Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([F:18])=[CH:4][C:5]([F:17])=[C:6](/[C:8](=[N:10]/[S@@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])/[CH3:9])[CH:7]=1.Br[C:20]([F:27])([F:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[CH2:24]([O:23][C:21](=[O:22])[C:20]([F:27])([F:26])[C@@:8]([C:6]1[CH:7]=[C:2]([Br:1])[C:3]([F:18])=[CH:4][C:5]=1[F:17])([NH:10][S@@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])[CH3:9])[CH3:25]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: C/C(=N\[S@](=O)C(C)(C)C)c1cc(Br)c(F)cc1F
Product: CCOC(=O)C(F)(F)[C@](C)(N[S@](=O)C(C)(C)C)c1cc(Br)c(F)cc1F

Procedure:
Starting from (R)-2-methyl-propane-2-sulfinic acid [1-(5-bromo-2,4-difluoro-phenyl)-eth-(E)-ylidene]-amide (intermediate A2.2) and ethyl 2-bromo-2,2-difluoroacetate, the product (R)-3-(5-bromo-2,4-difluoro-phenyl)-2,2-difluoro-3-((R)-2-methyl-propane-2-sulfinylamino)-butyric acid ethyl ester was obtained as an orange oil. MS (ISP): m/z=462.1 [M+H]+ and 464.1 [M+2+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]([C:12]1[N:17]=[C:16]([C:18](=O)[CH3:19])[CH:15]=[CH:14][CH:13]=1)[CH3:11].[C:21]1([CH3:28])[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH2:27]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([C:18](=[N:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH3:28])[CH3:19])[N:17]=1)[CH3:11]
Reactant: Cc1ccccc1N
Reactant: CC(=O)c1cccc(C(C)=Nc2c(C)cccc2C)n1
Solvent: Cc1ccccc1
Product: CC(=Nc1ccccc1C)c1cccc(C(C)=Nc2c(C)cccc2C)n1

Procedure:
5.0 g (0.0188 mol) of 1-{6-[1-(2,6-Dimethyl-phenylimino)-ethyl]-pyridin-2-yl}-ethanone 1 (5.0 g, 0.0188 mol), 2.62 g (0.02445 mol) of ortho-tolylamine 5, 100 g of fresh molecular sieves, and 100 ml of toluene were kept at 100° C. for 3 days under the flow of nitrogen. The solvent was removed in a rotary evaporator and the residue was recrystallized from 20 ml of ethanol. The yield of (2,6-dimethyl-phenyl)-{1-[6-(1-o-tolylimino-ethyl)-pyridin-2-yl]-ethylidene}-amine 4 was 4.74 g (71%) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:13]([OH:38])[CH2:14][NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=2[C:27]2[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[CH:30]=[CH:29][C:28]=2[O:36][CH3:37])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCN(C(C)C)C(C)C.Cl[C:51](Cl)([O:53]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]([F:39])([F:40])[C:3]1[CH:4]=[C:5]([CH:13]2[O:38][C:51](=[O:53])[N:15]([CH2:16][C:17]3[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[CH:19][C:18]=3[C:27]3[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[CH:30]=[CH:29][C:28]=3[O:36][CH3:37])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNCC(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1CC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-[3,5-bis(trifluoromethyl)phenyl]-2-({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethanol (31.9 mg, 0.0551 mmol) in CH2Cl2 (5 mL) at 0° C. was added DIPEA (67 μL, 0.386 mmol), followed by triphosgene (8.2 mg, 0.0276 mmol). The reaction was stirred at 0° C. for 30 minutes. The reaction was then poured into saturated NaHCO3 (15 mL) and the mixture was extracted with EtOAc (50 mL). The organic layer was washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography (20% EtOAc/hexanes) afforded 5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one. Rf=0.32 (25% EtOAc/hexanes). LCMS=606.3 (M+1)+. 1H NMR (CD2Cl2, 500 MHz) (atropisomers present in 1:1 ratio, doubling of some peaks) δ 7.90 (s, 1H), 7.77 (s, 2H), 7.57-7.62 (m, 2H), 7.37 (d, J=8.0 Hz, 1H), 7.27 (m, 1H), 6.98 (s, 1H), 6.93 (dd, J=8.4, 3.2 Hz, 1H), 5.42-5.53 (m, 1H), 4.15-4.59 (m, 2H), 3.72 & 3.73 (2 singlets, 3H), 3.05-3.65 (m, 2H), 2.88 (m, 1H), 1.19-1.23 (m, 6H).
Reaction SMILES: [N:1]([CH2:4][N:5]1[C:15]2[C:10](=[CH:11][C:12]([S:16]([N:19]3[CH2:23][CH2:22][CH2:21][C@H:20]3[CH2:24][O:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[F:33])(=[O:18])=[O:17])=[CH:13][CH:14]=2)[C:8](=[O:9])[C:6]1=[O:7])=[N+:2]=[N-:3].[F:34][CH2:35][C:36]#[CH:37].O=C1O[C@H]([C@H](CO)O)C(O)=C1O>[O-]S([O-])(=O)=O.[Cu+2].CN(C=O)C>[F:34][CH2:35][C:36]1[N:3]=[N:2][N:1]([CH2:4][N:5]2[C:15]3[C:10](=[CH:11][C:12]([S:16]([N:19]4[CH2:23][CH2:22][CH2:21][C@H:20]4[CH2:24][O:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=4[F:33])(=[O:18])=[O:17])=[CH:13][CH:14]=3)[C:8](=[O:9])[C:6]2=[O:7])[CH:37]=1
Reactant: C#CCF
Reactant: [N-]=[N+]=NCN1C(=O)C(=O)c2cc(S(=O)(=O)N3CCC[C@H]3COc3ccc(F)cc3F)ccc21
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CN(C)C=O
Product: O=C1C(=O)N(Cn2cc(CF)nn2)c2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccc(F)cc3F)cc21

Procedure:
is prepared as illustrated in FIG. 2(ii), by reaction of (S)-1-(azidomethyl)-5-(2-(2,4-difluorophenoxymethyl)-pyrrolidine-1-sulfonyl)isatin] (compound 37) with 3-fluoroprop-1-yne (compound 28). The reagents are as follows: (a) CuSO4, L-ascorbic acid, DMF. For the preparation of [18F]6, 3-[18F]fluoroprop-1-yne is used in place of 3-fluoroprop-1-yne.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([S:17]([C:20]3[CH:21]=[C:22]([NH2:26])[CH:23]=[CH:24][CH:25]=3)(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH2:34]([N:36]=[C:37]=[O:38])[CH3:35]>O1CCCC1>[CH2:34]([NH:36][C:37]([NH:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([S:17]([C:14]2[CH:13]=[CH:12][C:11](/[CH:10]=[CH:9]/[C:6]3[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=3)=[CH:16][CH:15]=2)(=[O:19])=[O:18])[CH:21]=1)=[O:38])[CH3:35]
Reactant: CCN=C=O
Reactant: Nc1cccc(S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3)cc2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1cccc(S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3)cc2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 24.5 %

Procedure:
A mixture of [3-({4-[(E)-2-(4-fluorophenyl)vinyl]phenyl}sulfonyl)phenyl]amine hydrochloride (Example 212, 100 mg, 0.26 mmol) and triethylamine (0.05 mL, 0.36 mmol) in tetrahydrofuran (2 mL) was cooled to 0° C. and ethyl isocyanate (0.08 mL, 0.31 mmol) added. The reaction was allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4 and evaporated. The residue was purified by flash column chromatography on silica, eluting with 40% ethyl acetate/isohexane, followed by trituration with diethyl ether to give the title compound as a white solid (27 mg, 24%). δH (500 MHz, d6 DMSO): 8.85 (1H, s), 8.15 (1H, s), 7.86 (2H, d, J=8.4 Hz), 7.79 (2H, d, J=8.4 Hz), 7.67 (2H, dd, J=5.7, 8.5 Hz), 7.50–7.48 (1H, m), 7.43–7.40 (3H, m), 7.27 (1H, d, J=16.5 Hz), 7.22 (2H, t, J=8.8 Hz), 6.20 (1H, t, J=5.4 Hz), 3.12–3.06 (2H, m), 1.03 (3H, t, J=7.1 Hz).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[CH:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.FC(F)(F)S(O)(=O)=O.FC(F)(F)S(O)(=O)=O.[SH:67][C@@H:68]1[CH2:72][N:71]([C:73]([O:75][CH2:76][C:77]2[CH:82]=[CH:81][C:80]([N+:83]([O-:85])=[O:84])=[CH:79][CH:78]=2)=[O:74])[C@H:70]([C:86]([N:88]2[CH2:94][CH2:93][CH2:92][N:91]([CH3:95])[CH2:90][CH2:89]2)=[O:87])[CH2:69]1>C(#N)C>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[O:13])=[C:8]([S:67][C@@H:68]3[CH2:72][N:71]([C:73]([O:75][CH2:76][C:77]4[CH:82]=[CH:81][C:80]([N+:83]([O-:85])=[O:84])=[CH:79][CH:78]=4)=[O:74])[C@H:70]([C:86]([N:88]4[CH2:94][CH2:93][CH2:92][N:91]([CH3:95])[CH2:90][CH2:89]4)=[O:87])[CH2:69]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CN1CCCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCCN(C)CC4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Temperature: 0 °C
Yield: 46.5 %

Procedure:
340 mg of 4-nitrobenzyl (1R, 5R, 6S)-6[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate were dissolved in 3.5 ml of anhydrous acetonitrile, and the solution was placed on an ice bath. Whilst the solution was still on the ice bath, 210 μl of diphenylphosphoryl chloride and 180 μl of diisopropylethylamine were added dropwise to it, and the resulting mixture was stirred for 1 hour at this ice-cooled temperature. 580 μl of diisopropylethylamine and 5 ml of an anhydrous acetonitrile solution containing 640 mg of (2S, 4S)-4-mercapto-2-(4-methyl-1-homopiperazinylcarbonyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine bis(trifluoromethanesulfonate) [prepared as described in step (1) above] were then added dropwise to the reaction mixture, still on an ice bath, and the resulting mixture was stirred overnight at this ice-cooled temperature. At the end of this time, the mixture was treated and purified by means similar to those described in Example 1(2), to give 316 mg of the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]([OH:25])=O.C(OC(Cl)=O)C(C)C.CN1CCOCC1.[CH3:41][C:42]([CH3:47])([CH3:46])[CH2:43][CH2:44][NH2:45]>ClCCl>[CH3:41][C:42]([CH3:47])([CH3:46])[CH2:43][CH2:44][NH:45][C:23](=[O:25])[CH2:22][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:2]1=[O:1]
Reactant: CC(C)(C)CCN
Reactant: O=C(O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)CCNC(=O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.8 %

Procedure:
To a stirred solution of (2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetic acid (0.25 g, 0.74 mmol), isobutylchloroformate (0.11 mL, 0.81 mmol), N-methylmorpholine (0.09 mL, 0.81 mmol) in dichloromethane (10 mL) was added 3,3-dimethylbutylamine (0.11 g, 1.1 mmol). The solution was stirred at ambient temperature for 16 h, diluted with dichloromethane (10 mL) and washed with 2 M sodium carbonate (2×25 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by flash chromatography with ethyl acetate in hexanes (30% to 50% gradient) to afford N-(3,3-dimethylbutyl)-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide (0.13 g, 41%) as a colorless solid: mp 161-163° C.; 1H NMR (300 MHz, DMSO-d6) δ8.14 (dd, J=5.4, 5.4 Hz, 1H), 7.25 (dd, J=7.6, 7.6 Hz, 1H), 7.11 (d, J=6.9 Hz, 1H), 7.03-6.95 (m, 1H), 6.90 (d, J=7.8 Hz, 1H), 6.53 (s, 1H), 6.37 (s, 1H), 4.71 (ABq, 2H), 4.51-4.40 (m, 2H), 4.38-4.20 (m, 2H), 3.12-3.01 (m, 2H), 2.93 (t, J=8.6 Hz, 2H), 1.37-1.27 (m, 2H), 0.85 (s, 9H); 13C NMR (75 MHz, DMSO-d6) δ177.6, 166.3, 161.5, 160.9, 143.1, 132.7, 129.0, 123.8, 123.3, 121.3, 120.2, 119.8, 109.4, 92.8, 80.2, 72.5, 57.3, 43.2, 43.0, 35.9, 30.0, 29.7, 28.8; MS (ES+) m/z 421.2 (M+1).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].C(O)(=O)C.N1[CH2:18][CH2:17][CH2:16][CH2:15]C1>C1(C)C=CC=CC=1>[C:1]([C:3](=[CH:15][CH:16]1[CH2:18][CH2:17]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: C1CCNCC1
Reactant: CCOC(=O)CC#N
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=CC1CC1
Yield: 43 %

Procedure:
A solution of 14 g (0.2 mol) of cyclopropylcarbaldehyde, 22.6 g (0.2 mol) of ethyl cyanoacetate, 1.4 ml of glacial acetic acid and 0.4 ml of piperidine in 200 ml of toluene was refluxed for 6 hours. After cooling, the mixture was washed with in each case 300 ml of 10% strength hydrochloric acid and water. The organic phase was dried and concentrated and the residue was subjected to distillation in vacuo. This gave 14.2 g (yield 43%) of ethyl 2-cyano-3-cyclopropyl-2-propenoate (b.p. 95° C./0.3 mbar).
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Br)(Br)[Br:7].[CH3:10][C:11]1([CH3:18])[CH2:16][CH2:15][CH2:14][C:13](=O)[CH2:12]1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Br:7][C:13]1[CH2:12][C:11]([CH3:18])([CH3:10])[CH2:16][CH2:15][C:14]=1[CH2:3][OH:4]
Reactant: BrP(Br)Br
Reactant: CN(C)C=O
Reactant: CC1(C)CCCC(=O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC1(C)CCC(CO)=C(Br)C1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
N,N-dimethylformamide (18.41 ml) was taken up in chloroform (64 ml) and the resulting solution was cooled in an ice bath. Phosphorus tribromide (20.18 ml) was added dropwise over 15 minutes. The resulting suspension was then heated to 70° C. for 30 minutes. A solution of 3,3-dimethylcyclohexanone (10 g) in chloroform (21 ml) was added dropwise over 30 minutes. The mixture was stirred at 70° C. for another 2 hours. The mixture was then allowed to cool to room temperature. The solution was cautiously poured over ice. Solid sodium bicarbonate was added to neutralize acid. The mixture was extracted three times with ether, and the extracts were washed with water and brine and dried (MgSO4). The solvent was removed under vacuum, and the crude material was flushed through a silica plug with ether as the eluent. After concentration, the crude material was dissolved in methanol. Sodium borohydride (1.757 g) was added cautiously. The resulting mixture was stirred at room temperature overnight, and diluted with ethyl acetate. The mixture was washed with water and brine and dried (MgSO4). The solvent was removed under vacuum, and the residue was purified by flash chromatography eluting with 20% ethyl acetate in hexanes to 100% ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18].[CH3:19][C:20](C)([O-:22])[CH3:21].[K+].C(C1OC1)Br>CC(N(C)C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH2:19][CH:20]1[CH2:21][O:22]1
Reactant: CC(C)(C)[O-]
Reactant: Oc1ccccc1CCCCc1ccccc1Cl
Agent: BrCC1CO1
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Clc1ccccc1CCCCc1ccccc1OCC1CO1
Yield: 88.5 %

Procedure:
Following a procedure similar to that described in Example 1(a), 800 mg of 2-[4-(2-chlorophenyl)butyl]phenol (prepared as described in Preparation 18), 344 mg of potassium t-butoxide and 835 mg of epibromohydrin were reacted in 20 ml of dimethylacetamide. The crude product, extracted as described in Example 1(a), was purified as described in Example 1(a), to give 860 mg (yield 88%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(O)C.[OH-].[Na+].[ClH:36]>O1CCCC1>[ClH:36].[CH2:1]([O:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:15][CH2:16][N:17]([C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=3)[CH2:18][CH2:19]2)=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccc(N2CCN(c3ccc(C(=O)OCC)cc3)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCCOc1ccc(N2CCN(c3ccc(C(=O)O)cc3)CC2)cc1

Procedure:
To a solution of ethyl 4-[4-(4-hexyloxyphenyl)piperazin-1-yl]benzoate (2.19 g) in the mixture of ethanol (22 ml) and tetrahydrofuran (22 ml) was added 2N NaOH aq. and refluxed for 5 hours. The reaction mixture was adjusted to pH 1-1.5 with 1N HCl and the resulting precipitate was collected by filtration to give 4-[4-(4-hexyloxyphenyl)piperazin-1-yl]benzoic acid hydrochloride (1.99 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[CH3:17])[O:9][CH2:8][CH2:7][O:6]1.[O:18]=[C:19]1[C:23]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[N:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:21][NH:20]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[CH3:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[C:5]1([O:9][CH2:8][CH2:7][O:6]1)[CH2:4][CH2:3][CH2:2][N:26]1[CH2:25][CH2:24][C:23]2([N:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:21][NH:20][C:19]2=[O:18])[CH2:28][CH2:27]1
Reactant: Cc1cc(F)ccc1C1(CCCCl)OCCO1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1C1(CCCN2CCC3(CC2)C(=O)NCN3c2ccccc2)OCCO1
Temperature: 0 °C

Procedure:
A mixture of 3 g of 4-chloro-1-(2-methyl-4-fluorophenyl)-1,1-ethylenedioxybutane, 2.3 g of 4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]decane, 1.4 g of anhydrous potassium carbonate, 0.05 g of potassium iodide and 30 ml of dimethylformamide was refluxed for 3 hours. The resulting mixture was poured into ice water. The precipitated crystals were collected by filtration and washed with water to give 8-[4-(2-methyl-4-fluorophenyl)-4,4-ethylenedioxybutyl]-4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]decane as crude crystals (5 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:10][NH:11][CH2:12][CH:13]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:40](=O)[CH3:41].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:31][O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:10][N:11]([CH2:12][CH:13]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:40][CH3:41])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC=O
Reactant: CC(C)(C)OC(=O)NC(CNC[C@@H](COCc1ccccc1)NC(=O)OC(C)(C)C)COCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCN(CC(COCc1ccccc1)NC(=O)OC(C)(C)C)C[C@@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.5 %

Procedure:
The product from Example 17C (0.15 g) in dichloroethane (5 mL) was treated with acetaldehyde (20 μL, 0.36 mmol). After stirring at ambient temperature for 10 minutes, the mixture was treated with sodium triacetoxyborohydride (0.10 g, 0.47 mmol) and acetic acid (20 μL, 0.35 mmol). After stirring at ambient temperature overnight, the mixture was diluted with CH2Cl2 (20 mL), washed with saturated aqueous NaHCO3 (2×20 mL) and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexanes:ethyl acetate, 1:1) to provide the title compound (75 mg, 44%). 1H NMR (CDCl3) δ 7.36-7.24 (m, 10 H), 4.93 (br s, 2H), 4.54-4.41 (m, 4H), 3.77-3.63 (m, 2H), 3.61 (dd, J=3.4, 9.2 Hz, 2H), 3.5-3.38 (m, 2H), 2.66-2.42 (m, 6H), 1.44 (s, 9H), 1.43 (s, 9H), 0.98 (t, J=7.1 Hz, 1.5H), 0.96 (t, J=7.1 Hz, 1.5H); MS (APCI+) m/z 572 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=[CH:16][C:4]=2[NH:3]1.ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)Cl>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6](=[O:29])[C:5]2[CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=[CH:16][C:4]=2[NH:3]1
Reactant: COC(=O)c1ccc2c(c1)Sc1ccccc1C(=O)N2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)S(=O)c1ccccc1C(=O)N2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 100.4 %

Procedure:
Suspend 1.14 gm (4 mmole) of the ester of Example 23 in 60 ml of methylene chloride and add 1.035 gm of commercial m-chloroperbenzoic acid. Stir at room temperature for 45 minutes and filter. Concentrate the filtrate and separate the solids. Combine the solids to obtain the title product (yield 1.21 gm).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].IC1C=CC(OC)=CC=1[C:19](O)=[O:20].FC1C=CC(I)=C(C=1)C(O)=O>>[CH3:19][O:20][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: COc1ccc(I)c(C(=O)O)c1
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Agent: O=C(O)c1cc(F)ccc1I
Product: COc1ccc(-n2nccn2)c(C(=O)O)c1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 41, substituting for 2-iodo-5-methoxy benzoic acid for 5-fluoro-2-iodo-benzoic acid in Step A. 1H NMR (400 MHz, CD3OD): 7.81 (s, J=6.4, 2H), 7.55 (d, J=8.8, 1H), 7.33 (d, J=2.9, 1H), 7.18 (dd, J=8.8, 2.9, 1H), 3.85 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].O>C(O)(=O)C>[C:16]([NH:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=2)=[CH:4][CH:3]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Oc2ncc(Cl)cn2)cc1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(Oc2ncc(Cl)cn2)cc1
Reaction time: 0.08 h

Procedure:
2-(4-Aminophenoxy)-5-chloropyrimidine (20 g), was dissolved in acetic acid (100 ml), and acetic anhydride (20 ml) was added to the solution. After standing for a period of 5 minutes the solution was heated on a steam bath and hot water (100 ml) was slowly added. On cooling the product crystallised and was collected and dried. Yield 20 g, m.p. 202° C.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[S:3])[NH2:2].[F:14][C:15]1[C:24]([F:25])=[C:23]([F:26])[C:22]([F:27])=[C:21]([F:28])[C:16]=1[C:17](=O)[CH2:18]Br>>[F:14][C:15]1[C:24]([F:25])=[C:23]([F:26])[C:22]([F:27])=[C:21]([F:28])[C:16]=1[C:17]1[N:2]=[C:1]([C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=2)[S:3][CH:18]=1
Reactant: O=C(CBr)c1c(F)c(F)c(F)c(F)c1F
Reactant: COC(=O)c1ccc(C(N)=S)cc1
Product: COC(=O)c1ccc(-c2nc(-c3c(F)c(F)c(F)c(F)c3F)cs2)cc1
Yield: 60 %

Procedure:
In the same manner as in Example 28, methyl 4-thiocarbamoylbenzoate was reacted with 2,3,4,5,6-pentafluorophenacyl bromide to obtain methyl 4-[4-(2,3,4,5,6-pentafluorophenyl)-2-thiazolyl]benzoate. The product was recrystallized from ethanol. Yield: 60%. Pale yellow prisms. Melting point: 141 to 142° C.