Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:15])=[CH:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[CH:8]([OH:11])[C:9]#[N:10].[CH3:16][C:17]1([CH3:27])[CH:19]([CH:20]=[C:21]([CH3:23])[CH3:22])[CH:18]1[C:24](Cl)=[O:25].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]([Cl:15])=[CH:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[CH:8]([O:11][C:24]([CH:18]1[CH:19]([CH:20]=[C:21]([CH3:23])[CH3:22])[C:17]1([CH3:27])[CH3:16])=[O:25])[C:9]#[N:10]
Reactant: CC(C)=CC1C(C(=O)Cl)C1(C)C
Reactant: N#CC(O)c1cccc(OC=C(Cl)Cl)c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)=CC1C(C(=O)OC(C#N)c2cccc(OC=C(Cl)Cl)c2)C1(C)C

Procedure:
To a solution of 9.8 g of 3-(2,2-dichlorovinyloxy)-mandelonitrile and 7.5 g of 2,2-dimethyl-3-(1-isobutenyl)-cyclopropanecarboxylic acid chloride in 100 cc toluene is added a solution of 3.5 g of pyridine in 200 ml toluene dropwise within 10 minutes. The resultant suspension is stirred for 15 hours at 20°-25° C., washed with dilute HCl and totally concentrated.
Reaction SMILES: [BH4-].[Na+].Cl[CH:4]([C:14]1[O:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[CH:18]=1)[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.COCCOCCOC.[OH-].[Na+]>CCCCCC>[N+:11]([C:8]1[CH:7]=[CH:6][C:5]([CH2:4][C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[CH:18]=2)=[CH:10][CH:9]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(C(Cl)c2cc3ccccc3o2)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: COCCOCCOC
Product: O=[N+]([O-])c1ccc(Cc2cc3ccccc3o2)cc1

Procedure:
A mixture of 13.6 g. (0.36 mol.) of sodium borohydride and 14.4 g. (0.05 mol.) of 2-(α-chloro-4'-nitrobenzyl)benzofuran in 200 ml. of 80% aqueous diglyme is stirred at 50° for four hours. The reaction mixture is then cooled and hexane followed by 4.0 g. (0.1 mol.) of sodium hydroxide are added. The layers are separated and the organic phase is dried (MgSO4) and concentrated to give 2-(4'-nitrobenzyl)benzofuran.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:9]1([NH:12][C:13]([C:15]2[CH:16]=[CH:17][C:18]([CH3:34])=[C:19]([NH:21][C:22](=[O:33])[C:23]3[CH:28]=[C:27](F)[CH:26]=[CH:25][C:24]=3[N+:30]([O-:32])=[O:31])[CH:20]=2)=[O:14])[CH2:11][CH2:10]1>>[CH:9]1([NH:12][C:13]([C:15]2[CH:16]=[CH:17][C:18]([CH3:34])=[C:19]([NH:21][C:22](=[O:33])[C:23]3[CH:28]=[C:27]([N:5]4[CH2:6][CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][CH2:4]4)[CH:26]=[CH:25][C:24]=3[N+:30]([O-:32])=[O:31])[CH:20]=2)=[O:14])[CH2:11][CH2:10]1
Reactant: CN1CCCNCC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(N2CCCN(C)CC2)ccc1[N+](=O)[O-]

Procedure:
Using an analogous procedure to that described paragraph (A) in the portion of Example 13 which is concerned with the preparation of starting materials 1-methylhomopiperazine was reacted with N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-fluoro-2-nitrobenzamide to give N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-(4-methyl-1,4-diazepan-1-yl)-2-nitrobenzamide; NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.67 (m, 2H), 1.91 (m, 2H), 2.26 (s, 3H), 2.29 (s, 3H), 2.44 (m, 2H), 2.64 (m, 2H), 2.82 (m, 1H), 3.61 (m, 2H), 3.66 (m, 2H), 6.81 (s, 1H), 6.88 (d, 1H), 7.28 (d, 1H), 7.55 (d, 1H), 7.96 (s, 1H), 8.03 (d, 1H), 8.36 (s, 1H), 9.88 (s, 1H); Mass Spectrum: M+H+ 452.
Reaction SMILES: O[CH2:2][CH2:3][C@H:4]1[CH2:6][C@H:5]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:39]I.N1C=CN=C1>ClCCl.C(OCC)C>[I:39][CH2:2][CH2:3][C@H:4]1[CH2:6][C@H:5]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1
Reactant: II
Reactant: CC(C)(C)OC(=O)N1CCC([C@@H]2C[C@@H]2CCO)CC1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC([C@@H]2C[C@@H]2CCI)CC1
Reaction time: 0.33 h

Procedure:
rac-cis-tert-butyl 4-[2-(2-hydroxyethyl)cyclopropyl]piperidine-1-carboxylate (100 mg, 0.37 mmol) from step 2 of this example was dissolved in dichloromethane (3.7 mL), triphenylphosphine (195 mg, 0.74 mmol), iodine (94 mg, 0.37 mmol) and imidazole (51 mg, 0.74 mmol) were added. After 20 minutes, diethyl ether (10 mL) was added, filtered through a silica gel pad (0.5 inch), concentrated and purified by column chromatography through a 24 gram AnaLogix™ silica gel cartridge eluting with 10% ethyl acetate/hexanes to give the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.CO[CH:13](OC)[CH2:14][NH2:15].O>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]2[C:3]=1[CH:4]=[N:15][CH:14]=[CH:13]2
Reactant: O=Cc1cccc(F)c1Br
Reactant: COC(CN)OC
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1ccc2ccncc2c1Br
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-bromo-3-fluorobenzaldehyde (4.06 g, 20 mmol, 1 eq.) and aminoacetaldehyde dimethyl acetal (2.18 mL, 20 mmol, 1 eq.) in toluene (50 mL) was stirred at 130° C. with concomitant removal of H2O (Dean-Stark) for 1 hour. The mixture was concentrated in vacuo and dried under h.v. The resulting imine was added dropwise over 20 min to hot H2SO4 (20 mL) at 140° C. After addition completion, the mixture was stirred at 130° C. for another 30 min. The mixture was allowed to cool to r.t., poured on ice (1 kg). Some black tar was removed by filtration over Celite. The filtrate was basified by addition of 32% aq. NaOH soln. The mixture was extracted with AcOEt (3×200 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by prep. HPLC (column: Water X-Bridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[F:27][C:28]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][OH:31]>>[F:27][C:28]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][O:31][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: OCc1cccc(F)c1F
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCc3cccc(F)c3F)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (70 mg; 0.184 mmol), intermediate 42.1, and 2,3-difluorobenzyl alcohol (113 mg; 0.736 mmol), example 80 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [NH2:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:11]2[C:12](=[O:25])[N:13]([CH2:23][CH3:24])[C:14]3[C:19]([CH:20]=2)=[CH:18][N:17]=[C:16]([NH:21][CH3:22])[CH:15]=3)[CH:3]=1.[Li]CCCC.[C:31]1([N:37]=[C:38]=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[C:6]([C:5]1[C:4]([C:11]2[C:12](=[O:25])[N:13]([CH2:23][CH3:24])[C:14]3[C:19]([CH:20]=2)=[CH:18][N:17]=[C:16]([NH:21][CH3:22])[CH:15]=3)=[CH:3][C:2]([NH:1][C:38]([NH:37][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:39])=[C:9]([F:10])[CH:8]=1)#[N:7]
Reactant: O=C=Nc1ccccc1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2C#N)cc2cnc(NC)cc21
Agent: [Li]CCCC
Solvent: ClCCl
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2C#N)cc2cnc(NC)cc21
Temperature: -60 °C
Reaction time: 0.67 h
Yield: 16.3 %

Procedure:
A −70° C. solution of 4-amino-2-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-5-fluorobenzonitrile (100 mg, 0.296 mmol) in DCM was treated drop-wise with n-BuLi (0.47 mL, 1.17 mmol), stirred at −60° C. for 40 min, treated with phenyl isocyanate (70.6 mg, 0.593 mmol), warmed to RT and stirred for 12 h. The mixture was concentrated and purified by HPLC to afford 1-(4-cyano-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (22 mg, 16% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.28 (s, 1H), 9.08 (s, 1H), 8.46 (s, 1H), 8.42 (d, J=8.0 Hz, 1H), 7.94 (s, 1H), 7.91 (s, 1H), 7.45-7.43 (m, 2H), 7.31-7.27 (m, 2H), 7.18-7.13 (q, J=4.8 Hz, 1H), 7.02-6.98 (m, 1H), 6.26 (s, 1H), 4.16 (q, J=7.2 Hz, 2H), 2.87 (d, J=4.8 Hz, 3H), 1.22 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 457.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3Br)[C:18]2=[O:27])=[CH:12][CH:11]=1.[C:29]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)([CH3:32])([CH3:31])[CH3:30]>>[C:29]([C:33]1[CH:38]=[CH:37][C:36]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:24]=2[CH2:25][N:17]([CH2:16][C:13]2[CH:14]=[CH:15][C:10]([C:9]([NH:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[NH2:1])=[O:28])=[CH:11][CH:12]=2)[C:18]3=[O:27])=[CH:35][CH:34]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(Br)cccc3C2=O)cc1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: CC(C)(C)c1ccc(-c2cccc3c2CN(Cc2ccc(C(=O)Nc4ccccc4N)cc2)C3=O)cc1
Yield: 58 %

Procedure:
The procedure of Example 2 was repeated except for using N-(2-aminophenyl)-4-((4-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 9 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and 4-tert-butylphenyl boronic acid instead of phenyl boronic acid, to obtain the title compound (58%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C:5]([N:7]([CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:6])[CH3:2].Cl.[CH2:31]([C:35]1[O:36][C:37]2[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=2[C:39]=1[CH2:40][NH2:41])[CH2:32][CH2:33][CH3:34].C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:29])[C:5]([N:7]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([NH:41][CH2:40][C:39]2[C:38]3[CH:42]=[CH:43][CH:44]=[CH:45][C:37]=3[O:36][C:35]=2[CH2:31][CH2:32][CH2:33][CH3:34])=[O:26])=[CH:27][CH:28]=1)[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=1)=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)N(Cc1ccc(C(=O)O)cc1)Cc1ccc(C(F)(F)F)cc1
Reactant: CCCCc1oc2ccccc2c1CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCCc1oc2ccccc2c1CNC(=O)c1ccc(CN(Cc2ccc(C(F)(F)F)cc2)C(=O)C(=O)OCC)cc1
Yield: 33 %

Procedure:
The same procedure as employed in the preparation of Example 1 (step d) but using 4-({[ethoxy(oxo)acetyl][4-(trifluoromethyl)benzyl]amino}methyl)benzoic acid and [(2-butyl-1-benzofuran-3-yl)methyl]amine hydrochloride, HOBT and TEA in DCM gave the title compound as a white solid (33%). 1H NMR (CDCl3, 300 MHz) δ 7.66 (m, 2H), 7.51 (m, 3H), 7.35-7.18 (m, 7H), 6.05 (br s, 1H), 4.64 (s, 2H), 4.44 (s, 2H), 4.29 (m, 4H), 2.78 (m, 2H), 1.66 (m, 2H), 1.46 (m, 2H), 1.24 (m, 3H), 0.88 (m, 3H). M−(LC/MS(ESI)): 593; M+(LC/MS(ESI)): 595. HPLC (Condition A), Rt: 6.38 min (HPLC purity: 99.6%).
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=[O:3].[C:19]1([S:25][CH2:26][S:27][CH2:28][C:29](Cl)=[O:30])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][CH:9]2[N:8]([C:11](=[O:12])[CH:10]2[NH:13][C:29](=[O:30])[CH2:28][S:27][CH2:26][S:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7]=1[C:16]([OH:18])=[O:17])(=[O:3])[CH3:1]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(Cl)CSCSc1ccccc1
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)CSCSc3ccccc3)C2SC1

Procedure:
3.1 gms. of 7-aminocephalosporanic acid and 3.4 gms. of [[(phenylthio)methyl]thio]acetyl chloride are treated according to the procedure of Example 3 to obtain DL-3-[(acetyloxy)methyl]-7-[[[[(phenylthio)methyl]thio]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. For purification, this product is converted to its potassium salt with potassium ethyl hexanoate. The reaction mixture is acidified and extracted with ethyl acetate to obtain the purified free acid. This is dissolved in methylene chloride and petroleum ether is added to the solution. The product precipitates in amorphous solid form.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23])[NH2:18]>>[CH3:25][O:24][C:20]1[CH:19]=[C:17]([NH:18][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:2]([OH:1])[CH:3]=2)[CH:16]=[C:15]([O:14][CH3:13])[C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(C(=O)O)cc1O
Reactant: COc1cc(N)cc(OC)c1OC
Product: COc1ccc(C(=O)Nc2cc(OC)c(OC)c(OC)c2)cc1O
Yield: 34 %

Procedure:
Using 3-hydroxyl-4-methoxybenzoic acid and 3,4,5-trimethoxyaniline as materials, compound 87 is synthesized following a similar method as in Example 28. Yield: 34%.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5](=[S:7])[S:4][N:3]=1.CC1C=CC(S(O[CH2:19][CH2:20][CH:21]=[C:22]([F:24])[F:23])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:23][C:22]([F:24])=[CH:21][CH2:20][CH2:19][S:7][C:5]1[S:4][N:3]=[C:2]([CH3:1])[N:6]=1
Reactant: Cc1nsc(=S)[nH]1
Reactant: Cc1ccc(S(=O)(=O)OCCC=C(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1nsc(SCCC=C(F)F)n1
Yield: 32 %

Procedure:
To a solution of 3-methyl-1,2,4-thiadiazole-5(4H)-thione (1.2 g) in acetone (100 cm3) was added 4,4-difluorobut-3-enyl 4-methylbenzenesulfonate (2.4 g) and potassium carbonate (1.2 g) and the mixture was refluxed for 4 hours after which tlc indicated complete consumption of starting material. The reaction was poured into ethyl acetate and water and the layers separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried (MgSO4). The solution of product was then filtered and evaporated under reduced pressure to give a brown oil which was purified by flash chromatography (silica, 7% ethyl acetate in hexane) to give 5-(4,4-difluorobut-3-enylthio)-3-methyl-1,2,4-thiadiazole as a brown oil (0.645 g). M+ =222; 1H NMR: δ 2.56(2H,br q); 2.63 (3H,s); 3.30(2H,t); 4.30(1H,m).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH:11]1([SH:16])[CH2:15][CH2:14][CH2:13][CH2:12]1.Br[CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1>C1COCC1>[CH:11]1([S:16][CH2:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: SC1CCCC1
Reactant: N#Cc1ccc(CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccc(CSC2CCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Add sodium bis(trimethylsilyl)amide (20 mL, 40 mmol, 2M solution in THF) to a solution of cyclopentanethiol (4.3 mL, 40 mmol) in anhydrous THF (100 mL) and stir at room temperature under nitrogen for 1 h. Add 4-bromomethyl-benzonitrile (7.85 g, 40 mmol) and stir the mixture for 24 h at room temperature. Reduce solvent in vacuo and wash with saturated aqueous NaHCO3. Extract with DCM (50 mL), wash organic phase with brine (50 mL) and dry over MgSO4 to obtain a light yellow oil suitable for use without additional purification. GC-MS m/z: 217 (M+).
Reaction SMILES: Br[C:2]1[C:3]2[O:10][CH:9]=[CH:8][C:4]=2[CH:5]=[N:6][CH:7]=1.[Cu](C#N)[C:12]#[N:13].CN(C)C=O>C(OCC)C.[Cu](I)I>[O:10]1[C:3]2[C:2]([C:12]#[N:13])=[CH:7][N:6]=[CH:5][C:4]=2[CH:8]=[CH:9]1
Reactant: Brc1cncc2ccoc12
Reactant: N#C[Cu]C#N
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCOCC
Product: N#Cc1cncc2ccoc12
Temperature: 25 °C

Procedure:
Combine 7-bromofuro[3,2-c]pyridine (4.673 g, 23.5 mmol), copper cyanide (4.21 g, 47.1 mmol), copper iodide (8.96 g, 47.1 mmol), and anhydrous dimethylformamide (100 mL) and at 130° C. for 30 hours. Cool to room temperature, dilute with diethyl ether and wash with 15% aqueous ammonium hydroxide. Extract combined aqueous layers with diethyl ether, wash combined organic layers with 15% aqueous ammonium hydroxide, and brine, dry over magnesium sulfate, and concentrate. Purification using flash chromatography, eluting with hexane: ethyl acetate gives the tide compound as a white solid.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:9]([N:11](OC)[CH3:12])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:23](N)C.CCO.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:1]1([CH2:7][C@H:8]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:9]([NH:11][CH2:12][CH3:23])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CON(C)C(=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reactant: CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCO
Solvent: CN(C)C=O
Product: CCNC(=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 34 %

Procedure:
To a solution of (S)-tert-butyl 3-cyclohexyl-1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (1.17 g, 4.3 mmol) and TEA (2.4 mL, 17.2 mmol) in anhydrous DMF was added 2.0 M EtNH2 solution in EtOH (6.5 mL, 13 mmol), followed by HBTU (1.96 g, 5.2 mmol). The resulting solution was stirred at rt for 3 h. The reaction was concentrated under reduced pressure and the residue dissolved in EtOAc (50 mL). The mixture was then washed with 1 M NaOH (4 times), 1 M HCl (3 times), sat. aq. NaHCO3, brine, dried over Na2SO4 and filtered. The concentrated residue gave (S)-tert-butyl 3-cyclohexyl-1-(ethylamino)-1-oxopropan-2-ylcarbamate (444 mg, 34%). MS ESI +ve m/z 299 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30]Br>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=2[Cl:27])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: CCOC(=O)c1cccc(Cc2cc(Cl)ccc2O)n1
Reactant: Clc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(Cc2cc(Cl)ccc2OCc2ccccc2Cl)n1
Temperature: 80 °C

Procedure:
A solution of ethyl 6-[(5-chloro-2-hydroxyphenyl)methyl]-2-pyridinecarboxylate (60 mg, 0.21 mmol) in dry dimethylformamide (2.1 ml) was stirred at room temperature under an atmosphere of argon. Potassium carbonate (44 mg, 0.32 mmol) was added to the stirred solution. 2-Chlorobenzyl bromide (51 mg, 0.25 mmol) was added to the stirred solution. The solution was heated to 80° C. for ˜17 hours (overnight). The reaction was worked up to yield the title compound.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[O:9]=[C:10]1[NH:14][C:13]([CH2:21][OH:22])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12](=[O:23])[N:11]1[C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([O:32][CH3:33])[CH:25]=1>CN(C=O)C>[O:9]=[C:10]1[N:14]([CH3:1])[C:13]([CH2:21][OH:22])([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:12](=[O:23])[N:11]1[C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([O:32][CH3:33])[CH:25]=1
Reactant: COc1cc(N2C(=O)NC(CO)(c3ccccc3)C2=O)ccc1C#N
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(N2C(=O)N(C)C(CO)(c3ccccc3)C2=O)ccc1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
173 mg potassium carbonate and 86 μL methyl iodide are added to a solution of 141 mg 4-[2,5-dioxo-4-hydroxymethyl-4-phenylimidazolidin-1-yl]-2-methoxybenzonitrile in 2 mL DMF. The mixture is stirred overnight at room temperature, evaporated to dryness, The residue is taken in water and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered, evaporated and chromatographed over silica gel while eluting with 70/30 heptane/ethyl acetate mixture to give the expected product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11][CH2:12][C:13](=O)[N:14]([CH3:16])[CH3:15])=[CH:9][NH:8][C:7]=1[CH3:18])=[O:5])[CH3:2].B.O1CCCC1.CO>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])=[CH:9][NH:8][C:7]=1[CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CCC(=O)N(C)C)c[nH]c1C
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1c(CCCN(C)C)c[nH]c1C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
To a heterogeneous mixture of 4-(2-dimethylcarbamoyl-ethyl)-2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (1.01 g, 4 mmol) in THF (9 mL) was added dropwise 8 mL of borane-tetrahydrofuran complex (1M in THF). The mixture was refluxed overnight. Then 9.0 mL of MeOH was added slowly to the reaction and refluxing was continued for another 2 hr. The reaction mixture was cooled, quenched with 1N HCl and extracted with EtOAc. The aqueous layer was basified with aqueous KOH and extracted with EtOAc. The EtOAc extract was washed with brine, dried and concentrated to give 616 mg (65%) of 4-(3-dimethylaminopropyl)-2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester as a faint orange oil.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[N:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[CH:24][CH:23]=3)[S:19][C:20]=2[CH3:21])[CH3:15])=[CH:8][C:7]=1[CH3:34].[OH-:36].[Na+].Cl>O1CCCC1.C(OCC)(=O)C>[CH3:34][C:7]1[CH:8]=[C:9]([O:12][CH2:13][CH:14]([C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[N:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[CH:24][CH:23]=3)[S:19][C:20]=2[CH3:21])[CH3:15])[CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][C:3]([OH:35])=[O:2].[C:9]([O:12][CH2:13][CH3:14])(=[O:36])[CH3:8]
Reactant: [OH-]
Reactant: COC(=O)CCc1ccc(OCC(C)c2nc(-c3ccc(-c4ncccn4)cc3)sc2C)cc1C
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(OCC(C)c2nc(-c3ccc(-c4ncccn4)cc3)sc2C)ccc1CCC(=O)O
Temperature: 25 °C

Procedure:
3-(2-Methyl-4-{2-[5-methyl-2-(4-pyrimidin-2-yl-phenyl)-thiazol-4-yl]-propoxy}-phenyl)-propionic acid methyl ester (698 mg, 1.43 mmol) is dissolved in tetrahydrofuran (2 mL) and 5N sodium hydroxide (2 mL) solution is added with stirring at room temperature. The reaction is heated to reflux and monitored by HPLC. Upon complete conversion, the reaction is allowed to cool to room temperature and neutralized with 5N hydrochloric acid (2 mL), diluted with ethyl acetate, and extracted. The organic layer is washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The pure 3-(2-Methyl-4-{2-[5-methyl-2-(4-pyrimidin-2-yl-phenyl)-thiazol-4-yl]-propoxy}-phenyl)-propionic acid (462 mg, 0.9755 mmol) may also be obtained by recrystalization from ethyl acetate (68% yield), MS (ES): ?? (M++1).
Reaction SMILES: Br[CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:3]1.[CH2:17]([OH:20])[CH2:18][OH:19].N1C(C)=CC=CC=1C>O.[B-](F)(F)(F)F.[Ag+]>[OH:19][CH2:18][CH2:17][O:20][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:3]1
Reactant: O=C(O)CCCCCCC1=CC(Br)CC1=O
Reactant: OCCO
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: O
Product: O=C(O)CCCCCCC1=CC(OCCO)CC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 19.1 g. of crude 4-bromo-2-(6-carboxyhexyl)cyclopent-2-en-1-one (Example 93) in 310 ml. of ethylene glycol is added 15.6 g. (80 mmole) of silver fluoborate during 2 minutes. The exothermic reaction is controlled to give a temperature of 29° C., and after 1 minute the mixture is treated during 1 minute with 8.6 g. (80 mmole) of 2,6-lutidine. The mixture is stirred at ambient temperature for 2 hours, diluted with water, and filtered. The filtrate is diluted with saturated sodium chloride solution and extracted with ether. The extract is washed with half-saturated sodium chloride solution containing a little hydrochloric acid and saturated sodium chloride solution. The extract is dried over magnesium sulfate and concentrated. Column chromatograph of the residue on silica gel gives an oil, λ maxMeOH = 216 mμ (8350); ν max = 3340 (hydroxyl groups), 1700 (carbonyl groups), and 1620 cm -1 (olefin group).