Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[OH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][C:9]=1[C:24](OCC)=[O:25]>C1(C)C=CC=CC=1>[OH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:10][C:9]=1[C:24]([NH:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1)=[O:25]
Reactant: CCOC(=O)C1=C(O)c2ccccc2N(c2ccccc2)C1
Reactant: Nc1nccs1
Solvent: Cc1ccccc1
Product: O=C(Nc1nccs1)C1=C(O)c2ccccc2N(c2ccccc2)C1
Yield: 67.1 %

Procedure:
A solution of 4.08 g of 2-aminothiazole and 8.0 g of 1,2-dihydro-4-hydroxy-1-phenyl-3-quinolinecarboxylic acid, ethyl ester in 250 ml of toluene was refluxed for 30 hours in a soxhlet apparatus containing 10 g of 4 Å molecular sieves. Evaporation of the volatiles afforded a residue which was purified by means of high pressure liquid chromatography (silica gel: 1:25 ethyl acetate-dichloromethane as the eluent). The resultant solution was degassed and evaporated. Recrystallization of the residue from diethyl ether yielded 6.35 g (67%) of 1,2-dihydro-4-hydroxy-1-phenyl-N-(2-thiazolyl)-3-quinolinecarboxamide, m.p. 220° C. (dec.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:19]([OH:21])=O)[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([O:29][C:30](=[O:38])[CH2:31][CH2:32][C@H:33]([C:35](=[O:37])[NH2:36])[NH2:34])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[CH2:22]([O:29][C:30](=[O:38])[CH2:31][CH2:32][C@H:33]([C:35](=[O:37])[NH2:36])[NH:34][C:19](=[O:21])[C@H:9]([CH2:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: NC(=O)[C@H](N)CCC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)N[C@H](CCC(=O)OCc1ccccc1)C(N)=O
Reaction time: 15 h
Yield: 44.2 %

Procedure:
N-t-butyloxycarbonyl-O-benzyl-L-serine (4.43 g, 15 m mols) and D-isoglutamine benzyl ester (3.54 g, 15 m mols) were dissolved in acetonitrile (100 ml), and under ice-cooling, N,N'-dicyclohexylcarbodiimide (3.50 g, 17 m mols) was added. The mixture was stirred under ice-cooling for 3 hours and, then, at room temperature for 15 hours. The precipitate was filtered off, the solvent was distilled off and the residue was dissolved in ethyl acetate (100 ml). The solution was washed with 1 N-hydrochloric acid, 5% aqueous sodium hydrogen carbonate and water in the order mentioned and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was crystallized from ethyl acetate-petroleum ether. By the above procedure there was obtained 3.40 g of N-t-butyloxycarbonyl-O-benzyl-L-seryl-D-isoglutamine benzyl ester. m.p. 65°-66° C.; [α]D23 +5.7° (c=0.5, ethanol); Rf1 -0.73.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[O:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:14](O)=[O:15].CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1>C1COCC1>[CH:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[NH:7][C:6]3[C:14](=[O:15])[NH:1][C:2]4[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=4[O:4][C:5]=3[C:13]=12
Reactant: Nc1ccccc1Oc1c(C(=O)O)[nH]c2ccccc12
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2Oc2c1[nH]c1ccccc21
Reaction time: 18 h

Procedure:
A solution of 1.5 g of 3-[o-aminophenoxy]-indole-2-carboxylic acid in 50 ml of THF was treated with 1.48 g of EEDQ and the clear solution left 18 hours at ambient temperature. The THF was removed by distillation, and the residue was rubbed with 2 N HCl to give a yellow solid. Recrystallization from ethanol gave analytical material, mp. 233°-4°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.[CH3:36][O:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:36][O:37][C:38]1[CH:46]=[CH:45][C:41]([C:42]([O:1][CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13][CH:12]3[O:24][CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)=[CH:7][CH:6]=2)=[O:43])=[CH:40][CH:39]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)OCCOc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3OCc3ccc4ccccc4c3)cc2)cc1
Temperature: 0 °C
Yield: 54.1 %

Procedure:
A solution of 150 mg (0.314 mmol) of tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate, 3.7 mg (0.031 mmol, 0.1 eq.) of 4-dimethylaminopyridine, 65.9 mg (0.375 mmol, 1.2 eq.) of 4-methoxy-benzoyl chloride and 51.7 μl of triethylamine in 10 ml of methylene chloride was stirred at room temperature for 15 hours. This reaction solution was poured into 50 ml of an ice/water mixture and extracted three times with ethyl acetate. The organic phases were washed once with water and once with saturated sodium chloride solution, dried over magnesium sulphate, evaporated under reduced pressure and dried in a high vacuum. The crude product (208 mg) was separated on silica gel using a 95:5 mixture of hexane and acetone as the eluent. There were obtained 104 mg (51% of theory) of tert-butyl (3RS,4RS)-4-[4-[2-(4-methoxy-benzoyloxy)-ethoxy]-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 612 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][C@@H:27]2[CH2:31][CH2:30][NH:29][CH2:28]2)[N:10]=1.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[CH2:36]([O:35][C:33]([N:29]1[CH2:30][CH2:31][C@@H:27]([NH:26][C:11]2[N:10]=[C:9]([NH2:8])[C:14]([C:15](=[O:16])[C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[O:24][CH3:25])=[CH:13][N:12]=2)[CH2:28]1)=[O:34])[CH3:37]
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(F)cc1C(=O)c1cnc(N[C@@H]2CCNC2)nc1N
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CC[C@@H](Nc2ncc(C(=O)c3cc(F)ccc3OC)c(N)n2)C1

Procedure:
The same procedure as described in Example 60 was used, starting from (R)-[4-amino-2-(pyrrolidin-3-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 70, and ethyl chloroformate (Aldrich) to give (R)-3-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-pyrrolidine-1-carboxylic acid ethyl ester. MS (M+H)+, 404.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[N:16][C:8]=3[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:5]2=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)C.C(=O)(O)[O-].[Na+].[C:34]([O:38][C:39]([NH:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)=[O:40])([CH3:37])([CH3:36])[CH3:35]>C1(C)C=CC=CC=1>[C:20]1([C:3]2[N:4]=[C:5]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[NH:9][C:8]4[N:16]=[CH:17][CH:18]=[CH:19][C:7]=4[N:6]3[C:2]=2[C:46]2[CH:47]=[CH:48][C:43]([CH2:42][NH:41][C:39](=[O:40])[O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:44][CH:45]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(B(O)O)cc1
Reactant: Brc1c(-c2ccccc2)nc2n1-c1cccnc1Nc1ccccc1-2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCc1ccc(-c2c(-c3ccccc3)nc3n2-c2cccnc2Nc2ccccc2-3)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
To a suspension of 3-bromo-2-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepine (0.250 g, 1 eq.) in a mixture of toluene (5 mL), ethanol (5 mL), and saturated sodium bicarbonate (1 mL) was added (4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid (0.1 g, 1.5 eq.). The reaction was degassed (nitrogen) for 5 minutes and tetrakis(triphenylphosphine)palladium(0) added (0.025 g). The reaction was again degassed for 5 minutes and stirred at 100° C. overnight. The reaction mixture was cooled to room temperature and poured onto water (50 mL). The aqueous phase was extracted with dichloromethane (2×50 mL) and the organic extracts were combined and washed with water (1×50 mL), brine (1×50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (25-75% ethyl acetate in hexanes) gave the product which was triturated with ether to give tert-butyl 4-(2-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)benzylcarbamate (0.133 g, 40%). LCMS: 516 [M+H].
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:34]([O:41][C:42]([NH:44][CH2:45][CH2:46][CH2:47][C@@H:48]([C:57]([OH:59])=O)[NH:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[CH2:60]([O:67][C:68](=[O:91])[NH:69][CH2:70][CH2:71][CH2:72][C@H:73]([NH2:90])[C:74]([NH:76][CH2:77][CH2:78][NH:79][C:80]([O:82][CH2:83][C:84]1[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=1)=[O:81])=[O:75])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>CN(C=O)C>[CH2:34]([O:41][C:42]([NH:44][CH2:45][CH2:46][CH2:47][C@@H:48]([C:57]([NH:90][C@H:73]([C:74]([NH:76][CH2:77][CH2:78][NH:79][C:80]([O:82][CH2:83][C:84]1[CH:85]=[CH:86][CH:87]=[CH:88][CH:89]=1)=[O:81])=[O:75])[CH2:72][CH2:71][CH2:70][NH:69][C:68]([O:67][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:91])=[O:59])[NH:49][C:50]([O:52][C:53]([CH3:54])([CH3:55])[CH3:56])=[O:51])=[O:43])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)NCCNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)NCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
350 mg (0.92 mmol) of HATU and 330 mg (2.56 mmol) of N,N-diisopropylethylamine are added to a solution of 320 mg (0.88 mmol) of N5-[(benzyloxy)carbonyl]-N2-(tert-butoxycarbonyl)-L-ornithine and 350 mg (0.73 mmol) of benzyl{(4S)-4-amino-5-[(2-{[(benzyloxy)carbonyl]amino}ethyl)amino]-5-oxopentyl}carbamate (Example 122A) in 5 ml of anhydrous DMF at 0° C. The reaction mixture is stirred at RT for 15 h. The solvent is then evaporated and the residue is stirred with water, collected by filtration and dried under high vacuum.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>CCO>[Cl:1][C:2]1[N:7]=[C:6]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: C1CCNCC1
Solvent: CCO
Product: O=[N+]([O-])c1cnc(Cl)nc1N1CCCCC1

Procedure:
Method 1 was followed using 2,4-dichloro-5-nitropyrimidine (1.0 eq), and piperidine (2.0 eq) in EtOH at 0° C. to rt, yielding after washing with 1M citric acid and 1M HCl (to remove the bis addition product), 2-chloro-5-nitro-4-(piperidin-1-yl)pyrimidine (67%) LCMS (m/z): 242.9 (MH+); LC Rt=4.09 min.
Reaction SMILES: [CH2:1]([N:3](C(C)C)[CH:4](C)C)C.[C:10]([C:13]1[CH:14]=[C:15]([C:30]([OH:32])=O)[CH:16]=[C:17]2[C:22]=1[O:21][C:20]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[CH:19][C:18]2=[O:29])(=[O:12])[CH3:11].Cl.CNC>C(Cl)Cl>[C:10]([C:13]1[CH:14]=[C:15]([C:30]([N:3]([CH3:4])[CH3:1])=[O:32])[CH:16]=[C:17]2[C:22]=1[O:21][C:20]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[CH:19][C:18]2=[O:29])(=[O:12])[CH3:11]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(=O)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Agent: CNC
Agent: Cl
Solvent: ClCCl
Product: CC(=O)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 44.4 %

Procedure:
N-ethyl-N-isopropylpropan-2-amine (9.4 mL, 53.9 mmol) was added to 8-acetyl-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (5.7 g, 18 mmol) in DCM (100 mL). Five minutes later dimethylamine hydrochloride (2.9 g, 35.9 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (6.92 g, 21.6 mmol) were added. The mixture was diluted with DCM, washed with NaHCO3, dried over magnesium sulfate and concentrated to afford the crude product which was purified by flash chromatography on silica gel eluting with 0 to 5% MeOH/DCM. The solvent was evaporated to dryness to afford 8-acetyl-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (2.75 g, 46%) as a yellow solid. Mass Spectrum: M+H+ 345.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2]1.[Cl:14][C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=1[CH2:17]Cl.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.C(Cl)Cl>[CH3:13][O:12][C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]([CH2:17][C:16]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:15]=2[Cl:14])[N:2]=1)=[O:11]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1n[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: COC(=O)c1nn(Cc2ccc(Cl)cc2Cl)c2ccccc12
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Next, a mixture of methyl indazole-3-carboxylate (2.05 g, 11.4 mmol), 2,4-dichlorobenzyl chloride (3.35 mL, 12.54 mml), and K2CO3 (7.0 g, 50 mmol) in acetone (22 mL) was refluxed overnight at a temperature of 70° C. The reaction mixture was cooled to room temperature, filtered, and the residue was washed with acetone. The combined filtrate was concentrated under vacuum (rotovapor). The solid thus obtained was dissolved in CH2Cl2 and filtered to remove any undissolved solid. The solution was then concentrated, diluted with hexane and left in the refrigerator overnight. The precipitated solid was then filtered, washed with a mixture of hexane/ethyl acetate (9:1) to yield the pure product as a white solid. Yield=3.5 g (89%); m.p.=144°-146° C.; 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J=8.8 Hz, 1H), 7.39-7.47 (m, 4H), 7.12 (d, J=8.8 Hz, 1H), 6.71 (d, J=8.8 Hz, 1H), 5.81 (s, 2H), 4.11 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:16]([O-])=O.[Na+].[Sn](Cl)(Cl)(Cl)Cl>Cl.O>[CH2:1]([O:8][C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH:11][NH2:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: Nc1ccccc1OCc1ccccc1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccccc1OCc1ccccc1
Reaction time: 0.5 h

Procedure:
The 2-benzyloxyaniline (4.99 g, 25.0 mmol) partially dissolved in conc hydrochloric acid (15 mL) was cooled to less than 0° C. and a solution of the sodium nitrite (2.07 g, 30.0 mmol) in water (10 mL) was added dropwise. The reaction was stirred at the same temp for 30 min, when tin chloride (16.9 g, 75.0 mmol) in hydrochloric acid (10 mL) was added dropwise again keeping temp ca 0° C. The reaction was stored overnight in the fridge. The aqueous was decanted off the resulting black oily gum and triturated with sat NaCl (cf. 50 mL) and then ether:hexane 1:2 (50 mL) before neutralising with 10M NaOH (aq) with external cooling and extracted into ether (2×100 mL). The combined ether layers were washed with water (100 mL) dried (MgSO4) and evaporated to give a brown oil which crystallised on standing (4.52 g, 84%). Material was used crude without further purification.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[I-].[CH2:20]([N:27]([CH3:36])[C:28](N1C=C[N+](C)=C1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)(=O)C.CCCCCCC>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:28](=[O:29])[N:27]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:36])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CN(Cc1ccccc1)C(=O)n1cc[n+](C)c1
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CN(Cc1ccccc1)C(=O)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 3-(benzyl-methyl-carbamoyl)-1-methyl-3H-imidazol-1-ium iodide. The crude product was subjected to flash chromatography (ethyl acetate/heptane, (1:5) (69%, colourless oil) HPLC-MS m/z=403.2 (M+1), Rt: 5.11 min
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:13])=[N:11][CH:12]=1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>CN(C)C=O>[CH3:13][C:10]1[N:11]=[CH:12][C:7]([CH2:6][N:1]=[N+:2]=[N-:3])=[CH:8][CH:9]=1
Reactant: Cc1ccc(CCl)cn1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(CN=[N+]=[N-])cn1
Reaction time: 1 h
Yield: 69.7 %

Procedure:
NaN3 (11.2 g, 172 mmol) was added to a solution of the 5-(chloromethyl)-2-methylpyridine (12.2 g, 86.2 mmol) in dimethylformamide (120 ml) while cooling on ice and the mixture was stirred at the same temperature for 1 hour and then at room temperature for 2 hours. The reaction mixture was poured into semi-saturated aqueous sodium hydrogencarbonate, extraction was performed with ethyl acetate and the extract was washed with water and saturated aqueous NaCl. After drying with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (8.9 g, 26%, two steps) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5](=[O:20])[CH2:6][C:7]([C:10]1[C:18]2[O:17][CH2:16][O:15][C:14]=2[C:13]([Br:19])=[CH:12][CH:11]=1)([CH3:9])[CH3:8])[CH3:2].[F:22][C:23]([Si](C)(C)C)([F:25])[F:24].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[CH2:1]([O:3][C:4](=[O:21])[C:5]([OH:20])([C:23]([F:25])([F:24])[F:22])[CH2:6][C:7]([C:10]1[C:18]2[O:17][CH2:16][O:15][C:14]=2[C:13]([Br:19])=[CH:12][CH:11]=1)([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(=O)CC(C)(C)c1ccc(Br)c2c1OCO2
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(O)(CC(C)(C)c1ccc(Br)c2c1OCO2)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
300 mg of 4-(7-bromo-1,3-benzodioxol-4-yl)-4-methyl-2-oxo-valeric acid and 0.1 ml of sulfuric acid (96%) in 5 ml of ethanol are heated for 4 hours to 70° C. Then, the batch is concentrated by evaporation in a vacuum and added to water. It is extracted with ethyl acetate, washed with brine, dried and concentrated by evaporation in a vacuum. 272 mg of 4-(7-bromo-1,3-benzodioxol-4-yl)-4-methyl-2-oxo-valeric acid-ethyl ester is obtained as a yellow oil. This ester and 0.32 ml of trifluoromethyl-trimethylsilane in 4 ml of THF are mixed with 0.14 ml of a tetrabutylammonium fluoride solution (1 M in THF) at −70° C. It is stirred for 1 hour at −70° C., for 1.5 hours at −0° C., for 1 hour a and for 2 hours at room temperature. Another spatula-tip full of tetrabutylammonium fluoride is added, and after stirring is continued for 20 minutes, it is added to water. It is extracted with ethyl acetate, washed with water, dried with sodium sulfate and concentrated by evaporation in a vacuum. 297 mg of 4-(7-bromo-1,3-benzodioxol-4-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid-ethyl ester is obtained as a yellow oil. This oil is mixed in 5 ml of ether at 0° C. with 29 mg of lithium aluminum hydride, and stirred for 1 hour at 0° C. and for another 10 hours at room temperature. The batch is added to dilute hydrochloric acid, extracted with ethyl acetate, washed with water, dried with sodium sulfate and concentrated by evaporation in a vacuum. 164 mg of 4-(7-bromo-1,3-benzodioxol-4-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentan-1-ol is obtained as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH2:14][CH2:15]I)=[CH:9][CH:10]=2)[N:5]([CH:17]2[CH2:20][CH2:19][CH2:18]2)[C:4]=1[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][CH:31]([CH3:33])[CH3:32])=[O:29])=[CH:23][CH:22]=1)#[N:2].[NH:34]1[CH:38]=[N:37][CH:36]=[N:35]1.[Na]>CN(C=O)C>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH2:14][CH2:15][N:34]3[CH:38]=[N:37][CH:36]=[N:35]3)=[CH:9][CH:10]=2)[N:5]([CH:17]2[CH2:20][CH2:19][CH2:18]2)[C:4]=1[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][CH:31]([CH3:33])[CH3:32])=[O:29])=[CH:23][CH:22]=1)#[N:2]
Reactant: CC(C)NC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCCCI)cc3n2C2CCC2)cc1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(C)NC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCCCn4cncn4)cc3n2C2CCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To 1 mL of the DMF solution above, 1-{4-[3-cyano-1-cyclobutyl-6-(3-iodopropoxy)-1H-indol-2-yl]-phenyl}-3-isopropyl-urea (34 mg, 0.062 mmol) is added anhydrous 1,2,4-triazole, sodium salt (10.0 mg, 0.110 mmol). After stirring overnight at rt, the reaction mixture is filtered and purified by preparatory LC/UV purification. The solvent is removed to obtain 12.3 mg (40%) of 1-{4-[3-cyano-1-cyclobutyl-6-(3-[1,2,4]triazol-1-yl-propoxy)-1H-indol-2-yl]-phenyl}-3-isopropyl-urea (compound 1314), as a white powder.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36](F)(F)F)=[CH:31][CH:30]=3)=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:40](OC1C=CC(B(O)O)=CC=1)C>>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH3:40])=[CH:31][CH:30]=3)=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1ccc(B(O)O)cc1
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2-c2ccc(OC(F)(F)F)cc2)CC1
Product: CCOc1ccc(-c2c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc3cc([C@]4(C)COC(=O)N4)ccc23)cc1

Procedure:
(R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-ethoxyphenyl)naphthalen-2-yl)-4-methyloxazolidin-2-one was synthesized as per (R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-(trifluoromethoxy)phenyl)naphthalen-2-yl)-4-methyloxazolidin-2-one (Example 220) in 70% yield using 4-(ethoxy)phenylboronic acid as the reagent.