Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([O:10][CH:11]([F:13])[F:12])[N:7]([CH3:14])[N:6]=1)=O.[NH3:15]>>[C:3]([C:5]1[CH:9]=[C:8]([O:10][CH:11]([F:13])[F:12])[N:7]([CH3:14])[N:6]=1)(=[O:2])[NH2:15]
Reactant: COC(=O)c1cc(OC(F)F)n(C)n1
Reactant: N
Product: Cn1nc(C(N)=O)cc1OC(F)F

Procedure:
80.6 g (0.39 mole) 3-Methoxycarbonyl-5-difluoromethoxy-1-methylpyrazole and 300 ml aqueous ammonia (33%) was stirred under reflux for 1 hour. The reaction solution was cooled, the precipitate filtered off and washed with water and diisopropyl ether.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=O)[CH2:11][C@H:10]2[CH2:15][C:16]([O:18][CH3:19])=[O:17])=[O:8])=[CH:3][CH:2]=1.[CH3:26][O:27][NH3+:28].[Cl-].C(N(CC)CC)C>C(Cl)(Cl)Cl.ClCCl>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:28][O:27][CH3:26])[CH2:11][C@H:10]2[CH2:15][C:16]([O:18][CH3:19])=[O:17])=[O:8])=[CH:3][CH:2]=1
Reactant: CO[NH3+]
Reactant: COC(=O)C[C@@H]1CC(=O)CN1C(=O)c1ccc(-c2ccccc2)cc1
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON=C1C[C@@H](CC(=O)OC)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 84 %

Procedure:
A solution of methyl [(2S)-1-(biphenyl-4-ylcarbonyl)-4-oxopyrrolidin-2-yl]acetate (43 mg, 0.13 mmol), hydroxylamine methyl ether hydrochloride (32 mg, 0.38 mmol) and triethylamine (53 μl, 0.38 mmol) in chloroforme (3 ml) was stirred at 70° C. for 5 days. The reaction mixture was diluted with dichloromethane and washed with HCl 1N. The organic phase was dried (MgSO4) and concentrated to afford methyl [(2S,4EZ)-1-(biphenyl-4-yl-carbonyl)--4-(methoxyimino)pyrrolidin-2-yl]acetate (40 mg). Yield: 62%. HPLC purity: 94%
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[N:6][CH:5]=[CH:4][N:3]=1.[C:10]([O:14][CH3:15])(=[O:13])[CH2:11][OH:12].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[C:10]([C:11]1[O:12][C:2]2[N:3]=[CH:4][CH2:5][NH:6][C:7]=2[C:8]=1[NH2:9])([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CO
Reactant: N#Cc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1oc2c(c1N)NCC=N2
Yield: 31.4 %

Procedure:
2-Chloro-3-cyanopyrazine (0.751 g, 5.38 mmol) was treated with methyl glycolate (0.533 g, 5.92 mmol) and potassium carbonate (1.12 g, 8.07 mmol) in 20 ml DMF as described in Example 85A. Column chromatograhpy on silica gel eluting with 1:1 hexanes:ethyl acetate gave the title compound (0.33 g, 32%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ4.02 (s, 3H), 5.29 (br s, 2H), 8.47 (d, 1H), 8.56 (d, 1H). MS (DCI/NH3) m/e 194 (M+H)+, 211 (M+NH4)+.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:17]=[C:16]([CH2:18][CH:19]([CH3:21])[CH3:20])[S:15][C:14]=3[S:22]([NH:25]C(C)(C)C)(=[O:24])=[O:23])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.B(Cl)(Cl)Cl.O>C(Cl)Cl>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:17]=[C:16]([CH2:18][CH:19]([CH3:21])[CH3:20])[S:15][C:14]=3[S:22]([NH2:25])(=[O:24])=[O:23])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)Cc1cc(-c2ccc(Cn3ccnc3)cc2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)Cc1cc(-c2ccc(Cn3ccnc3)cc2)c(S(N)(=O)=O)s1
Reaction time: 0.5 h

Procedure:
To a solution of 3-(4-imidazol-1-ylmethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (0.097 mmol, 42.0 mg, see step (b) above) in CH2Cl2 (10 mL) was added BCl3 (0.5 mL, 1M, 0.5 mmol) under N2 (g). The mixture was stirred for 0.5 h. Water (50 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with brine and dried over MgSO4 and the solvent was removed in vacuo. The crude product was used directly in the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][S:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[NH:27][C:28](=[NH:33])[CH2:29][CH2:30][O:31][CH3:32]>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH:11]([C:23]3[O:25][N:33]=[C:28]([CH2:29][CH2:30][O:31][CH3:32])[N:27]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][S:20][CH2:21][CH2:22]3)=[O:16])[CH2:14]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCSCC3)C2)cc1
Reactant: COCCC(=N)NO
Product: CCc1ccc(C2CC(c3nc(CCOC)no3)CN(C(=O)N3CCSCC3)C2)cc1

Procedure:
According to General Method 6A, 300 mg (0.828 mmol) of the compound from Example 7A and 134 mg (0.910 mmol) of N-hydroxy-3-methoxypropanimidamide were reacted Yield: 185 mg (49% of theory)
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Br.BrCC1OC(C(F)(F)F)=CC=1.[F:24][C:25]1[C:30]([C:31]#[N:32])=[CH:29][C:28]2[C:33]3([CH2:43][O:44][C:27]=2[CH:26]=1)[C:41]1[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=1)[NH:35][C:34]3=[O:42].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1>>[F:24][C:25]1[C:30]([C:31]#[N:32])=[CH:29][C:28]2[C:33]3([CH2:43][O:44][C:27]=2[CH:26]=1)[C:41]1[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=1)[N:35]([CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[C:2]([F:12])([F:11])[F:1])[C:34]3=[O:42]
Reactant: N#Cc1cc2c(cc1F)OCC21C(=O)Nc2ccccc21
Reactant: FC(F)(F)c1ccccc1CBr
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: N#Cc1cc2c(cc1F)OCC21C(=O)N(Cc2ccccc2C(F)(F)F)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 2-(trifluoromethyl)benzyl bromide to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, and 6-fluoro-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, 6-fluoro-2′-oxo-1′-[2-(trifluoromethyl)benzyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile was obtained (55%): mp 193-195° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.76-7.73 (m, 1H), 7.53-7.39 (m, 2H), 7.27-7.22 (m, 1H), 7.17-7.07 (m, 3H), 7.01-6.99 (m, 1H), 6.82-6.79 (m, 1H), 6.70-6.67 (m, 1H), 5.27-5.09 (m, 3H), 4.90-4.87 (m, 1H); MS (ES+) m/z 419.0 (M−19).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[S:8][CH2:7]1.[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[Br-]>C(OCC)(=O)C.CO.C(Cl)Cl.C(#N)C>[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[N:23]1[CH2:24][CH2:25][N:26]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[S:8][CH2:7]2)[CH2:27][CH2:28]1
Reactant: c1ccc2sc(N3CCNCC3)nc2c1
Reactant: CC1(C)SCN(CCCCBr)C1=O
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [I-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1(C)SCN(CCCCN2CCN(c3nc4ccccc4s3)CC2)C1=O
Temperature: 65 °C
Reaction time: 19 h
Yield: 77.9 %

Procedure:
A mixture of 3-(4-bromobutyl)-5,5-dimethyl-4-thiazolidinone (3.42 g), 1-(2-benzothiazolyl)piperazine (3.10 g), K2CO3 (6.19 g), NaI (250 mg) and acetonitrile was heated at 65° C. (bath temperature) under nitrogen. After 19 hours, TLC analysis (5% methanol/methylene chloride) showed the absence of starting bromide and the presence of a major product, Rf=0.29. The reaction mixture was cooled to room temperature, ethyl acetate the (100 ml) was added and the mixture filtered. The filtrate was concentrated in vacuo to a solid which was redissolved in hot ethyl acetate causing a solid to precipitate. The mixture was filtered and the filtrate concentrated in vacuo to an off-white solid. Chromatography of the crude product by HPLC (Waters Prep 500, one silica gel column, 5% methanol/methylene chloride) yielded 4.05 g of a solid, mp 99.5-100.5° C. It was recrystallized from methylene chloride/hexane to give 2.83 g of fine needles, mp 101-102° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[CH3:21].[CH3:22][O:23][C:24](OC)([O:29]C)[CH2:25][CH2:26][CH2:27]Br>O1CCCC1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[CH2:21][CH2:27][CH2:26][CH2:25][C:24]([O:23][CH3:22])=[O:29]
Reactant: Cc1cc(Cl)ccc1Cl
Reactant: COC(CCCBr)(OC)OC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)CCCCc1cc(Cl)ccc1Cl
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Diisopropylamine (841 ul, 6 mmol) was added to 20 ml of tetrahydrofuran under nitrogen atmosphere and cooled to 0° C. 5.5 ml of 2.5 N n-butyllithium (13 mmol) was added and the reaction was stirred for 20 minutes. The reaction was then cooled to −78° C. 2,5-Dichlorotoluene (642 ul, 5 mmol) was added and stirring was continued for 2 hours at −78° C. Trimethyl 4-bromoorthobutyrate (1.14 g, 5 mmol) was added to the reaction mixture in 10 ml tetrahydrofuran. The reaction was stirred for 5 minutes at −78° C., allowed to come to room temperature and stirred overnight. The reaction was worked-up by adding 10 ml of saturated KH2PO4, removal of most of the tetrahydrofuran on a rotary evaporator followed by partitioning of the aqueous residue between ethyl acetate and 1 N HCl. The organic phase was washed twice with 1 N HCl, once with 5% sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated to a residue. Flash chromatogaphy (silica gel; hexane/toluene (39/1)) of the residue gave 1.10 g (84%; GC retention time=15.8 minutes) of a water white oil. 1H NMR (300 MHz, CDCl3) delta=7.24 (d, J=8.5 Hz, H3), 7.18 (d, J=2.5 Hz, H6), 7.09 (dd, J=2.5, 8.5 Hz, H4), 3.66 (s, —COOCH3), 2.69 (t, J=7.8 Hz, Ar—CH2—), 2.35 (t, J=7.0 Hz, —CH2—COO—), 1.70-1.55 (m, —CH2—CH2—CH2—CH2—).
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[SH:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1>>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([S:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][CH:9]=1)[CH3:7]
Reactant: Oc1ccc(S)cc1
Reactant: CCOC(=O)C(Br)c1ccc(-c2cccs2)cc1
Product: CCOC(=O)C(Sc1ccc(O)cc1)c1ccc(-c2cccs2)cc1
Yield: 73 %

Procedure:
Ethyl[(4-hydroxyphenyl)sulfanyl][4-(2-thienyl)phenyl]acetate was prepared according to the general method as outlined in example 1 (step 1), starting from ethyl bromo[4-(2-thienyl)phenyl]acetate (2 g, 6.15 mmol) and 4-mercaptophenol (0.82 g, 6.5 mmol); 1.68 g white solid. mp: 103° C.; Yield 73%; MS: 369.1 (M−H)−
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13].C([O-])([O-])=O.[K+].[K+].Cl[CH2:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=2)[CH2:31][CH2:30]1)=[O:28]>CC#N>[Cl:41][C:37]1[CH:36]=[C:35]([N:32]2[CH2:31][CH2:30][N:29]([C:27](=[O:28])[CH2:26][N:8]3[C:9](=[O:11])[C:10]4[C:2]([CH3:1])=[C:3]([C:12]([N:14]5[CH2:18][CH2:17][CH2:16][CH2:15]5)=[O:13])[S:4][C:5]=4[N:6]=[CH:7]3)[CH2:34][CH2:33]2)[CH:40]=[CH:39][CH:38]=1
Reactant: Cc1c(C(=O)N2CCCC2)sc2nc[nH]c(=O)c12
Reactant: O=C(CCl)N1CCN(c2cccc(Cl)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(C(=O)N2CCCC2)sc2ncn(CC(=O)N3CCN(c4cccc(Cl)c4)CC3)c(=O)c12
Yield: 21.7 %

Procedure:
To a suspension of 5-methyl-6-(pyrrolidine-1-carbonyl)thieno[2,3-d]pyrimidin-4(3H)-one, (0.06 g, 0.23 mmol) in CH3CN (5 mL) was added K2CO3 (0.032 g, 0.23 mm (38 mg, 0.23 mmol), and 2-chloro-1-(4-(3-chlorophenyl)piperazin-1-yl)ethanone, (0.062 g, 0.23 mmol). The reaction mixture was refluxed overnight and then quenched with H2O (20 mL). The resultant precipitate was filtered and dried to provide a crude solid which was purified by flash chromatography (Et2O:DCM, 1:1) providing 0.025 g of pure 3-(2-(4-(3-chlorophenyl)piperazin-1-yl)-2-oxoethyl)-5-methyl-6-(pyrrolidine-1-carbonyl)thieno[2,3-d]pyrimidin-4(3H)-one, (yield: 22%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C:10]([CH2:17][O:18][CH3:19])([CH2:14][O:15][CH3:16])[CH2:9]1)C1C=CC=CC=1.[ClH:20]>CO.[OH-].[OH-].[Pd+2]>[ClH:20].[CH3:16][O:15][CH2:14][C:10]1([CH2:17][O:18][CH3:19])[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: COCC1(COC)CN(Cc2ccccc2)CCO1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: COCC1(COC)CNCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-benzyl-2,2-bis(methoxymethyl)morpholine (6 g) and conc HCl (2.41 ml) in MeOH (60 ml) was added 20% palladium hydroxide on charcoal (1.2 g), and the whole was stirred for 2 hours at room temperature under hydrogen (2.0 atm). The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give 2,2-bis(methoxymethyl)morpholine hydrochloride (3.6 g). The obtained HCl salt was diluted with CH2Cl2 and washed with 1N—NaOH. The organic phase was concentrated under reduced pressure to give gave free form, which was used for next reaction.
Reaction SMILES: C(OC(=O)C)(=O)C.[N+]([O-])(O)=O.C(=O)(O)[O-].[Na+].[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([C@H:29]([CH3:40])[C:30]([O:32][CH2:33][CH2:34]S(CCO)=O)=[O:31])[CH:23]=[CH:22]2>C(OCC)(=O)C>[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([C@H:29]([CH3:40])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:23]=[CH:22]2
Reactant: COc1ccc2cc([C@H](C)C(=O)OCCS(=O)CCO)ccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: O=[N+]([O-])O
Product: CCOC(=O)[C@@H](C)c1ccc2cc(OC)ccc2c1
Temperature: 25 °C
Yield: 22 %

Procedure:
To acetic anhydride (9.1 mL, 98.1 mmol) at 0° C. was added fuming nitric acid (90%, 2.86 mL, 61.3 mmol) with stirring. After addition was complete, the mixture was stirred at 0° C. for 5 minutes, then added drop-wise to a solution of the product of Example 1a (4.10 g, 12.3 mmol) in ethyl acetate (20 mL) at 0° C. The reaction mixture was stirred at 0° C. for 10 minutes, then poured into a pre-cooled (0° C.) mixture of 25 mL of ethyl acetate and 50 mL of sodium bicarbonate. The mixture was stirred cold for 20 minutes, and then warmed to room temperature for 1 hour. The reaction mixture was partitioned between ethyl acetate and water, washed with sodium bicarbonate, water, and brine, and dried over sodium sulfate. The solvent was evaporated and the residue was purified by column chromatography on silica, eluting with methanol/ethyl acetate (gradient, 0% to 20%), gave 2-((2-nitrooxy)ethyl)sulfinyl)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate as a pale yellow solid (1.07 g, 22% yield) and 2-((2-hydroxyethyl)sulfinyl)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate as a white solid. 2-((2-hydroxyethyl)sulfinyl)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate (1.87 g, 44% yield). Mp 74-86° C. 1H NMR (300 MHz, CDCl3) δ 7.70 (d, J=8.6 Hz, 2H), 7.65 (d, J=1.0 Hz, 1H), 7.37 (dt, J=1.9, 8.5 Hz, 1H), 7.15 (dd, J=2.5, 8.8 Hz, 1H), 7.11 (d, J=2.3 Hz, 1H), 4.52 (m, 2H), 3.91 (s, 3H), 3.87 (q, J=7.2 Hz, 1H), 2.97 (m, 2H), 2.84 (br.s, 1H), 2.62 (m, 2H), 1.59 (d, J=7.2 Hz, 3H) Mass spectrum (API-TIS) m/z 351 (MH+). 2-((2-(nitrooxy)ethyl)sulfinyl)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate. Mp 72-88° C. 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J=8.4 Hz, 1H), 7.70 (d, J=8.9 Hz, 1H), 7.64 (br s, 1H), 7.35 (dt, J=2.1, 8.5 Hz, 1H), 7.16 (dd, J=2.5, 8.9 Hz, 1H), 7.11 (br s, 1H), 4.54-4.29 (m, 4H), 3.91 (s, 3H), 3.86 (q, J=7.2 Hz, 1H), 3.01-2.83 (m, 2H), 2.64-2.46 (m, 2H), 1.60 (d, J=7.2 Hz, 3H). Mass spectrum (API-TIS) m/z 396 (MH+), 413 (M+18+).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.Cl.[C:17]1([NH:23][CH:24]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[C:25]([OH:27])=[O:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1C=CC2N(O)N=NC=2C=1.[N:48]12[CH2:55][CH2:54][CH:51]([CH2:52][CH2:53]1)[C@@H:50](O)[CH2:49]2>C1COCC1>[N:48]12[CH2:55][CH2:54][CH:51]([CH2:52][CH2:53]1)[C@@H:50]([O:26][C:25](=[O:27])[CH:24]([NH:23][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:30][CH:29]=1)[CH2:49]2
Reactant: O=C(O)C(Nc1ccccc1)c1ccc(C(F)(F)F)cc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccccc1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
PS-DCC (907 mg, 1.21 mmol, loading: 1.33 mmol/g) is suspended in dry THF (10 mL). Phenylamino-(4-trifluoromethyl-phenyl)-acetic acid hydrochloride (I104) (200 mg, 0.60 mmol), HOBT (185 mg, 1.21 mmol), and (R)-quinuclidin-3-ol (230 mg, 1.81 mmol) are added and the mixture is shaken at RT overnight. PS-DCC is filtered off, the filtrate is evaporated and the residue is dissolved in EtOAc and washed with NaHCO3, water and brine. The organic layer is dried over Na2SO4, filtered and evaporated to dryness. The resulting crude compound is purified by filtration through a pad of silica-gel using DCM/MeOH=9/1 as the eluent. The title compound is obtained as a colorless oil (110 mg, 45% yield, mixture of diastereoisomers).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[N:11]1([CH2:18][CH2:19][O:20][C:21]2[CH:49]=[CH:48][C:24]([C:25]([NH:27][C:28]3[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=3[CH:36]3[CH2:45][CH2:44][C:43]4[C:38](=[CH:39][CH:40]=[C:41]([O:46][CH3:47])[CH:42]=4)[CH2:37]3)=O)=[CH:23][CH:22]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.N>O1CCCC1>[N:11]1([CH2:18][CH2:19][O:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:25][NH:27][C:28]3[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=3[CH:36]3[CH2:45][CH2:44][C:43]4[C:38](=[CH:39][CH:40]=[C:41]([O:46][CH3:47])[CH:42]=4)[CH2:37]3)=[CH:48][CH:49]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NC(=O)c1ccc(OCCN3CCCCCC3)cc1)C2
Agent: N
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCc1ccc(OCCN3CCCCCC3)cc1)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.9 %

Procedure:
To a suspension of 4-(2-azepan-1-ylethoxy)benzoic acid hydrochloride (300 mg) in 1,2-dichloroethane (15 ml) was added thionyl chloride (0.3 ml), the solution was refluxed for 40 minutes, then the reaction solution was concentrated in vacuo. To a suspension of the resulting 4-(2-azepan-1-ylethoxy)benzoyl chloride hydrochloride in 1,4-dioxane (4 ml) were added 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine (150 mg) and N,N-diisopropylethylamine (1 ml), and the solution was stirred for 1.5 hours at 90° C. Water was added thereto followed by stirring, and the solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate-methanol system) to provide 4-(2-azepan-1-ylethoxy)-N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]benzamide (156 mg). To a suspension of lithium aluminum hydride (33 mg) in tetrahydrofuran (1.5 ml) was added aluminum chloride (116 mg) on an ice bath under a nitrogen atmosphere, the solution was stirred for 10 minutes at room temperature, 4-(2-azepan-1-ylethoxy)-N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]benzamide (153 mg) was then added thereto, followed by stirring for 2 hours at room temperature. Tetrahydrofuran and aqueous ammonia were sequentially added thereto, the solution was filtered through celite pad, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate-methanol system) to provide the title compound (116 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:35][C:36]1[C:41]([C:42]([F:45])([F:44])[F:43])=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].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>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:37]5[CH:38]=[CH:39][CH:40]=[C:41]([C:42]([F:45])([F:44])[F:43])[C:36]=5[Cl:35])[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cccc(C(F)(F)F)c5Cl)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2-chloro-3-(trifluoromethyl)phenylboronic acid. Additionally, (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used as the catalyst in place of tetrakis(triphenylphosphine)palladium(0).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:16]([C:19](=[O:25])[CH:20](OCC)O)=[CH:15][C:10]=1[C:11]([O:13]C)=O)C1C=CC=CC=1.[CH2:26]([C:33]1([NH2:36])[CH2:35][CH2:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.FC(F)(F)C([O-])=O>>[CH2:26]([C:33]1([NH:36][CH2:20][CH:19]([C:16]2[CH:17]=[CH:18][C:9]([OH:8])=[C:10]([CH2:11][OH:13])[CH:15]=2)[OH:25])[CH2:35][CH2:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NC1(Cc2ccccc2)CC1
Reactant: CCOC(O)C(=O)c1ccc(OCc2ccccc2)c(C(=O)OC)c1
Agent: O=C([O-])C(F)(F)F
Product: OCc1cc(C(O)CNC2(Cc3ccccc3)CC2)ccc1O

Procedure:
Prepared according to general method 5 from 344 mg (1 mmol) methyl 2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-benzoate and 147 mg (1 mmol) 1-benzyl-cyclopropylamine. Yield: 184 mg (43%, trifluoroacetate); mass spectroscopy: [M+H]+=314.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[C:10]([CH:11]=[O:12])=[C:9]([C:13]([F:16])([F:15])[F:14])[N:8]=[CH:7][N:6]=1.O>CO>[CH3:3][O:4][C:5]1[C:10]([CH2:11][OH:12])=[C:9]([C:13]([F:15])([F:14])[F:16])[N:8]=[CH:7][N:6]=1
Reactant: COc1ncnc(C(F)(F)F)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ncnc(C(F)(F)F)c1CO
Reaction time: 3 h
Yield: 32 %

Procedure:
0.24 g (6.3 mmoles) of sodium borohydride was gradually added, at room temperature, to a solution of 1.3 g (6.3 mmoles) of 4-methoxy-6-trifluoromethylpyrimidine-5-carboaldehyde dissolved in 30 ml of methanol. The mixture was stirred for 3 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 0.42 g (yield: 32.1%) of (4-methoxy-6-trifluoromethylpyrimidin-5-yl)-methanol