Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][NH:18][CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.C(N(CC)C(C)C)(C)C.Br[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[C:52]#[N:53])=[CH:42][CH:41]=1>CC#N>[NH2:53][CH2:52][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=1[C:43]1[CH:44]=[CH:45][C:40]([CH2:39][N:18]([CH2:17][C:9]2[NH:8][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=2)[CH:19]2[C:28]3[N:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:22][CH2:21][CH2:20]2)=[CH:41][CH:42]=1
Reactant: CC(C)(C)OC(=O)n1c(CNC2CCCc3cccnc32)nc2ccccc21
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: NCc1ccccc1-c1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Yield: 32.7 %

Procedure:
Using the general alkylation procedure: To a solution of (1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (0.194 g, 0.51 mmol) in CH3CN (5 mL) was added N,N-diisopropylethylamine (0.30 mL, 1.72 mmol) followed by 4′-bromomethyl-2-cyanobiphenyl (0.303 g, 1.11 mmol) and the resultant mixture heated to 60° C. for 25 h. Purification of the crude material by column chromatography on silica gel (10:1:1 CH2Cl2—CH3OH—NH4OH) followed by radial chromatography on silica gel (2 mm plate, 100:1:1 CH2Cl2—CH3OH—NH4OH) provided a tan foam (79 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][S:5]([CH2:8][CH2:9]Cl)(=[O:7])=[O:6].[O-][CH2:13]C.[Na+].[CH3:16][C:17]([C:20]1[CH:25]=[C:24]([SH:26])[CH:23]=[C:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:21]=1[OH:31])([CH3:19])[CH3:18]>>[CH2:1]([O:2][C:3](=[O:11])[CH2:4][S:5]([CH2:8][CH2:9][S:26][C:24]1[CH:23]=[C:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([OH:31])=[C:20]([C:17]([CH3:16])([CH3:18])[CH3:19])[CH:25]=1)(=[O:7])=[O:6])[CH3:13]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CC[O-]
Reactant: COC(=O)CS(=O)(=O)CCCl
Agent: [Na+]
Product: CCOC(=O)CS(=O)(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
The title compound was prepared according to the method of Example 12 from the title compound of Example 16, sodium ethoxide and 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol, m.p. ca. 95° C.
Reaction SMILES: [OH-].[K+].FC(F)(F)C([N:7]1[CH2:12][CH2:11][CH2:10][CH:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[CH2:8]1)=O.O>CO>[F:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][C:18]2[CH:17]=[CH:16][C:15]([CH2:14][O:13][CH:9]3[CH2:10][CH2:11][CH2:12][NH:7][CH2:8]3)=[CH:20][CH:19]=2)=[CH:23][CH:24]=1
Reactant: O=C(N1CCCC(OCc2ccc(Oc3ccc(F)cc3)cc2)C1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Fc1ccc(Oc2ccc(COC3CCCNC3)cc2)cc1
Yield: 95.6 %

Procedure:
A 1 mol/L aqueous potassium hydroxide solution (2 mL) was added to 1-trifluoroacetyl-3-[4-(4-fluorophenoxy)benzyloxy]piperidine (434 mg, 1.09 mmol) in methanol (4 mL). The mixture was refluxed for 2 hours and was allowed to cool. Water was then added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and the washed product was dried over magnesium sulfate. The solvent was evaporated to give 314 mg (95%) of the desired compound as a colorless oil.
Reaction SMILES: [CH:1]([N:4]([CH:25]([CH3:27])[CH3:26])[C:5](=[O:24])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([CH:21]=[O:22])=[CH:16][C:15]=2[Cl:23])=[CH:10][CH:9]=1)([CH3:3])[CH3:2].[O:28]1CCCC1.O.Cl([O-])=O.[Na+].NS(O)(=O)=O>C(OCC)(=O)C.O>[CH:25]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:24])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([OH:28])=[O:22])=[CH:16][C:15]=2[Cl:23])=[CH:12][CH:13]=1)([CH3:27])[CH3:26]
Reactant: CC(C)N(C(=O)COc1ccc(-c2c(Cl)cc(C=O)cc2Cl)cc1)C(C)C
Reactant: C1CCOC1
Agent: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)N(C(=O)COc1ccc(-c2c(Cl)cc(C(=O)O)cc2Cl)cc1)C(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
124 mg of the product of Stage E were mixed with 2 ml of tetrahydrofuran, 3.5 ml of water, 98 mg of sodium chlorite monohydrate and 87 mg of amidosulfonic acid and the mixture was stirred for 90 minutes at ambient temperature and evaporated under reduced pressure to obtain a residue which was obtained which is taken up in ethyl acetate. The organic phase was washed with IN sodium hydroxide, dried over magnesium sulfate and evaporated under reduced pressure to obtain 97.8 mg of the expected product with a Rf=0.26 (cyclohexane/ethyl acetate 8/2).
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: 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
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
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]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=1[F:21])=[CH:9][C:8]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[C:7]([O:30][CH3:31])[CH:6]=2.Cl[C:33](OC(Cl)(Cl)Cl)=[O:34].C([O-])([O-])=O.[Na+].[Na+].O>ClCCl.CCN(C(C)C)C(C)C>[CH2:23]([O:22][C:8]1[C:7]([O:30][CH3:31])=[CH:6][C:5]2[N:4]=[CH:3][C:2]3[NH:1][C:33](=[O:34])[N:12]([C:13]4[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=4[F:21])[C:11]=3[C:10]=2[CH:9]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1cc2ncc(N)c(Nc3ccc(C#N)cc3F)c2cc1OCc1ccccc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2ncc3[nH]c(=O)n(-c4ccc(C#N)cc4F)c3c2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
4-(3-Amino-6-benzyloxy-7-methoxyquinolin-4-ylamino)-3-fluorobenzonitrile (2.99 g, 7.2 mmol) was dissolved in dichloromethane (69 ml) together with Hünig's base (iPr2EtN, 1.43 ml). The solution obtained was subsequently added dropwise with ice-bath cooling to a mixture of trichloromethyl chloroformate (diphosgene, 938 μl, 7.72 mmol) and dichloromethane (42 ml). When the addition was complete, the mixture was stirred at room temperature for a further 30 min. Saturated Na2CO3 (30 ml) and water (170 ml) were subsequently added. After stirring for a further 30 min, the mixture was extracted twice with ethyl acetate (225 ml each time). The combined organic phases were washed once with water (150 ml), dried over Na2SO4, filtered and evaporated to dryness in vacuo. The residue was chromatographed over flash silica gel (solvent gradient ethyl acetate/0-17% by vol. of ethanol), giving 4-(8-benzyloxy-7-methoxy-2-oxo-2,3-dihydroimidazo[4,5-c]quinolin-1-yl)-3-fluorobenzonitrile (1.87 g, 4.3 mmol) as solid. MS: 441.1 (M+H+), TLC (HPTLC): Rf=0.44 (ethyl acetate/ethanol 8:1, parts by volume).
Reaction SMILES: F[C:2](F)(F)[C:3]([NH2:5])=[O:4].[NH:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)C(=O)C2)[CH2:10][CH2:9]1.[OH-].[K+]>CO.O>[O:4]=[C:3]1[CH2:2][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:8][CH2:9][CH2:10]2)[CH2:12][CH2:13][NH:5]1
Reactant: NC(=O)C(F)(F)F
Reactant: O=C1CC2(CCNCC2)c2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1CC2(CCN1)CCNc1ccccc12
Yield: 91.1 %

Procedure:
A solution of 49 mg (0.157 mmol) of the high RF material from Step B in methanol/water 4:1 with excess potasium hydroxide was stirred over night. The solution was concentrated and water and ethyl acetate were added to the residue. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to give 31 mg (0.143 mmol) of the title compound.
Reaction SMILES: [Mg].[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:13]S(C3C=CC=CC=3)(=O)=O)[CH2:12][O:11][CH2:10]2)=[CH:5][C:4]=1[OH:23].CCOCC>CO>[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH3:13])[CH2:10][O:11][CH2:12]2)=[CH:5][C:4]=1[OH:23]
Reactant: Cc1ccc(C2(CS(=O)(=O)c3ccccc3)COC2)cc1O
Agent: [Mg]
Solvent: CCOCC
Solvent: CO
Product: Cc1ccc(C2(C)COC2)cc1O
Reaction time: 0.03 h

Procedure:
Magnesium (granulate) (8.70 g, 358 mmol) was added to a solution of crude 2-methyl-5-(3-((phenylsulfonyl)methyl)oxetan-3-yl)phenol (7.6 g, 23.9 mmol) in MeOH (100 mL). The resulting mixture was stirred for 2 min in an ultrasound bath. The flask was then fitted with a condenser. Stirring was continued for 3 h, at which point the reaction mixture turned cloudy and off white in color. The reaction was exothermic, which caused the solvent to reflux. Water bath was added to lower the reaction mixture temperature to room temperature. The reaction mixture was then stirred overnight and became heterogeneous and pale orange in color. Et2O (525 mL) was added, followed by Na2SO4.10H2O (85 g). The resulting mixture was stirred for 2 h at room temperature and Celite® was then added. The resulting mixture was stirred for another 1 h and filtered through a Buchner funnel packed with Celite®. The cake was washed with EtOAc (2×) and MeOH (1×). The light yellow filtrate was concentrated and the residue was triturated with CHCl3 (220 mL) and filtered. The filtrate was concentrated to provide 2-methyl-5-(3-methyloxetan-3-yl)phenol. 1H NMR (400 MHz, CD2Cl2) δ ppm 7.14 (d, J=7.83 Hz, 1 H) 6.73 (d, J=7.58 Hz, 1 H) 6.69 (d, J=1.77 Hz, 1 H) 4.92 (d, J=5.31 Hz, 2 H) 4.61 (d, J=5.56 Hz, 2 H) 2.26 (s, 3 H) 1.72 (s, 3 H)
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].Cl.[NH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)(O)[O-].[Na+]>>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)CNc1nc(Cl)nc(Cl)n1

Procedure:
36.9 g of cyanuric chloride, 27.9 g of ethyl glycinate hydrochloride and 33.6 g of sodium bicarbonate were heated under reflux in 200 ml of dioxanefor 30 minutes. At the end of this time, the dioxane was removed by distillation under reduced pressure, and a mixture of ethyl acetate and water was added to the resulting residue, after which the mixture was shaken. The ethyl acetate layer was separated, dried and concentrated by evaporation under reduced pressure, and the resulting residue was recrystallized from a mixture of hexane and ethyl acetate, to yield 45.0 gof the title compound as crystals melting at 82° to 87° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[CH2:7][O:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12]O)([CH3:4])([CH3:3])[CH3:2].N1C(C)=CC(C)=CC=1C.[Cl-].[Li+].CS([Cl:30])(=O)=O>CN(C)C=O>[C:1]([O:5][C:6](=[O:14])[CH2:7][O:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][Cl:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)COC/C=C\CO
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: CC(C)(C)OC(=O)COC/C=C\CCl

Procedure:
To a solution of 420 mg of 2-[4-hydroxy-(Z)-2-buten-1-yloxy]acetic acid tert-butyl ester in 10 ml of N,N-dimethylformamide, 1.00 g of 2,4,6-collidine and 350 mg of lithium chloride were added. While stirring under ice cooling, 0.64 ml of methanesulfonyl chloride was added dropwise, followed by stirring at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate after adding iced water, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 350 mg of the desired compound as a colorless oily substance.
Reaction SMILES: N.[Na].[C:3]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH3:4].Cl[CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16]>O.[Na].C(O)(=O)C.CCOCC>[CH3:16][C:15]([CH3:17])=[CH:14][CH2:13][CH2:4][C:3](=[O:5])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CC(C)=CCCl
Reactant: CCOC(=O)CC(C)=O
Agent: N
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)CC(=O)CCC=C(C)C
Reaction time: 0.17 h
Yield: 38.4 %

Procedure:
A mixture of 1.4 g of ferric nitrate in 1200 ml of liquid ammonia was formed at -60° C. and was then stirred for 5 minutes after which 2 g of sodium were added thereto at -60° C. The mixture was stirred for 10 minutes and 104 g of sodium were added at -55±5° C. over 21/2 hours. The mixture was stirred at -55° C. for one hour. 300 g of ethyl acetylacetate were added thereto over 30 minutes at less than -30° C. 1000 ml of ether at -20° C. were added to the mixture which was then stirred for 5 minutes. 289 g of 1-chloro-3-methyl-2-butene were added over 30 minutes at less than -25° C. and the mixture stood at room temperature for 17 hours. 1000 ml of ether were progressively added at less than ±15° C. followed by a solution of 250 ml of acetic acid in 1000 ml of water. The decanted aqueous phase was extracted with ether and the combined organic phases were washed with 2 N hydrochloric acid, then with water, dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue was rectified under reduced pressure to obtain 175.5 g of ethyl 7-methyl-3-oxo-6-octenoate with a boiling point of 98° to 107° C. at 3 mmHg.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[C:9]([C:12]1[C:20]2[O:19][C:18]([S:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]([NH:33][C:34]4[C:39]([CH:40]([CH3:42])[CH3:41])=[CH:38][CH:37]=[CH:36][C:35]=4[CH:43]([CH3:45])[CH3:44])=[O:32])[CH2:26][CH2:25]3)=[N:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)(=[O:11])[CH3:10]>CN(C=O)C>[CH3:3][N:4]([CH3:6])[CH:5]=[CH:10][C:9]([C:12]1[C:20]2[O:19][C:18]([S:21][CH2:22][CH2:23][N:24]3[CH2:25][CH2:26][N:27]([CH2:30][C:31]([NH:33][C:34]4[C:35]([CH:43]([CH3:45])[CH3:44])=[CH:36][CH:37]=[CH:38][C:39]=4[CH:40]([CH3:41])[CH3:42])=[O:32])[CH2:28][CH2:29]3)=[N:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)=[O:11]
Reactant: CC(=O)c1cccc2nc(SCCN3CCN(CC(=O)Nc4c(C(C)C)cccc4C(C)C)CC3)oc12
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN1CCN(CCSc2nc3cccc(C(=O)C=CN(C)C)c3o2)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 106 %

Procedure:
Dimethylformamide dimethylacetal (146 mg, 1.2 mmol) was dropped into a solution of 2-[4-[2-(7-acetylbenzoxazol-2-ylthio)ethyl]piperazin-1-yl]-N-(2,6-diisopropylphenyl)acetamide (214 mg, 0.4 mmol) in DMF (15 ml), followed by stirring at 80° C. for 4 hours. The reaction solution was allowed to cool and extracted with ethyl acetate. The organic layer was washed with water and diluted hydrochloric acid solution successively and dried over sodium sulfate to provide 245 mg of crude 2-[4-[2-[7-(3-dimethylaminoacryloyl)benzoxazol-2-ylthio]ethyl]piperazin-1-yl]-N-(2,6-diisopropylphenyl)acetamide.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][C:15]2[C:23]3[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=3)[NH:17][C:16]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:9]=1)=[O:7])(=[O:4])=[O:3].[C:31](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O.O>[CH3:1][S:2]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][C:15]2[C:23]3[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=3)[N:17]([CH3:31])[C:16]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:9]=1)=[O:7])(=[O:3])=[O:4]
Reactant: Cc1ccc2c(Cc3cccc(C(=O)NS(C)(=O)=O)n3)c(-c3ccccc3)[nH]c2c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1ccc2c(Cc3cccc(C(=O)NS(C)(=O)=O)n3)c(-c3ccccc3)n(C)c2c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 37.1 %

Procedure:
To a solution of N-methanesulfonyl-6-(6-methyl-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carboxamide (100 mg) in N,N-dimethylformamide (1.2 mL) were added cesium carbonate (155 mg) and methyl iodide (0.023 mL), and this mixture was stirred at room temperature for 17 hours. The reaction mixture was diluted with water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (38.3 mg). 1H-NMR (DMSO-d6) δ ppm: 2.43 (3H, s), 3.38 (3H, s), 3.57 (3H, s), 4.21 (2H, s), 6.82-6.89 (1H, m), 7.24-7.33 (2H, m), 7.37 (1H, d, J=8.0 Hz), 7.43-7.58 (5H, m), 7.81-7.90 (2H, m), 10.90-11.55 (1H, br). ESI-MS (m/z): 434 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[Li]CCCC.[Cl:14][C:15]1[N:20]=[C:19](Cl)[CH:18]=[C:17]([C:22]2[C:27](F)=[CH:26][CH:25]=[CH:24][C:23]=2Cl)[N:16]=1.C(=O)(O)[O-].[Na+]>C1COCC1.C(Cl)(Cl)Cl.C(OCC)(=O)C>[Cl:14][C:15]1[N:20]=[C:19]([NH:1][C:2]2[CH:7]=[N:6][C:5]([Cl:8])=[CH:4][CH:3]=2)[CH:18]=[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:16]=1
Reactant: Fc1cccc(Cl)c1-c1cc(Cl)nc(Cl)n1
Reactant: Nc1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Clc1ccc(Nc2cc(-c3ccccc3)nc(Cl)n2)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Cooled a solution of 5-amino-2-chloropyridine (218.55 mg, 1.7 mmol) in dry THF (4.3 mL) in a dry-ice/acetone bath under nitrogen. The mixture was treated with a solution of nBuLi in hexanes (0.68 mL, 2.5M, 1.7 mmol) dropwise and stirred cold for 10 minutes. Allowed to warm to room temperature and ˜1.7 mL of the mixture was added dropwise to a solution of 2,4-dichloro-6-phenylpyrimidine (X) (190 mg, 0.844 mmol) in dry THF (2 mL). The mixture was stirred for 15 minutes and treated with an additional ˜0.3 mL of the lithium anilide solution and stirred for another 15 minutes. The reaction was poured into a mixture of saturated sodium bicarbonate and ethyl acetate. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organics was dried over magnesium sulfate, filtered and concentrated to yield a film. The film was taken up in chloroform and loaded onto 100 g of silica gel. The silica gel was eluted with ethyl acetate/hexanes (10%, 20%, 30%, 40%). The appropriate fractions were concentrated on a rotary evaporator to yield 2-chloro-N-(6-chloropyridin-3-yl)-6-phenylpyrimidin-4-amine (XII) as a film (41.15 mg). ESI/MS 317.0756, 319.0810 (M+H).
Reaction SMILES: [C:1]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:24][C:20]=3[C:21](O)=[O:22])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.Cl.[NH2:40][C@H:41]1[CH2:45][CH2:44][C@@H:43]([C:46]([O:48][CH3:49])=[O:47])[CH2:42]1>>[C:1]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:2]=[CH:3][C:4]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:24][C:20]=3[C:21]([NH:40][C@H:41]3[CH2:45][CH2:44][C@@H:43]([C:46]([O:48][CH3:49])=[O:47])[CH2:42]3)=[O:22])=[CH:13][CH:14]=2)=[CH:5][CH:6]=1
Reactant: COC(=O)[C@@H]1CC[C@H](N)C1
Reactant: CCOC(=O)c1ccc(OCCCc2ccc(OCc3ccc(-c4ccccc4)cc3)cc2)c(C(=O)O)c1
Agent: Cl
Product: CCOC(=O)c1ccc(OCCCc2ccc(OCc3ccc(-c4ccccc4)cc3)cc2)c(C(=O)N[C@H]2CC[C@@H](C(=O)OC)C2)c1

Procedure:
Preparation takes place in analogy to Example 5 from 2-{3-[4-(1,1′-biphenyl-4-yl-methoxy)phenyl]propoxy}-5-(ethoxycarbonyl)benzoic acid and methyl (1R,3S)-3-aminocyclopentanecarboxylate hydrochloride.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=O)=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Br:50][C:51]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH:54]=[C:53]([NH2:61])[N:52]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.O>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:2]=[CH:3][C:4]([CH2:7][C:8]([NH:61][C:53]2[N:52]=[C:51]([Br:50])[C:60]3[C:55]([CH:54]=2)=[CH:56][CH:57]=[CH:58][CH:59]=3)=[O:10])=[CH:5][CH:6]=1
Reactant: Nc1cc2ccccc2c(Br)n1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1ccc(-c2ccccc2)cc1)Nc1cc2ccccc2c(Br)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.7 %

Procedure:
To a solution of 4-biphenylacetic acid (1.0 g, 4.7 mmol) in 10 ml of anhydrous DMF was added HBTU (2.1 g, 5.7 mmol) and 1.0 ml of DIEA. The mixture was stirred at room temperature for 10 min, and then 1-bromo-3-isoquinolinamine (0.68 g, 4.7 mmol) was added. After stirring over night, the mixture was poured into water, acidified with 10% citric acid, and extracted with ethyl acetate. The organic extracts were washed with water and brine, dried over Na2SO4. After the condensation of the solvent, the residue was purified by flash column chromatography (SiO2, 1:1 hexane:ethyl aceate) to provide the title compound (1.7 g, 86%) as a light yellow solid.