Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][N:10]=[C:9]2[S:18][C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[OH-].[Na+].CO.C1COCC1>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]2[S:18][C:19]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc(SC(c2ccccc2)(c2ccccc2)c2ccccc2)n1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cnc(SC(c2ccccc2)(c2ccccc2)c2ccccc2)n1-c1ccc(F)cc1

Procedure:
To a solution of ethyl 1-(4-fluorophenyl)-2-mercapto-1H-imidazole-5-carboxylate (3) (4.09 g, 15.34 mmol) in THF (70 mL) was added triethyl amine (4.50 mL, 32.29) and triphenylmethyl chloride (4.67 g, 16.76 mmol) and the solution was stirred for 1 hour at room temperature. The reaction was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (10%-40% EtOAc in hexanes) to give ethyl 1-(4-fluorophenyl)-2-(tritylthio)-1H-imidazole-5-carboxylate. A solution of ethyl 1-(4-fluorophenyl)-2-(tritylthio)-1H-imidazole-5-carboxylate (6.34 g, 12.47 mmol), sodium hydroxide (0.74 g, 18.39 mmol), methanol (10 mL), THF (20 mL), and water (10 mL) was stirred at room temperature for 16 hour and was then concentrated in vacuo. The aqueous was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to yield 1-(4-fluorophenyl)-2-(tritylthio)-1H-imidazole-5-carboxylic acid (6).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:17])[N:4]([CH2:14][CH2:15][CH3:16])[C:5](=[O:13])[N:6]([CH2:9][CH:10]([OH:12])[CH3:11])[C:7]=1[NH2:8].[C:18](O)(=O)[CH3:19]>>[OH:12][CH:10]([CH3:11])[CH2:9][N:6]1[C:7]2[N:8]=[C:18]([CH3:19])[NH:1][C:2]=2[C:3](=[O:17])[N:4]([CH2:14][CH2:15][CH3:16])[C:5]1=[O:13]
Reactant: CC(=O)O
Reactant: CCCn1c(=O)c(N)c(N)n(CC(C)O)c1=O
Product: CCCn1c(=O)c2[nH]c(C)nc2n(CC(C)O)c1=O

Procedure:
About 15 g of 5,6-diamino-1-(2-hydroxypropyl)-3-propyl-2,4-(1H, 3H)-pyrimidinedione as an oil was refluxed for one hour in 50 ml of acetic acid. The solution was evaporated and the residue was dissolved in water. Active carbon was added and filtered off. To the filtrate 25 ml of 5-N NaOH was added and the solution was refluxed for 30 minutes. Hydrochloric acid was added until acid reaction and the received crystals were filtered off and recrystallized from 200 ml of water. Yield 2.7 g. NMR.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:26]([NH:29][CH2:30][CH2:31][C:32]([O:34]C)=[O:33])([CH3:28])[CH3:27])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.[OH-].[Li+]>O1CCCC1.CO>[F:1][C:2]1[CH:3]=[C:4]([C:26]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])([CH3:27])[CH3:28])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2
Reactant: COC(=O)CCNC(C)(C)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(NCCC(=O)O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of methyl 3-(2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)propan-2-ylamino)propanoate (0.067 g, 0.137 mmol) in tetrahydrofuran (1 mL) and methanol (0.5 mL) was added 1 M lithium hydroxide solution (0.4 mL, 0.4 mmol) and stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo and the resulting slurry was diluted with water and neutralized (to pH=˜7) with aqueous 1 N HCl solution. The aqueous suspension was extracted with 15% MeOH/CHCl3; the organic extracts were combined, dried (K2CO3), filtered, and concentrated in vacuo to give a crude golden yellow solid (˜0.040 g). Trituration with MeOH afforded the title compound as an off-white amorphous solid. MS (ESI) m/z: Calculated: 475.5; Observed: 476.1 (M++1).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][C:6]=1[O:15][CH2:16][CH3:17])(=O)C.[CH2:18](O)[CH2:19][CH3:20]>OS(O)(=O)=O.C(OCC)C>[CH2:18]([O:14][C:12](=[O:13])[CH2:11][C:8]1[CH:9]=[CH:10][C:5]([OH:4])=[C:6]([O:15][CH2:16][CH3:17])[CH:7]=1)[CH2:19][CH3:20]
Reactant: CCCO
Reactant: CCOc1cc(CC(=O)O)ccc1OC(C)=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCCOC(=O)Cc1ccc(O)c(OCC)c1
Temperature: 90 °C

Procedure:
Intermediate 4 (1.40 g, 5.87 mmol) was dissolved in an excess of 1-propanol (50 mL), concentrated H2SO4 (3 drops) was added, and the mixture was heated at 90° C. for ˜18 hours. The volume of 1-propanol was reduced under vacuum, then the mixture was diluted with diethyl ether, washed with saturated sodium bicarbonate solution (2×), distilled water (1×), brine (1×), dried over magnesium sulfate and solvent was removed under vacuum, giving intermediate 5 as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([F:26])=[CH:22][C:23]=3[F:25])[N:18]=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[C:16]=2[CH3:33])[C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[NH:34]1[CH2:39][CH2:38][CH:37]([C:40]#[N:41])[CH2:36][CH2:35]1.C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[F:25][C:23]1[CH:22]=[C:21]([F:26])[CH:20]=[C:19]2[C:24]=1[C:15]([NH:14][C:4]1[CH:3]=[C:2]([N:34]3[CH2:39][CH2:38][CH:37]([C:40]#[N:41])[CH2:36][CH2:35]3)[CH:7]=[N:6][C:5]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[C:16]([CH3:33])[C:17]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)=[N:18]2
Reactant: N#CC1CCNCC1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(Br)cnc1N1CCOCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCC(C#N)CC2)cnc1N1CCOCC1
Temperature: 100 °C
Reaction time: 21.5 h

Procedure:
A stirred mixture of N-(5-bromo-2-morpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine (0.049 g, 0.096 mmol), piperidine-4-carbonitrile (commercially available from Oakwood Products, Inc.) (0.023 g, 0.21 mmol), 2-dicyclohexylphosphino-2,4,6,-triisopropylbiphenyl (0.0097 g, 0.020 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.0095 g, 10.4 μmol), and sodium tert-butoxide (0.044 g, 0.46 mmol) in dry toluene (3.0 mL) was purged three times with argon and placed under vacuum three times, then the mixture was heated to 100° C. After 21.5 h, the reaction was cooled to rt, then treated with water. After extracting twice with DCM:MeOH (95:5), the organics were combined and dried over anhydrous magnesium sulfate. After filtration and concentration the residue was purified on basic alumina (10-50% EtOAc in hexanes) to afford a light yellow solid as 1-(5-((5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)amino)-6-(4-morpholinyl)-3-pyridinyl)-4-piperidinecarbonitrile. Mass Spectrum ESI (pos.) m/e: 542.2 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[C:11]([CH2:13][C:14]([NH2:16])=[S:15])#[N:12].N>CCO>[C:5]1([C:3]2[N:16]=[C:14]([CH2:13][C:11]#[N:12])[S:15][CH:2]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N#CCC(N)=S
Reactant: O=C(CBr)c1ccccc1
Agent: N
Solvent: CCO
Product: N#CCc1nc(-c2ccccc2)cs1
Temperature: 80 °C
Yield: 74.9 %

Procedure:
A mixture of 2-bromoacetophenone (2 g, 10 mmol) and 2-cyanothioacetamide (1 g, 10 mmol) in EtOH (25 mL) was heated to 80° C. for 4 h. The reaction mixture was cooled to room temperature and poured into an aqueous ammonia solution (final pH was >7). The mixture was then extracted with EtOAc and the organic layer was washed with H2O and brine. Solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (silica gel 230-400 mesh, eluent 8% EtOAc in petroleum ether) to afford 2-(4-phenylthiazol-2-yl)acetonitrile (1.5 g, yield 75%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.88-7.91 (m, 2H), 7.49 (s, 1H), 7.27-7.48 (m, 3H), 4.19 (s, 2H). MS (ESI) m/z: Calculated for C11H8N2S: 200.04. found: 201.2 (M+H)+.
Reaction SMILES: Br[C:2]1([F:12])[CH2:10][CH2:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[C:3]1=[O:11].C(=O)([O-])[O-].[Li+].[Li+].[Br-].[Li+].Cl>CN(C)C=O>[F:12][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[C:3]=1[OH:11]
Reactant: O=C1c2ccsc2CCC1(F)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CN(C)C=O
Product: Oc1c(F)ccc2sccc12
Temperature: 25 °C
Yield: 79.4 %

Procedure:
Heat a mixture of 5-bromo-5-fluoro-6,7-dihydro-5H-benzo[b]thiophen-4-one (6.97 g, 28.0 mmol, 1 equiv.), lithium carbonate (4.34 g, 58.7 mmol, 2.1 equiv.), and lithium bromide (5.61 g, 64.6 mmol, 2.3 equiv.) in dry dimethylformamide (150 mL) at 150° C. (internal temperature) for 2 hours. Cool the reaction mixture to room temperature, add ice water, and then carefully add 5N HCl until gas evolution ceases and the mixture is acidic. Add ethyl acetate, separate the layers, and extract the aqueous layer with ethyl acetate (3 times). Extract the combined organic extracts with 2N sodium hydroxide (2 times), reacidify the aqueous layers with hydrochloric acid, and then re-extract the aqueous layer with dichloromethane (3 times). Dry the dichloromethane extracts over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the resultant crude material by medium pressure liquid chromatography eluting with 0 to 10% ethyl acetate in hexanes to afford the title compound as a colorless solid (3.738 g, 79%). δH (400 MHz, CDCl3) 5.35 (br s, 1H), 7.13 (dd, 1H, J=10, 8 Hz), 7.34 (ddd, 1H, J=8, 4, 1 Hz), 7.42 (d, 1H, J=6 Hz), 7.49 (dd, 1H, J=6, 1 Hz).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([C:14]2[N:15]=[CH:16][N:17](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:18]=2)(O)[CH3:12])[CH:4]=[CH:3][CH:2]=1.O.[OH-].[Na+]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1.C(O)(=O)C>[NH:17]1[CH:18]=[C:14]([C:11]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[N:1]=[CH:2][CH:3]=[CH:4]3)=[CH2:12])[N:15]=[CH:16]1
Reactant: CC(O)(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cccc2cccnc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(c1c[nH]cn1)c1cccc2cccnc12
Temperature: 25 °C

Procedure:
1-Quinolin-8-yl-1-(1-trityl-1H-imidazol-4-yl)-ethanol (Intermediate C1) and p-toluenesulfonic acid catalyst in toluene was heated to reflux in a Dean-Stark apparatus for 18 h. The mixture was cooled to rt and freed of solvent. The residue was dissolved in 70% acetic acid:water and heated to 100° C. for 1 h. The reaction mixture was cooled to rt and basified with 2 M NaOH and extracted with chloroform:isopropyl alcohol (3:1). The organic layers were pooled, dried over MgSO4, filtered and concentrated onto silica gel. The product was eluted from a column of silica gel with 4% NH3-MeOH:CH2Cl2 to give 8-[1-(1H-imidazol-4-yl)-vinyl]-quinoline.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:14][CH3:15])(=[O:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10].[CH:16]([C:18]([CH3:20])=[O:19])=[CH2:17].CC(OC)(C)C>O>[CH3:12][O:11][C:9](=[O:10])[CH:8]([CH2:17][CH2:16][C:18](=[O:19])[CH3:20])[C:7]([O:14][CH3:15])=[O:13]
Reactant: C=CC(C)=O
Reactant: COC(=O)CC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: O
Product: COC(=O)C(CCC(C)=O)C(=O)OC
Temperature: 15 °C

Procedure:
Potassium carbonate (5.62 kg), dimethyl malonate (54.8 kg) and acetonitirile (90 kg) were charged to the reaction vessel and stirred together at 15° C. Methyl vinyl ketone (28.5 kg) was pumped into the vessel over 2 hours at below 25° C. The slurry was stirred at 18-20° C. for 2 hours. MTBE (132 kg) was charged to the vessel to dilute the reaction mixture followed by water (114 kg). The mixture was stirred for five minutes then the layers were allowed to separate and the aqueous layer run off. More water (57 kg) was charged to the vessel, the reaction mixture stirred for another 5 minutes, the layers allowed to separate, and again the aqueous layer run off. The organic layer was concentrated under reduced pressure until most of the solvent had been removed (volume approx 80 L) affording 76 kg of A-1 as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:14][C@@:13]([C:22](=[O:24])[NH2:23])([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[C:12]2[CH:25]=[C:26]([CH2:32][CH3:33])[C:27]([CH2:30][CH3:31])=[C:28]([Cl:29])[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(OCC)(=O)C>[ClH:29].[Cl:29][C:28]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:14][C@@:13]([C:22](=[O:24])[NH2:23])([C:15]3[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=3)[C:12]=2[CH:25]=[C:26]([CH2:32][CH3:33])[C:27]=1[CH2:30][CH3:31]
Reactant: CCc1cc2c(c(Cl)c1CC)CCN(C(=O)OC(C)(C)C)C[C@@]2(C(N)=O)c1ccc(O)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCc1cc2c(c(Cl)c1CC)CCNC[C@@]2(C(N)=O)c1ccc(O)cc1
Reaction time: 72 h

Procedure:
A solution of 14.3 g(0.03 moles) of (R)-3-t-butyloxycarbonyl-6-chloro-7,8-diethylcarbamyl-1-(4'-hydroxyphenyl) 2,3,4,5-tetrahydro-1H-3-benzazepine, in 100 ml of ethyl acetate at 25° C. was treated with 50 ml of ethereal hydrogen chloride under argon atmosphere. After stirring for 72 hours, the reaction mixture was concentrated under reduced pressure and chased with 200 ml. of dry toluene. The resulting residue was triturated with 00 ml of ethyl acetate to give (R)-6-chloro-7,8-diethycarbamoyl-1-(4-hydroxyphenyl)-2,3,4,5-tetrahydro-1H 3-benzazepine hydrochloride, M.P. 185°-190° C. The Rf and the NMR of this compound was similar to that of the corresponding racemic compound of Example 5.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH2:10]([C:12]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:13][CH:14]=O)[CH3:11]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:11]/[CH2:10][C:12]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCC(CC)(CC)CC=O
Solvent: ClCCl
Product: CCC(CC)(CC)C/C=N/CC(=O)OC(C)(C)C
Yield: 100.7 %

Procedure:
Step F In a manner similar to the method described in Example 1a, glycine tert-butyl ester (0.92 g, 7 mmol) was reacted with 3,3-diethyl-pentanal (1 g, 7 mmol) in CH2Cl2 at room temperature for 5 h to give [3,3-diethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1.8 g, 100%).
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([C:19]3[N:23]=[C:22](C(Cl)(Cl)Cl)[O:21][N:20]=3)[CH:16]=[CH:15][N:14]=2)[CH2:9][CH2:8]1)=[O:6].[CH3:30][NH:31][CH3:32].CO>CO>[CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([C:19]3[N:23]=[C:22]([N:31]([CH3:32])[CH3:30])[O:21][N:20]=3)[CH:16]=[CH:15][N:14]=2)[CH2:9][CH2:8]1)=[O:6]
Reactant: CC(C)(C)CCC(=O)N1CCN(c2cc(-c3noc(C(Cl)(Cl)Cl)n3)ccn2)CC1
Reactant: CNC
Solvent: CO
Product: CN(C)c1nc(-c2ccnc(N3CCN(C(=O)CCC(C)(C)C)CC3)c2)no1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(4,4-Dimethylpentanoyl)-4-{4-[5-(trichloromethyl)-1,2,4-oxadiazol-3-yl]pyridin-2-yl}piperazine (48.1 mg) was dissolved in methanol (2 mL), and 2.0 M dimethylamine/methanol solution (1 mL) was added thereto and stirred at room temperature for 2 hours. Then, the solvent was evaporated away and the resulting residue was isolated and purified through thin-layer silica gel chromatography (hexane/ethyl acetate=1/1) to obtain 17.5 mg of the entitled compound as a yellow oil.
Reaction SMILES: [O:1]1[C@H:6]([CH2:7][CH3:8])[C@H:2]1[C:3]([OH:5])=[O:4].[OH-].[Na+].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[CH2:11]([NH:18][C@H:2]([C@H:6]([OH:1])[CH2:7][CH3:8])[C:3]([OH:5])=[O:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: CC[C@H]1O[C@@H]1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC[C@@H](O)[C@@H](NCc1ccccc1)C(=O)O
Yield: 75 %

Procedure:
To 14.2 g (0.05 mol) of the (2S,3R)-2,3-epoxypentanoic acid obtained in (4) above were added 500 ml of water and 6.4 g (0.16 mol) of sodium hydroxide, and 42.6 g (0.15 mol) of benzylamine (VI) was added thereto, followed by refluxing for 8 hours. Water was evaporated, and the concentrate was adjusted to pH 5 to 6 with diluted hydrochloric acid and extracted with 500 ml of ethyl acetate. After drying, ethyl acetate was removed by evaporation to yield 8.36 g (0.0375 mol, 75%) of the title compound. Optical rotation [α]D25 =+12.84° (c=0.1, CHCl3 :CH3OH=1:1 by volume)
Reaction SMILES: [C:1]([NH:10][NH2:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:12](OCC)(OCC)(OCC)[CH3:13]>C(O)CC>[CH3:12][C:13]1[O:9][C:1]([C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[OH:4])=[N:10][N:11]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: NNC(=O)c1ccccc1O
Solvent: CCCO
Product: Cc1nnc(-c2ccccc2O)o1
Yield: 44.5 %

Procedure:
90 g (0.6 mole) of salicylic acid hydrazide and 388.8 g (2.4 moles) of triethyl orthoacetate in 500 ml of n-propanol are refluxed for 84 hours. When the mixture has cooled, the precipitate is filtered off and recrystallized from a mixture of toluene and petroleum ether. 47 g of colorless crystals (26.7% of theory) are obtained; melting point 74°-76° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([OH:10])[CH2:5]1)(=[O:3])[CH3:2].[OH-].[Na+].Cl[C:14]1[N:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([Cl:29])[CH:22]=2)[N:17]=[C:16]([NH:30][CH:31]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[N:15]=1>C1C=CC=CC=1>[Cl:29][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[O:27][CH3:28])[NH:20][C:18]1[N:17]=[C:16]([NH:30][CH:31]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[N:15]=[C:14]([O:10][CH:6]2[CH2:7][CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5]2)[N:19]=1
Reactant: CC(=O)N1CCCC(O)C1
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(OC3CCCN(C(C)=O)C3)n2)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of N-acetyl-3-hydroxypiperidine (0.335 g, 2.27 mmol) and sodium hydroxide (95 mg, 2.27 mmol) in benzene (10 mL) was heated to reflux for 2 hours with stirring under nitrogen atmosphere and then cooled to 25° C. followed by the addition of compound 133 (0.3 g, 0.78 mmol) at same temperature. The mixture was heated to reflux for 6 hours, concentrated under vacuum and diluted with water (10 mL). The precipitated solid was filtered off and purified by column chromatography to afford the title compound E20 as an off-white solid (0.35 g, 91%). mp 138-140° C.; HPLC: Inertsil ODS 3V (250×4.6 mm) 5 microns [solvent A=0.01 M KH2PO4 (pH 7.0); solvent B=CH3CN], Gradient elution program: T/% B=0/60, 10/60,25/80, 40/80, 45/60, 50/60; 268 nm, Rt 17.20 min, 91.70% purity; MS (CI): m/z 489 (M+, 100).
Reaction SMILES: CC1C=CC(S(OCC2CC3C=CC=C(/C=C/C(C)(C)C)C=3O2)(=O)=O)=CC=1.[N-]=[N+]=[N-].[Na+].[CH3:32][C:33]([CH3:50])([CH3:49])/[CH:34]=[CH:35]/[C:36]1[C:44]2[O:43][CH:42]([CH2:45][N:46]=[N+]=[N-])[CH2:41][C:40]=2[CH:39]=[CH:38][CH:37]=1.[N-]=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH3:32][C:33]([CH3:50])([CH3:49])/[CH:34]=[CH:35]/[C:36]1[C:44]2[O:43][CH:42]([CH2:45][NH2:46])[CH2:41][C:40]=2[CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)/C=C/c1cccc2c1OC(CN=[N+]=[N-])C2
Agent: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(/C=C/C(C)(C)C)c3O2)cc1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Product: CC(C)(C)/C=C/c1cccc2c1OC(CN)C2
Yield: 28 %

Procedure:
Treatment of (±)-{7-[(1E)-3,3-dimethylbut-1-enyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate (6.54 g, 16.92 mmol) with sodium azide (4.37 g, 67.68 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-{7-[(1E)-3,3-dimethylbut-1-enyl]-2,3-dihydro-1-benzofuran-2-yl}methyl azide. Treatment of the azide (1.78 g, 6.92 mmol) with triphenylphosphine (1.81 g, 6.92 mmol) generally according to the procedure described for Example 21 afforded 0.454 g (28%) of (±)-1-{7-[(1E)-3,3-dimethylbut-1-enyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine as a white solid, hydrochloride salt. mp 216-218° C.; Anal. calcd. for C15H21NOHCl: C, 67.28; H, 8.28; N, 5.23. Found: C, 66.19; H, 8.27; N, 5.14.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([OH:33])=O)[C:25]=1[CH3:34])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH:56]1([NH:59][C:60]([C@@H:62]2[CH2:67][CH2:66][CH2:65][NH:64][CH2:63]2)=[O:61])[CH2:58][CH2:57]1>CN(C=O)C.C(Cl)Cl>[CH:56]1([NH:59][C:60]([C@@H:62]2[CH2:67][CH2:66][CH2:65][N:64]([C:31](=[O:33])[CH2:30][C:26]3[C:25]([CH3:34])=[C:24](/[CH:23]=[C:16]4\[C:17](=[O:22])[NH:18][C:19]5[C:15]\4=[CH:14][C:13]([S:10]([CH2:9][C:3]4[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])(=[O:12])=[O:11])=[CH:21][CH:20]=5)[NH:28][C:27]=3[CH3:29])[CH2:63]2)=[O:61])[CH2:58][CH2:57]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Reactant: O=C(NC1CC1)[C@@H]1CCCNC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)N1CCC[C@@H](C(=O)NC2CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
A mixture of {5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (250 mg, 0.5 mmol), HOBt (65 mg), EDAC (191 mg), (R)-piperidine-3-carboxylic acid cyclopropylamide (250 mg) and TEA (7 drops) in DMF (3 mL) was stirred at rt for overnight. The reaction was diluted with DCM, washed with water, 10% sodium carbonate, dried and concentrated. The residue was purified on a silica gel column to give 107 mg of the titled compound.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[I-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cl:28][C:29]1[CH:30]=[CH:31][C:32]2[O:36][CH2:35][C:34](=O)[C:33]=2[C:38]=1[NH:39][C:40](=[O:45])[C:41]([F:44])([F:43])[F:42]>C1(C)C=CC=CC=1>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]2[O:36][CH2:35][C:34](=[CH2:1])[C:33]=2[C:38]=1[NH:39][C:40](=[O:45])[C:41]([F:44])([F:43])[F:42]
Reactant: O=C1COc2ccc(Cl)c(NC(=O)C(F)(F)F)c21
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=C1COc2ccc(Cl)c(NC(=O)C(F)(F)F)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of potassium tert-butoxide (2.0) and methyltriphenylphosphonium iodide (7.1 g) was added dry toluene (70 ml) and the mixture stirred at room temperature for 30 min, then heated under reflux for 30 min. The mixture was cooled to room temperature, a solution of Intermediate 22 (1.0 g) in toluene (30 ml) added dropwise and the mixture heated under reflux for 30 min. The mixture was cooled and quenched by the dropwise addition of saturated ammonium chloride solution. The mixture was partitioned between ethyl acetate and water and the organic phase washed with water. The combined aqueous layers were re-extracted with ethyl acetate and the combined organic layers dried over sodium sulphate and concentrated in vacuo to give a dark brown oil. Purification by column chromatography on silica gel, eluting with 10% ethyl acetate in cyclohexane, gave the title compound as a rose coloured solid (0.5 g).