:51]([CH2:62][CH:63]([CH3:65])[CH3:64])[C:49](=[O:50])[NH:48][C@@H:47]([CH2:66][CH:67]([CH3:69])[CH3:68])[C:45](=[O:46])[NH:44][C@@H:43]([CH2:70][CH2:71][NH2:72])[C:41](=[O:42])[NH:40][C@@H:39]([CH2:73][CH2:74][NH2:75])[C:37](=[O:38])[NH:36][C@@H:35]([C@H:76]([OH:78])[CH3:77])[C:33](=[O:34])[NH:32][CH2:31][CH2:30]1)=[O:27])[CH2:23][CH2:24][NH2:25])=[O:86])[C@H:79]([OH:81])[CH3:80])=[O:17])[CH2:13][CH2:14][NH2:15])=[O:10])[CH3:4]
Reactant: CCC(C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@@H](CN[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O)[C@@H](C)O
Reactant: CC(C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@@H](CN[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O)[C@@H](C)O
Agent: CC(=O)[O-]
Agent: N
Product: CC[C@@H](C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@H](C(=O)N[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O)[C@@H](C)O

Procedure:
The salt content in the colistin acetate solution from reverse osmosis is adjusted to approx. 200 mM by adding (NH4)2SO4 and pH is adjusted to approx. 7 with diluted ammonia. The concentration of the colistin acetate solution is 15-20 g/l. The solution is passed through the HIC column, flow 950-1050 ml/min. Elution proceeds with 10 times bed volume. Collection of effluent fractions is made automatically by PLC. Samples are drawn from each fraction and analyzed. Fractions complying with pre-set specifications are pooled, yielding a batch with a purity of 94-98% with regards to polymyxin E1. Concentration of polymyxin E1 and removal of ammonium sulphate is performed by ultra filtration to a concentration of 10-20 g/l.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH2:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[N:14]1([CH2:20][C:21]2[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=2)[O:24][CH2:25][CH2:26][CH2:27][C:28](O)=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.Cl.C(O)(=O)CCC.N>O>[CH2:8]([O:7][C:5]([C:4]1[CH:10]=[CH:11][C:12]2[N:13]=[C:28]([CH2:27][CH2:26][CH2:25][O:24][C:23]3[CH:31]=[CH:32][CH:33]=[C:21]([CH2:20][N:14]4[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)[CH:22]=3)[NH:1][C:2]=2[CH:3]=1)=[O:6])[CH3:9]
Reactant: O=C(O)CCCOc1cccc(CN2CCCCC2)c1
Reactant: CCOC(=O)c1ccc(N)c(N)c1
Agent: Cl
Agent: N
Solvent: O
Solvent: CCCC(=O)O
Product: CCOC(=O)c1ccc2nc(CCCOc3cccc(CN4CCCCC4)c3)[nH]c2c1

Procedure:
A mixture of ethyl 3,4-diaminobenzoate (0.9 g), 4-(3-piperidinomethylphenoxy)butyric acid (2.1 g) prepared as described in Example 42 and 4N hydrochloric acid (6 ml) was heated and stirred under reflux for 90 minutes. A further portion of the butyric acid (2.1 g) and of 4N hydrochloric acid (6 ml) was added and the mixture heated under reflux for 90 minutes. The reaction mixture was cooled and poured into water (10 volumes). Aqueous ammonia (S.G. 0.880) was added until the solution was alkaline and the mixture was extracted with ethyl acetate. The extracts were washed with water, dried and on removal of the solvent gave a residue which was purified by preparative layer chromatography on silica gel plates using a 1:1 mixture of dichloromethane and methanol to give 5-ethoxycarbonyl-2-[3-(3-piperidinomethylphenoxy)propyl]benzimidazole as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[NH:8][CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[CH:18]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:25][C:26]1[C:30](B(O)O)=[C:29]([CH3:34])[O:28][N:27]=1>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:25][C:26]1[C:30]([C:2]2[CH:3]=[CH:4][C:5]3[O:10][C:9](=[O:11])[NH:8][CH:7]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:6]=3[CH:18]=2)=[C:29]([CH3:34])[O:28][N:27]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: O=C1NC(c2ccccc2)c2cc(Br)ccc2O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: Cc1noc(C)c1-c1ccc2c(c1)C(c1ccccc1)NC(=O)O2
Temperature: 100 °C

Procedure:
To a solution of 6-Bromo-4-phenyl-3,4-dihydro-benzo[e][1,3]oxazin-2-one (90 mg, 0.296 mmol) in 1,2-dimethoxyethane (3 mL) is added saturated Na2CO3 in water (3 mL), 3,5-dimethylisoxazole-4-boronic acid (90 mg, 0.607 mmol) and Pd(dppf)Cl2 (13.5 mg, 0.016 mml) The mixture is refluxed at 100° C. overnight.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[H-].[Na+].Cl[C:9]1[CH:14]=[C:13]([Cl:15])[N:12]=[C:11]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:10]=1.[OH-].[Na+].Cl>C1COCC1.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>[Cl:15][C:13]1[N:12]=[C:11]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:10]=[C:9]([CH:2]([C:1]#[N:5])[C:3]#[N:4])[CH:14]=1
Reactant: N#CCC#N
Reactant: Clc1cc(Cl)nc(N2CCOCC2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: N#CC(C#N)c1cc(Cl)nc(N2CCOCC2)n1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 111.4 %

Procedure:
To a solution of malononitrile (277 mg, 4.2 mmol) in THF cooled to 0° C., sodium hydride (189 mg, 4.7 mmol) was added. When the evolution of gas ceased, 4,6-dichloro-2-morpholinopyrimidine (1aa) (500 mg, 2.1 mmol) was added to the reaction mixture, followed by Pd(PPh3)4. The resulting suspension was refluxed at 80° C. overnight. The mixture was treated with aq. 2M NaOH (10 mL) and stirred for 15 min. The organic layer was discharged and the aqueous was acidified with aq. 2M HCl and extracted with ethyl acetate, yielding 2-(6-chloro-2-morpholinopyrimidin-4-yl)malononitrile (2aa) (617 mg) after drying and solvent evaporation.
Reaction SMILES: [OH-].[Na+].F[C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][I:12])=[O:9])=[CH:6][CH:5]=1>O.[N+]([O-])([O-])=O.[Ag+]>[C:8]([O:10][CH2:11][I:12])(=[O:9])[C:7]1[CH:13]=[CH:14][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OCI)c1ccc(F)cc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(OCI)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Synthesis of pentachlorophenyl (E)-3-[4-[bis(4-fluorobenzoyloxymethoxyphosphinyl)difluoromethyl]phenyl]-but-2-enoate (6b1 R1=4-Fluorobenzoyloxymethyl) NaOH (80 mg, 2.0 mmol) in 2 mL of H2O was added dropwise to a stirred suspension of pentachlorophenyl (E)-3-(4-phosphonyldifluoromethyphenyl) but-2-enoate (500 mg, 0.92 mmol) in 5 mL of H2O. When the mixture became clear (pH˜9), AgNO3 (510 mg, 3.0 mmol) was added. After 2 h at 4° C. the gray precipitate was collected by filtration, dried over P2O5 in vacuo, and pulverized in a mortar and pestle. The powder (400 mg) was suspended in dry toluene (10 mL) and iodomethyl 4-fluorobenzoate (290 mg, 1.03 mmol) was added and stirred for 48 h at room temperature. After filtration the solvent was removed in vacuo and the crude product was purified by silica gel column chromatography eluting with 30% EtOAc-hexanes to give colorless oil. Yield 290 mg, (61%). 1H NMR (300 MHz, CDCl3): δ 2.49 (s, 3H), 5.87 (m, 4H), 6.3 (s, 1H), 7.01 (m, 4H), 7.45 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.94 (m, 4H). 13C NMR (75 MHz, CDCl3): δ 18.3, 82.5, 82.8, 115.0, 115.7, 116.1, 124.5, 126.7, 127.9, 131.4, 132.0, 132.7, 132.9, 144.2, 161.6, 163.6, 164.7, 168.1. HRMS (M+H) calc, 844.9272; found, 844.9278.