Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)C)(=O)C.[S:8](=[O:11])(=[O:10])=[O:9].[CH:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([S:8]([OH:11])(=[O:10])=[O:9])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccccc1
Reactant: O=S(=O)=O
Solvent: CC(=O)OC(C)=O
Product: O=S(=O)(O)c1ccccc1
Temperature: 40 °C
Yield: 98 %

Procedure:
Mono-sulfonation of benzene was carried out in the apparatus of FIG. 1. Dry benzene (390 g., 5 gram molecules) was placed in the three-necked reaction flask (1 litre capacity) together with acetic anhydride (1 g) which was added to suppress sulfone formation. The reaction flask was heated to 40°C and the pressure gradually reduced until the benzene refluxed vigorously at 400 mm Hg. The sulfur trioxide generator was charged with liquid, stabilized sulfur trioxide (200 g, 2.5 gram molecules) and the two flasks were connected to allow the sulfur trioxide to be aspirated into the reaction flask. External heating of the reaction flask was discontinued but the trioxide generator was gently warmed to maintain an internal temperature of 30°C to aid evaporation. The reaction was completed when all the sulfur trioxide had been evaporated from the generator and had passed into the reaction vessel. At this point reflux ceased. Anhydrous benzene sulfonic acid was isolated by distilling off the excess benzene in vacuo, leaving a light amber coloured oil which crystallized slowly when kept in a desiccator over concentrated sulfuric acid. The sulfonic acid was contaminated by 0.2% sulfuric acid and 1.5% diphenyl sulfone. The yield was 98% calculated with respect to the amount of sulfur trioxide employed.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[C:9]([C:18]#[N:19])[CH:10]=[C:11]([C:14]([O:16]C)=[O:15])[CH:12]=2)[CH:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>CO>[CH2:1]([N:5]1[C:13]2[C:8](=[C:9]([C:18]#[N:19])[CH:10]=[C:11]([C:14]([OH:16])=[O:15])[CH:12]=2)[CH:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1ccc2c(C#N)cc(C(=O)OC)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCn1ccc2c(C#N)cc(C(=O)O)cc21
Temperature: 40 °C
Yield: 4.5 %

Procedure:
To a mixture of methyl 1-butyl-4-cyano-1H-indole-6-carboxylate (10.5 g) in methanol (15 mL) was added 1N NaOH (3.0 mL). The mixture was heated at 40° C. for 2 h then cooled to room temperature. The mixture was poured into 1N HCl and extracted into ethyl acetate. The ethyl acetate extract was dried over anhydrous magnesium sulfate and concentrated to give 0.45 g of the title compound: 1H NMR (CDCl3) δ 0.973, 1.38, 1.88, 4.27, 6.79, 7.48, 8.24, 8.38.
Reaction SMILES: [F:1][C:2]([F:17])([C:7]1[CH:16]=[CH:15][C:10]([CH2:11][N:12]=[C:13]=[S:14])=[CH:9][CH:8]=1)[C:3]([F:6])([F:5])[F:4].[F:18][C:19]([F:23])([F:22])[CH2:20][NH2:21]>C(OCC)(=O)C>[F:17][C:2]([F:1])([C:7]1[CH:16]=[CH:15][C:10]([CH2:11][NH:12][C:13]([NH:21][CH2:20][C:19]([F:23])([F:22])[F:18])=[S:14])=[CH:9][CH:8]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: NCC(F)(F)F
Reactant: FC(F)(F)C(F)(F)c1ccc(CN=C=S)cc1
Solvent: CCOC(C)=O
Product: FC(F)(F)CNC(=S)NCc1ccc(C(F)(F)C(F)(F)F)cc1
Reaction time: 24 h
Yield: 90.3 %

Procedure:
2.1 g of 4-pentafluoroethylbenzyl isothiocyanate and 0.78 g of 2,2,2-trifluoroethylamine were dissolved in 20 ml of ethyl acetate, and the solution was left to stand at room temperature for 24 hours. Ethyl acetate was evaporated under reduced pressure. The resulting white crystals were recrystallized from hexane to give 2.6 g of the captioned compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][OH:12].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:10][CH2:11][OH:12]
Reactant: OCCBr
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: OCCOc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-bromo-phenol (10 g, 56.64 mmol), 2-bromoethanol (4.65 mL) and cesium carbonate (18.64 g, 1 eq.) in DMF (25 mL) was stirred at rt for overnight. The mixture was then heated in a 70° C. oil bath for about 3 hours. More 2-bromoethanol (3 mL) was added and heating was increased to 80° C. and stirred for overnight. The reaction was allowed to cool to rt and the insolubles were filtered off. The filtrate was poured into water and extracted with ethyl acetate (2×200 mL), washed with 10% Na2CO3 (3×), brine (2×), dried and concentrated. The residue was purified on a silica gel column to give 2-(3-bromo-phenoxy)-ethanol.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[O:8][C:9]3[C:14]([C:15](=[O:17])[CH:16]=2)=[CH:13][C:12]([C:18]([O:20][CH3:21])=[O:19])=[CH:11][C:10]=3[CH:22]2[CH2:26][CH2:25][CH2:24][NH:23]2)[CH2:3][CH2:2]1.Br[C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[F:34][C:32]1[CH:33]=[C:28]([N:23]2[CH2:24][CH2:25][CH2:26][CH:22]2[C:10]2[CH:11]=[C:12]([C:18]([O:20][CH3:21])=[O:19])[CH:13]=[C:14]3[C:9]=2[O:8][C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[CH:16][C:15]3=[O:17])[CH:29]=[C:30]([F:35])[CH:31]=1
Reactant: COC(=O)c1cc(C2CCCN2)c2oc(N3CCOCC3)cc(=O)c2c1
Reactant: Fc1cc(F)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COC(=O)c1cc(C2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Temperature: 80 °C
Reaction time: 23 h
Yield: 58.4 %

Procedure:
Palladium complex (33 mg, 0.04 mmol, see below) was added to a stirred mixture of methyl 2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxylate (270 mg, 0.75 mmol), 1-bromo-3,5-difluorobenzene (0.095 ml, 0.83 mmol) and cesium carbonate (368 mg, 1.13 mmol) dissolved in 1,4-dioxane (5 mL). The resulting suspension was degassed with argon and then stirred at 80° C. for 23 h. The reaction mixture was allowed to cool to room temperature, filtered and concentrated. The crude product was purified by flash chromatography on silica gel eluting with 0 to 6% MeOH in EtAc. The solvent was evaporated to dryness to afford methyl 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (206 mg, 58%) as a clear yellow foam.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[CH2:18]([N:21]=[C:22]=[O:23])[CH2:19][CH3:20]>CC(C)=O>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:22]([NH:21][CH2:18][CH2:19][CH3:20])=[O:23])(=[O:10])=[O:9]
Reactant: CCCN=C=O
Reactant: NS(=O)(=O)c1ccccc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCNC(=O)NS(=O)(=O)c1ccccc1I

Procedure:
4 g of iodobenzene-sulfonamide and 40 ml of acetone were mixed together and 3.92 g of potassium carbonate were added. The reaction was heated to reflux and 1.46 ml of n-propyl isocyanate were added. The medium was maintained at reflux for 2 hours, and after concentrating, 200 ml of water were added. Then, while cooling the reaction mixture to approximately 0°-5° C., a 2N hydrochloric acid solution was added until a pH of 3 was obtained. After crystallizing from acetone-isopropyl ether, 4.9 g of the expected product melting at 211°-212° C. were obtained.
Reaction SMILES: C([NH:8][C:9]1[C:10]([CH3:25])=[CH:11][C:12]2[O:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13]=2[C:23]=1[CH3:24])C1C=CC=CC=1>C(OCC)(=O)C.CCCCCC>[CH3:24][C:23]1[C:13]2[CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][O:16][C:12]=2[CH:11]=[C:10]([CH3:25])[C:9]=1[NH2:8]
Reactant: Cc1cc2c(c(C)c1NCc1ccccc1)C(c1ccccc1)CO2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc2c(c(C)c1N)C(c1ccccc1)CO2
Yield: 84 %

Procedure:
Using N-benzyl-4,6-dimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 357, the title compound was synthesized in the same manner as in Reference Example 30. Yield 84%. Melting point: 127-128° C. (ethyl acetate-hexane).
Reaction SMILES: [Na].CO.Cl.[NH2:5][C:6]([NH2:8])=[NH:7].[Cl:9][C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH3:21])[CH:19]=2)[N:14]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH:13]=1)=[O:11]>COCCOC>[ClH:9].[NH:7]([C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH3:21])[CH:19]=2)[N:14]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH:13]=1)=[O:11])[C:6]([NH2:8])=[NH:5]
Reactant: N=C(N)N
Reactant: Cc1ccc2c(c1)c(C(=O)Cl)cn2-c1ccnc2ccccc12
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: COCCOC
Product: Cc1ccc2c(c1)c(C(=O)NC(=N)N)cn2-c1ccnc2ccccc12
Temperature: 22 °C
Reaction time: 2 h
Yield: 55.7 %

Procedure:
0.365 g (15.9 mmol) of sodium is added at 22° C. under an argon atmosphere to 45 cm3 of methanol. After complete dissolution, 1.4 g (15 mmol) of guanidine hydrochloride are added. After stirring at 22° C. for 2 hours, the reaction mixture is filtered under an argon atmosphere. The filtrate is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is dissolved in 25 cm3 of 1,2-dimethoxyethane. 1 g of 3-chlorocarbonyl-5-methyl-1-(quinol-4-yl)-1H-indole, suspended in 20 cm3 of 1,2-dimethoxyethane, is subsequently added at 22° C. under an argon atmosphere. After stirring at 22° C. for 19 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is triturated in 20 cm3 of water. After stirring at 22° C. for 1 hour, the suspension is filtered and dried to give a beige-coloured powder which is purified by flash chromatography [eluent: cyclohexane/ethyl acetate (7/3 by volume) and then dichloromethane/methanol/20% aqueous ammonia (18/3/0.5 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa), 1.1 g of a beige-coloured solid are obtained, which solid is triturated in 10 cm3 of N hydrochloric acid for 1 hour. After filtering off, the residue is recrystallised under hot conditions from 180 cm3 of methanol to give 0.66 g of 3-guanidinocarbonyl-5-methyl-1-(quinol-4-yl)-1H-indole hydrochloride in the form of pale yellow crystals melting at 268° C. (Analysis C20H17N5O.HCl; % calculated C, 63.24, H: 4.78, Cl: 9.33, N: 18.44, O: 4.21, % found C: 63.26, H: 4.72, Cl: 9.47, N: 18.57).
Reaction SMILES: BrC1C=CC(C(NC(NC2CCCC2)=O)(C2C=C(C(F)(F)F)C=C(F)C=2)CC2C=CC=CC=2)=NC=1.C([O-])([O-])=O.[Na+].[Na+].[C:42]([C:44]1[CH:45]=[CH:46][C:47]([C@:50]([NH:69][C:70]([NH:72][CH:73]2[CH2:77][CH2:76][CH2:75][CH2:74]2)=[O:71])([C:58]2[CH:63]=[C:62]([C:64]([F:67])([F:66])[F:65])[CH:61]=[C:60]([F:68])[CH:59]=2)[CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[N:48][CH:49]=1)#[N:43]>CC(N(C)C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:42]([C:44]1[CH:45]=[CH:46][C:47]([C@@:50]([NH:69][C:70]([NH:72][CH:73]2[CH2:74][CH2:75][CH2:76][CH2:77]2)=[O:71])([C:58]2[CH:63]=[C:62]([C:64]([F:65])([F:66])[F:67])[CH:61]=[C:60]([F:68])[CH:59]=2)[CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[N:48][CH:49]=1)#[N:43]
Reactant: N#Cc1ccc([C@](Cc2ccccc2)(NC(=O)NC2CCCC2)c2cc(F)cc(C(F)(F)F)c2)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C(NC1CCCC1)NC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Br)cn1
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc([C@@](Cc2ccccc2)(NC(=O)NC2CCCC2)c2cc(F)cc(C(F)(F)F)c2)nc1
Temperature: 120 °C
Reaction time: 0.23 h
Yield: 18 %

Procedure:
1-(1-(5-Bromopyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-3-cyclopentylurea (100 mg, 0.18 mmol, prepared in a similar manner as described in Example 1), K4Fe(CN)6 (45 mg, 0.107 mmol), Pd(OAc)2 (catalytic amount, spatula tip), and Na2CO3 (31 mg, 0.29 mmol) were stirred in DMAC (0.4 mL) at room temperature. Argon was purged several times. The reaction mixture was stirred and heated at 120° C. for 6 h. After cooling, EtOAc was added. The reaction mixture was filtered through Celite and the filtrate was washed with H2O, 5% NH4OH, dried (MgSO4), filtered, and concentrated to dryness. The crude reaction mixture was purified by flash chromatography (silica gel, hexanes/EtOAc, came out 50% EtOAc). The reaction mixture was then further purified by reverse phase HPLC (20%-100% CH3CN in H2O with 0.1 TFA in a 18 min run, came out at 13.38 to 13.88 min) to give pure racemic mixture of (R)-1-(1-(5-cyanopyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-3-cyclopentylurea and (S)-1-(1-(5-cyanopyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-3-cyclopentylurea as white solids (16 mg, yield: 18%). LC-MS ESI (10-90% MeOH in H2O with 10 mM NH4Cl in a 4-min run), retention time=3.93 min, 494.9 (M−H);
Reaction SMILES: [C-:1]#[N:2].[K+].[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Br)=[C:7]([CH3:13])[CH:6]=1.O>C(O)C.O>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:1]#[N:2])=[C:7]([CH3:13])[CH:6]=1
Reactant: Cc1cc(Br)ccc1CBr
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1cc(Br)ccc1CC#N
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 63 %

Procedure:
After carbon tetrabromide (6.7 g, 20 mmol) and triphenylphosphine (5.2 g, 20 mmol) were added to a solution of (4-bromo-2-methylphenyl)methanol (3.7 g, 18.4 mmol) which was synthesized according to the method described in literature (Dawson, M. I., et al., J. Med. Chem., 1984, vol. 27, pp. 1516-1531) under ice-cooling, the mixture was stirred at room temperature for 1 hour. Hexane was added to the reaction mixture and the insolubles were removed by filtration. After the obtained filtrate was poured into water and the mixture was extracted with ethyl acetate, the organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=10/0-10/1) to give a crudely purified 4-bromo-1-(bromomethyl)-2-methylbenzene. Potassium cyanide (1.3 g, 20 mmol) was added to a solution of crude 4-bromo-1-(bromomethyl)-2-methylbenzene obtained in the above in a mixture of ethanol-water (3:1, 40 ml), and the mixture was stirred at 60° C. for 1.5 hours. After the reaction mixture was poured into water and the mixture was extracted with ethyl acetate, the organic layer was washed with a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=6/1-3/1) to give (4-bromo-2-methylphenyl)acetonitrile as a pale orange solid (2.4 g, two-step total yield: 63%).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25]([OH:27])=O)[CH2:21][CH2:20]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.FC(F)(F)C(O)=O.[NH2:56][CH2:57][C:58]([N:60]1[CH2:65][CH2:64][N:63]([C:66](=[O:77])[C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=2[C:73]([F:76])([F:75])[F:74])[CH2:62][CH2:61]1)=[O:59]>CN(C=O)C.O>[O:59]=[C:58]([N:60]1[CH2:61][CH2:62][N:63]([C:66](=[O:77])[C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=2[C:73]([F:76])([F:75])[F:74])[CH2:64][CH2:65]1)[CH2:57][NH:56][C:25]([CH:22]1[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][CH2:16][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:24][CH2:23]1)=[O:27]
Reactant: O=C(O)C1CCN(CCCc2ccccc2)CC1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)C1CCN(CCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 59.2 %

Procedure:
DIPEA (95.64 mg, 0.11 mL, 0.74 mmol) was added to a stirred solution of 1-(3-Phenyl-propyl)-piperidine-4-carboxylic acid (55.22 mg, 0.22 mmol) in DMF (1 mL). HOBT (30.19 mg, 0.22 mmol) and EDCI (42.74 mg, 0.22 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone trifluoroacetic acid salt (80 mg, 0.18 mmol) was added and the resulting mixture was stirred at room temperature for 16 hrs. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 58 mg (57.16% yield) of 1-(3-Phenyl-propyl)-piperidine-4-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 95.21%. 1H NMR (CDCl3): δ 7.8-7.5 (d, 3H), 7.38-7.3 (s, 1H), 7.22-7.08 (s, 3H), 6.62-6.5 (s, 1H), 4.2-3.8 (m, 4H), 3.7-3.4 (m, 4H), 3.4-3.2 (m, 3H), 3.0 (s, 2H), 2.7-2.6 (s, 2H), 2.5-2.1 (m, 4H), 2.0-1.8 (m, 6H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])C(=O)C(F)(F)F)=[CH:15][CH:14]=2)=[O:10])[CH:2]=1.[OH-].[Na+]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9](/[CH:11]=[CH:12]/[C:13]2[CH:14]=[CH:15][C:16]([NH:19][CH2:26][C:27]([OH:29])=[O:28])=[CH:17][CH:18]=2)=[O:10])[CH:2]=1
Reactant: CC(C)(C)OC(=O)CN(C(=O)C(F)(F)F)c1ccc(/C=C/C(=O)NCc2cccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CNc1ccc(/C=C/C(=O)NCc2cccnc2)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of t-butyl [[4-[(E)-2-[N-(3-pyridylmethyl)carbamoyl]ethenyl]-phenyl](trifluoroacetyl)amino]acetate (580 mg) in aqueous methanol was mixed with 74 mg of sodium hydroxide, and then stirred at room temperature for 24 hours and subsequently at 60° C. for 1 hour. After evaporation of methanol, the reaction mixture was mixed with 0.4 ml of 2 mol/l hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The drying agent was filtered off and the solvent was evaporated to precipitate a solid, which was then washed with methanol/ethyl acetate and dried by heating under reduced pressure to provide [[4-[(E)-2-[N-(3-pyridylmethyl)carbamoyl]ethenyl]phenyl]amino]acetic acid of interest (78 mg, 20%) as a pale yellow solid.
Reaction SMILES: O[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1/[C:12](=[N:16]/[OH:17])/[CH2:13][CH2:14][CH3:15].S(Cl)(Cl)=O.N1C=CC=CC=1.Cl>C(OCC)C>[CH2:13]([C:12]1[C:3]2[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=2[O:17][N:16]=1)[CH2:14][CH3:15]
Reactant: CCC/C(=N\O)c1cc(C(=O)OC)ccc1O
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCCc1noc2ccc(C(=O)OC)cc12
Temperature: 0 °C
Yield: 58.6 %

Procedure:
To an ice-cold stirred solution of methyl 4-hydroxy-3-[(1E)-N-hydroxybutanimidoyl]benzoate (170 mg, 0.7 mmol) in diethyl ether (5 mL) was added a mixture of thionyl chloride (60 μL, 0.8 mmol) and pyridine (580 μL, 7.2 mmol) in diethyl ether (5 mL). After 2.5 h the mixture was poured over ice-water and acidified to pH=1 with 1 N hydrochloric acid. The mixture was then partitioned between water and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, dried (sodium sulfate), filtered, and concentrated under reduced pressure to afford a crude oil. Purification by flash column chromatography (silica, 10:1 hexanes/ethyl acetate) provided methyl 3-propyl-1,2-benzisoxazole-5-carboxylate (90 mg): 1H NMR (300 MHz, CDCl3): δ 8.36–8.35 (m, 1H), 8.07–8.04 (m, 1H), 7.52–7.49 (m, 1H), 3.95 (s, 3H), 2.96–2.91 (m, 2H), 2.00–1.87 (m, 2H), 1.09–1.04 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.[CH2:10]([NH2:13])[C:11]#[CH:12].C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>C(O)CCC.O>[CH2:10]([NH:13][C:7]1[C:2]([NH2:1])=[C:3]([Cl:9])[N:4]=[CH:5][N:6]=1)[CH:11]=[CH2:12]
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: C#CCN
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCNc1ncnc(Cl)c1N
Yield: 54 %

Procedure:
A solution of 8 g 5-amino-4,6-dichloropyrimidine, 5 ml propargylamine and 42 ml diisopropyl ethyl amine in 100 ml butanol was stirred for 6 hours and 10 minutes in a nitrogen atmosphere at 140° C. Ethyl acetate and H2O were added to the reaction mixture, and this mixture was filtered through Celite, and the residue was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the residue was purified by silica gel column chromatography (eluted with ethyl acetate:n-hexane=1:1), and the objective fractions were concentrated. The residue was crystallized from diethyl ether, to give the title compound (4.8 g, 54%) as pale brown crystals.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:16]2[O:20][N:19]=[C:18]([CH2:21][O:22][CH2:23][C:24]([O:26]CC)=[O:25])[N:17]=2)[CH2:11][C:12]([NH:14][OH:15])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+]>O1CCOCC1.O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:16]2[O:20][N:19]=[C:18]([CH2:21][O:22][CH2:23][C:24]([OH:26])=[O:25])[N:17]=2)[CH2:11][C:12]([NH:14][OH:15])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)COCc1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)COCc1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
A solution of ethyl [(5-{(1R)-4-cyclohexyl-1-[2-(hydroxyamino)-2-oxoethyl]butyl}-1,2,4-oxadiazol-3-yl)methoxy]acetate (Example 49) (158 mg, 0.40 mmol) in 1,4-dioxan (4 ml) and water (2 ml) was treated with lithium hydroxide monohydrate (2 mg, 0.48 mmol) and stirred at room temperature for 2 hours. The reaction mixture was diluted with water and washed with diethylether (×2). The aqueous layer was acidified to pH 1 with hydrochloric acid (2M) and washed with ethyl acetate (×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulphate, filtered and the solvent was removed under reduced pressure to afford the title compound as a colourless oil (141 mg).
Reaction SMILES: [NH2:1][C:2]1[C:31]([Cl:32])=[CH:30][C:5]([C:6]([NH:8][CH2:9][CH:10]2[O:15][CH2:14][CH2:13][N:12]([CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[CH2:11]2)=[O:7])=[C:4]([O:33][CH3:34])[CH:3]=1.N[C:36]1C2CCOC=2C(C(O)=O)=CC=1Cl>>[NH2:1][C:2]1[C:3]2[CH2:36][CH2:34][O:33][C:4]=2[C:5]([C:6]([NH:8][CH2:9][CH:10]2[O:15][CH2:14][CH2:13][N:12]([CH2:16][CH:17]3[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]3)[CH2:11]2)=[O:7])=[CH:30][C:31]=1[Cl:32]
Reactant: Nc1c(Cl)cc(C(=O)O)c2c1CCO2
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CN(CC2CCN(C(=O)OC(C)(C)C)CC2)CCO1
Product: CC(C)(C)OC(=O)N1CCC(CN2CCOC(CNC(=O)c3cc(Cl)c(N)c4c3OCC4)C2)CC1

Procedure:
In place of 4-amino-5-chloro-2-methoxybenzoic acid of Example 1, 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid was treated in the similar manner to Example 1 to give the titled compound as an amorphous solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:17]([OH:20])[C:18]#[CH:19])[CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].I[C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1>[Cu](I)I.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>[C:1]([C:5]1[CH:6]=[C:7]([CH:17]([OH:20])[C:18]#[C:19][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)[CH:8]=[CH:9][C:10]=1[N:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1ccc(I)cc1
Reactant: C#CC(O)c1ccc(N2CCCCC2)c(C(C)(C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Product: CC(C)(C)c1cc(C(O)C#Cc2ccc(C(=O)O)cc2)ccc1N1CCCCC1
Yield: 46.1 %

Procedure:
In a manner analogous to example 1 e, the process is carried out by a reaction of 1.18 g (4.4 mmol) of 1-(3-tert-butyl-4-piperidin-1-ylphenyl)prop-2-yn-1-ol with 890 mg (3.6 mmol) of 4-iodobenzoic acid, 35 mg (0.18 mmol) of copper iodide and 63 mg (0.09 mmol) of bis(triphenylphosphine)palladium chloride. 650 mg of 4-[3-(3-tert-butyl-4-piperidin-1-ylphenyl)-3-hydroxyprop-1-ynyl]benzoic acid are obtained in the form of a beige solid (Mp=112° C., yield=46%).