Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:9]1[N:17]=[C:16]2[C:12]([N:13]=[CH:14][N:15]2[OH:18])=[C:11]([O:19][CH3:20])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[CH2:29][CH2:30]/[CH:31]=[CH:32]/[P:33](=[O:42])([O:38][CH:39]([CH3:41])[CH3:40])[O:34][CH:35]([CH3:37])[CH3:36].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:24]([O:23][C:21]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]1[N:17]=[C:16]2[C:12]([N:13]=[CH:14][N:15]2[O:18][CH2:29][CH2:30]/[CH:31]=[CH:32]/[P:33]([O:38][CH:39]([CH3:40])[CH3:41])([O:34][CH:35]([CH3:36])[CH3:37])=[O:42])=[C:11]([O:19][CH3:20])[N:10]=1)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: COc1nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc2c1ncn2O
Reactant: CC(C)OP(=O)(/C=C/CCO)OC(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc2c1ncn2OCC/C=C/P(=O)(OC(C)C)OC(C)C
Temperature: 0 °C
Yield: 61.9 %

Procedure:
To a mixture of 2-[di-(t-butoxycarbonyl)]amino-9-hydroxy-6-methoxypurine (154 mg, 404 μmol), diisopropyl (E)-4-hydroxybut-1-enylphosphonate (89 mg, 404 μmol) and triphenylphosphine (159 mg, 606 μmol) in dry tetrahydrofuran (4 ml) stirred at 0° C. was added diethyl azodicarboxylate (105 mg, 606 μmol). The mixture was allowed to warm to room temperature and stirred for 2.3 hr. The solvent was removed and the residue was purified by column chromatography on silica gel eluting with ethyl acetate-methanol (20:1) to give (E)-2-[di-(t-butoxycarbonyl)]amino-9-[4-(diisopropoxyphosphoryl)but-3-enyloxy]-6-methoxypurine as a colourless gum (150 mg, 62%); λmax (EtOH) 255 (12,300)nm; υmax (KBr) 3440, 3220, 2975, 1790, 1600, 1370, 1280 and 1100 cm-1 ; δH [(CD3)2SO] 1.22 (12H, dd, J 6 Hz and 7 Hz, CH(CH3)2), 1.40 (18H, S, C(CH3)3), 2.70 (2H, m, CH2), 4.08 (3H, s, CH3O), 4.53 (4H, m, CH2O and CH(CH3)2), 5.98 (1H, dd, J 17 Hz and 19 Hz, PCH=CH), 6.25 (1H, ddt, J 6 Hz, 17 Hz and 22 Hz, PCH=CH), 8.71 (1H, s, 8-H) (Found: M+ 599.2724. C26H42N5O9P requires M+ 599.2720).
Reaction SMILES: C1(CO[C:9]([NH:11][CH:12]2[CH2:15][N:14]([C:16]([N:18]3[CH2:32][CH2:31][CH2:30][C@H:19]3[C:20]([O:22]CC3C=CC=CC=3)=[O:21])=[O:17])[C:13]2=[O:33])=[O:10])C=CC=CC=1.[C:34]1(C)[CH:39]=[CH:38][C:37](S(O)(=O)=O)=[CH:36][CH:35]=1.C(N(C(C)C)CC)(C)C.C(Cl)(=O)C1C=CC=CC=1>CN(C)C=O.[Pd].O>[C:9]([NH:11][C@H:12]1[CH2:15][N:14]([C:16]([N:18]2[CH2:32][CH2:31][CH2:30][C@H:19]2[C:20]([OH:22])=[O:21])=[O:17])[C:13]1=[O:33])(=[O:10])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(NC1CN(C(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)C1=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: O
Solvent: O=C(Cl)c1ccccc1
Product: O=C(N[C@H]1CN(C(=O)N2CCC[C@H]2C(=O)O)C1=O)c1ccccc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 27.1 %

Procedure:
A solution of (S)-1-[[3-[[(phenylmethoxy)carbonyl]amino]-2-oxo-1-azetidinyl]carbonyl]-L-proline, phenylmethyl ester (0.35 g, 0.78 mmole; prepared as described in examples 22 and 23) in 4.5 ml of dimethylformamide with 0.15 g (0.8 mmole) of p-toluenesulfonic acid and 0.2 g of 10% palladium on charcoal was hydrogenated at 1 atmosphere and 25° C. for 3 hours. The solution was chilled to 0° C. and treated with 0.3 g (2.3 mmoles) of diisopropylethylamine followed by 0.16 g (1.1 mmole) of benzoyl chloride, and stirred at 5° C. for 31/2 days. Water (10 ml) was added to the dimethylformamide solution and the slurry filtered on Celite. The pH was 3.35, and this was adjusted to 2.0 with dilute hydrochloric acid. The solution was extracted with ethyl acetate, saturated with solid sodium chloride and extracted again. The organics were dried (sodium sulfate) and evaporated to a yellow oil which showed one major component by TLC (Rf=0.56) with some less polar impurities. The oil was dissolved in dichloromethane and diluted to cloud with hexane. Scratching gave 70 mg of a white solid, melting point 148°-151° C.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:6][C:7]([C:10]([NH:12][C:13]([CH3:23])([C:18]3[N:19]=[N:20][NH:21][N:22]=3)[CH2:14][CH:15]3[CH2:17][CH2:16]3)=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[C:30](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([C:4]2[C:5]([O:24][CH2:25][C:26]([F:27])([F:28])[F:29])=[CH:6][C:7]([C:10]([NH:12][C:13]([C:18]3[N:19]([CH3:30])[N:20]=[N:21][N:22]=3)([CH3:23])[CH2:14][CH:15]3[CH2:17][CH2:16]3)=[O:11])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: CC(CC1CC1)(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)c1nn[nH]n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1nnnc1C(C)(CC1CC1)NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10.6 %

Procedure:
To a solution of 5-cyclopropyl-N-[2-cyclopropyl-1-methyl-1-(2H-tetrazol-5-yl)ethyl]-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxamide (example 150b, 100 mg, 0.244 mmol) in dry DMF (1.2 ml) was added potassium carbonate (43.8 mg, 0.317 mmol). The reaction mixture was stirred at room temperature for 10 minutes followed by addition of iodomethane (30.5 μl, 0.487 mmol). The reaction mixture was then stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and extracted with water and brine. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by preparative HPLC to yield the title compound (11 mg, 11%) and also a second by-product as the regioisomer (40 mg, 39%). MS (ESI, m/z): 425.5 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC(N)=O.[C:12](=[O:17])([O:14][CH2:15][CH3:16])N.N>CCCCCCCC([O-])=O.CCCCCCCC([O-])=O.[Zn+2].C(O)C>[CH2:15]([O:14][C:12](=[O:17])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:16]
Reactant: Nc1ccccc1
Reactant: CCOC(N)=O
Agent: CCCCCCCC(=O)[O-]
Agent: N
Agent: NC(N)=O
Solvent: CCO
Product: CCOC(=O)Nc1ccccc1
Temperature: 200 °C

Procedure:
931 g of aniline, 360 g of urea, 356 g of ethyl carbamate, 1160 g of ethanol (approximately 96%) and 5.3 g of zinc octoate were introduced into the pressure vessel. After the pressure vessel and the column had been purged with nitrogen, the mixture was heated while being stirred. By adjusting the head condenser and the valve at the head of the column, the pressure prevailing in the apparatus was regulated in such a way that it was just sufficient to achieve the required reaction temperature. The mixture was heated to 200° C. and maintained at 200° C. for 6.0 hours. The ammonia given off was rectified in the column and thus separated from covolatilizing substances. The ammonia gas removed was substantially pure. On completion of the reaction, the mixture was cooled and the apparatus vented. The reaction mixture was removed from the pressure vessel, filtered and subjected to fractional distillation. Most of the excess alcohol was initially separated off at atmospheric pressure. The mixture was then distilled at 0.2 mbar. 1435 g (96.9% of the theoretical yield) of N-phenyl carbamic acid ethyl ester having a melting point of from 50° to 51° C. were obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:5]2[N:6]([N:17]=[CH:18][N:19]=2)[C:7]([NH2:16])=[N:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:20][C:21]([CH3:26])([CH3:25])[C:22](Cl)=[O:23]>>[CH3:20][C:21]([CH3:26])([CH3:25])[C:22]([O:1][CH2:2][CH2:3][C:4]1[C:5]2[N:6]([N:17]=[CH:18][N:19]=2)[C:7]([NH2:16])=[N:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:23]
Reactant: Nc1nc(-c2ccccc2)c(CCO)c2ncnn12
Reactant: CC(C)(C)C(=O)Cl
Product: CC(C)(C)C(=O)OCCc1c(-c2ccccc2)nc(N)n2ncnc12

Procedure:
The title compound, m.p. 160°, was prepared by the method of Example 2 using 2.5 g (0.01 mole) of the product compound of Example 1 and 1.3 g (0.01 mole) of trimethylacetyl chloride, except that the reaction mixture was poured into 150 ml of water, giving a solid precipitate. Recrystallization from ethyl acetate/diethyl ether, rather than chromatography, afforded the title product.
Reaction SMILES: [CH2:1]([C@@:4]1([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].Br[C:36]1[S:37][CH:38]=[CH:39][N:40]=1.[O-]S([O-])(=O)=O.[Na+].[Na+].C1COCC1>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C@@:4]1([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:36]3[S:37][CH:38]=[CH:39][N:40]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(=O)O1
Reactant: Brc1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3nccs3)cc2)C(=O)O1
Temperature: 140 °C
Yield: 33 %

Procedure:
(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (20 mg, 0.043 mmol), 2-bromothiazole (14 mg, 2 equiv), 2M aq Na2SO4 solution (0.5 mL) and Pd(PPh3)2Cl2 were mixed with THF (0.6 mL) and heated in a microwave oven for 2 h at 140° C. LC-MS found reaction completed. The mixture was diluted with EtOAc (8 mL), washed with water (2 mL), 1% aq HCl (2 mL) and brine (1.5 mL). After concentration, the residue was purified by preparative HPLC to afford (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(thiazol-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (6.0 mg, 33%). LC-MS (3 min) tR=1.86 min, m/z=423 (M+1).
Reaction SMILES: [C:1]([O:6][C:7]1([CH3:20])[CH:14]2[CH2:15][C:10]3([C:17](O)=[O:18])[CH2:11][CH:12]([CH2:16][CH:8]1[CH2:9]3)[CH2:13]2)(=[O:5])[C:2]([CH3:4])=[CH2:3].C(Cl)(=O)C([Cl:24])=O>C1(C)C=CC=CC=1>[C:1]([O:6][C:7]1([CH3:20])[CH:14]2[CH2:15][C:10]3([C:17]([Cl:24])=[O:18])[CH2:11][CH:12]([CH2:16][CH:8]1[CH2:9]3)[CH2:13]2)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=C(C)C(=O)OC1(C)C2CC3CC1CC(C(=O)O)(C3)C2
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OC1(C)C2CC3CC1CC(C(=O)Cl)(C3)C2

Procedure:
In toluene solvent, 4-methacryloyloxy-4-methyladamantanecarboxylic acid was reacted with oxalyl chloride into a corresponding carboxylic acid chloride. To 1.8 g (6 mmol) of 4-methacryloyloxy-4-methyladamantanecarboxylic acid chloride thus obtained, 2.5 g (5 mmol) of triphenylsulfonium 2-hydroxy-1,1,3,3,3-pentafluoropropane-1-sulfonate (which was synthesized with reference to JP-A 2007-145803) and 20 g of methylene chloride were added, followed by ice cooling. To the solution, a solution of 0.7 g (7 mmol) of triethylamine and 0.06 g (0.5 mmol) of N,N-dimethylaminopyridine in 5 g of methylene chloride was added at such a rate that the temperature might not exceed 10° C., followed by stirring for 12 hours at room temperature. Thereafter, 10 g of 5% dilute hydrochloric acid solution was added to the reaction solution. The organic layer was taken out and washed with water, whereupon methylene chloride was distilled off in vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:20](=[CH:24][N:25]([CH2:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([OH:34])=O)=[CH:30][CH:29]=4)[N:26]=3)[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[CH3:37][O:38][CH2:39][CH2:40][NH2:41].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:20](=[CH:24][N:25]([CH2:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([NH:41][CH2:40][CH2:39][O:38][CH3:37])=[O:34])=[CH:30][CH:29]=4)[N:26]=3)[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: O=C(O)c1ccc(Cn2cc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3n2)cc1
Reactant: COCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCNC(=O)c1ccc(Cn2cc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3n2)cc1
Yield: 229.5 %

Procedure:
A solution of 4-{[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]methyl}benzoic acid (45 mg), 2-methoxyethylamine (9 mg), 1-hydroxybenzotriazole (18 mg), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (26 mg) and triethylamine (0.08 mL) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 30 hrs. After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (basic silica gel; ethyl acetate) to give the title compound (115 mg) as a pale-yellow solid.
Reaction SMILES: O.O.O.O.O.O.O.O.[OH-].[Ba+2:10].[OH-].[C:12]([OH:35])(=[O:34])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>O>[C:12]([O-:35])(=[O:34])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].[Ba+2:10].[C:12]([O-:35])(=[O:34])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)[O-]
Reaction time: 0.25 h

Procedure:
To 100 ml of water at 60° C. temperature 23.3 g of barium hydroxide octahydrate is added and into this suspension 50.0 g of behenic acid in flakes form (AN 165, titer 75° C.) is incorporated so that a paste is obtained having an acid/water ratio of 1:2. This paste is then reacted for 15 minutes at 60° C. followed by 15 minutes at 80° C. temperature. When the melting point of the fatty acid is exceeded, momentary viscosity increase takes place requiring vigorous mixing of the mass. The remaining water which has now a pH of 7 is decanted and the resultant granulate consisting of fractured hollow spheres is dried. The free fatty acid content of the end product is 1.3%.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:11].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.O>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]2[S:15][C:14]([CH3:24])=[N:13][C:12]=2[C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@H:8]([CH3:9])[C@@H:3]2[CH:2]=[O:1])=[O:11])=[CH:18][CH:19]=1
Reactant: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2CO)c(-c2ccc(F)cc2)s1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O
Product: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2C=O)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of rac-cis-(2-(hydroxymethyl)-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone in DCM was added Dess-Martin periodinane (1.5 eq) and stirred at rt for 4 h. The reaction mixture was transferred to a seperatory funnel, diluted with more DCM, water and the layers were separated. The organic layer was washed with brine, dried (MgSO4), and concentrated in vacuo to give a crude residue which was purified by chromatography on silica gel (EtOAc/hex) to afford the title compound. MS (ESI) 347.1 (M+H).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([N:16]2[CH:20]=[C:19]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[N:18]=[CH:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[F:50][C:51]1[CH:63]=[CH:62][C:54]([O:55][CH:56]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)=[CH:53][C:52]=1[C:64]([F:67])([F:66])[F:65]>CN(C=O)C.O>[F:50][C:51]1[CH:63]=[CH:62][C:54]([O:55][CH:56]2[CH2:61][CH2:60][N:59]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:19]3[N:18]=[CH:17][N:16]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH:20]=3)=[O:22])[CH2:58][CH2:57]2)=[CH:53][C:52]=1[C:64]([F:67])([F:65])[F:66]
Reactant: O=C(O)CNC(=O)c1cn(-c2ccccc2)cn1
Reactant: Fc1ccc(OC2CCNCC2)cc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2ccc(F)c(C(F)(F)F)c2)CC1)c1cn(-c2ccccc2)cn1
Reaction time: 0.03 h
Yield: 49 %

Procedure:
DIPEA (97 mg, 0.75 mmol) was added to a stirred solution of [(1-phenyl-1H-imidazole-4-carbonyl)-amino]-acetic acid (prepared from Intermediate 68 by means of Step 3 of the General Scheme) (61 mg, 0.25 mmol) in DMF (2 mL) followed by HOBt (35 mg, 0.26 mmol) and EDCI (50 mg, 0.26 mmol). After 2 minutes of stirring, 4-(4-fluoro-3-trifluoromethyl-phenoxy)-piperidine hydrochloride (prepared by the method used for the synthesis of Intermediate 15) (75 mg, 0.25 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated under reduced pressure. The residue obtained was purified by column chromatography (using silica gel 60-120 and 40% EtOAc in hexane as eluent) to afford 59.3 mg (49% Yield) of 1-phenyl-1H-imidazole-4-carboxylic acid {2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 491, 96%. 1H NMR (300 MHz, DMSO-d6): δ 8.4 (m, 1H), 8.3 (m, 1H), 8.05 (m, 1H), 7.75 (m, 2H), 7.55 (m, 2H), 7.4 (m, 4H), 4.8 (m, 1H), 4.2 (m, 2H), 3.9 (m, 1H), 3.6 (m, 1H), 3.4 (b, 1H), 3.3 (m, 1H), 2.0 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: O=[C:2]1[C:6]2[NH:7][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:9][C:5]=2[CH2:4][CH2:3]1.[F:15][C:16]1[CH:17]=[C:18]([Mg]Br)[CH:19]=[CH:20][C:21]=1[F:22]>>[F:15][C:16]1[CH:17]=[C:18]([CH:2]2[C:6]3[NH:7][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:9][C:5]=3[CH2:4][CH2:3]2)[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: Fc1ccc([Mg]Br)cc1F
Reactant: CCOC(=O)c1cc2c([nH]1)C(=O)CC2
Product: CCOC(=O)c1cc2c([nH]1)C(c1ccc(F)c(F)c1)CC2

Procedure:
The title compound was synthesized in two steps. First, ethyl 6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate was reacted with (3,4-difluorophenyl)magnesium bromide according to General Procedure 3. The resulting product was converted to the title compound by hydrogenation according to General Procedure 6.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.CO.C[O-].[Na+].[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:30][C:29]([C:31](Cl)=[O:32])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)([O-:19])=[O:18]>ClCCl>[N:6]12[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7]1)[CH:4]([NH:3][C:31]([C:29]1[O:30][C:26]([C:23]3[CH:22]=[CH:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:25][CH:24]=3)=[CH:27][CH:28]=1)=[O:32])[CH2:5]2
Reactant: O=C(Cl)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Reactant: NC1CN2CCC1CC2
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C(NC1CN2CCC1CC2)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1

Procedure:
A mixture of (±)3-aminoquinuclidine dihydrochloride, methanol (250 ml), sodium methoxide (5.1 g, 95 mmol) was stirred at reflux for 1 hour. The mixture was evaporated and was mixed with methanol (150 ml) and dichloromethane (100 ml) was added and cooled on ice, and 5-(4-nitrophenyl)-2-furoyl chloride (11.2 g, 44.5 mmol), solved in dichloromethane (200 ml) was added drop-wise at 0° C. The mixture was stirred at room temperature for 21 hours. The mixture was evaporated, water (200 ml) was added and the pH was adjusted to 8.5 with triethylamine. The mixture was extracted with ethyl acetate (3×200 ml) and the pure product was isolated as free base. Yield 5.0 g (33%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.O.C(=O)(O)[O-].[Na+].[IH:16]>>[I:16][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1
Reactant: I
Reactant: CSc1nccc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CSc1nccc(I)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 g (0.31 mole) of 4-chloro-2-methylthiopyrimidine is solubilised in 300 mL of hydriodic acid at room temperature. The reaction mixture is stirred at room temperature for 8 hours. The reaction mixture is poured into 1.2 L of water and the pH adjusted to 8 with solid sodium bicarbonate. The mixture is extracted with dichloromethane and washed with sodium thiosulfate. After concentration the oily residue gives 74 g of 4-iodo-2-methylthiopyrimidine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([CH2:21][OH:22])[CH:15]=1)[CH2:8][CH:9]([F:11])[F:10])([CH3:4])([CH3:3])[CH3:2]>CC#N.O=[Mn]=O>[C:1]([O:5][C:6](=[O:23])[N:7]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([CH:21]=[O:22])[CH:15]=1)[CH2:8][CH:9]([F:11])[F:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(Cl)c(CO)c1)CC(F)F
Agent: O=[Mn]=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(CCc1ccc(Cl)c(C=O)c1)CC(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.7 %

Procedure:
MnO2 (6.35 g, 65.7 mmol) was added to a sol. of [2-(4-chloro-3-hydroxymethyl-phenyl)-ethyl]-(2,2-difluoro-ethyl)-carbamic acid tert-butyl ester (4.60 g, 13.2 mmol) in CH3CN (133 mL). The mixture was stirred at rt for 4 h. The mixture was filtered over celite, and the precipitate was washed with CH3CN and CH2Cl2. The filtrate was evaporated under reduced pressure to yield to crude title compound (4.30 g, 94%) that was used further without purification. LC-MS: tR=1.06 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:34])[NH:12][C:13]1[C:14]([CH3:33])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=1)[CH3:9].Br[C:36]1[CH:41]=[CH:40][C:39]([CH:42]([CH2:46][CH3:47])[C:43]([OH:45])=[O:44])=[CH:38][CH:37]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11]([NH:12][C:13]1[C:14]([CH3:33])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:36]2[CH:41]=[CH:40][C:39]([CH:42]([CH2:46][CH3:47])[C:43]([OH:45])=[O:44])=[CH:38][CH:37]=2)=[CH:20][CH:19]=1)=[O:34])[CH3:9]
Reactant: Cc1noc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1NC(=O)O[C@H](C)c1ccccc1Cl
Reactant: CCC(C(=O)O)c1ccc(Br)cc1
Product: CCC(C(=O)O)c1ccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@H](C)c3ccccc3Cl)cc2)cc1

Procedure:
Prepared as described in Example 36, Step 6 using {3-methyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-isoxazol-4-yl}-carbamic acid (R)-1-(2-chloro-phenyl)-ethyl ester and 2-(4-bromophenyl)butanoic acid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([SH:9])[CH3:8].[CH2:10]([O:12][C:13]([C:15]1[C:16](Cl)=[N:17][C:18]2[C:23]([C:24]=1[CH3:25])=[CH:22][CH:21]=[C:20]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:19]=2)=[O:14])[CH3:11].CCCCCC>CN(C=O)C.O>[CH2:10]([O:12][C:13]([C:15]1[C:16]([S:9][CH2:7][CH3:8])=[N:17][C:18]2[C:23]([C:24]=1[CH3:25])=[CH:22][CH:21]=[C:20]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:19]=2)=[O:14])[CH3:11]
Reactant: CCOC(=O)c1c(Cl)nc2cc(C(C)(C)C)ccc2c1C
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(SCC)nc2cc(C(C)(C)C)ccc2c1C
Temperature: 60 °C
Reaction time: 16 h
Yield: 65.2 %

Procedure:
190 mg (1.38 mmol) K2CO3 and 100 μl (1.38 mmol) ethanethiol were added to a solution of 140 mg (0.46 mmol) 7-tert-butyl-2-chloro-4-methyl-quinoline-3-carboxylic acid ethyl ester in DMF (3 ml) and the mixture was stirred for 16 h at 60° C. Then it was diluted with water and extracted with EE. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 19:1) of the residue yielded 100 mg (0.30 mmol, 65%) 7-tert-butyl-2-ethylsulfanyl-4-methyl-quinoline-3-carboxylic acid ethyl ester.