Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5](=O)[CH2:6][C:7]1[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][C:8]=1[N+:15]([O-])=O)[CH3:2].[H][H]>CCO.[Pd]>[CH2:1]([O:3][C:4]([C:5]1[NH:15][C:8]2[C:7]([CH:6]=1)=[CH:12][C:11]([C:13]#[N:14])=[CH:10][CH:9]=2)=[O:19])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(=O)Cc1cc(C#N)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc2cc(C#N)ccc2[nH]1
Yield: 51 %

Procedure:
Add to 1.2 g 3-(5-cyano-2-nitrophenyl)-2-oxopropionic acid ethyl ester 2 (m=0) in EtOH (40 mL), 10% Pd/C (0.40 g) and stir under a hydrogen atmosphere until the theoretical amount of hydrogen is absorbed. Filter the mixture and concentrate the filtrate to afford 1.1 g of crude product. Purify by chromatography on SiO2 eluting with CH2Cl2. Concentrate the desired fractions and vacuum dry the residue over night (40° C.) to provide the title compound (0.5 g) as white crystals, Rf=0.9 (silica gel, 10% MeOH/CH2Cl2).
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]([C:21]#[C:22][Si](C)(C)C)[CH:10]=[C:11]2[C:16]=1[O:15][C:14]([CH3:18])([CH3:17])[CH2:13][C:12]2([CH3:20])[CH3:19])=[O:6])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[CH:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]([C:21]#[CH:22])[CH:10]=[C:11]2[C:16]=1[O:15][C:14]([CH3:18])([CH3:17])[CH2:13][C:12]2([CH3:20])[CH3:19])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)c1cc(C#C[Si](C)(C)C)cc2c1OC(C)(C)CC2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cc(C(=O)OC(C)C)c2c(c1)C(C)(C)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.2 %

Procedure:
A solution of 2,2,4,4-tetramethyl-6-trimethylsilanylethynylchroman-8-carboxylic acid isopropyl ester (Intermediate 43, 0.23 g, 0.62 mmol) in methanol (5 mL) was treated with potassium carbonate (0.85 g, 6.2 mmol) and the resulting reaction mixture was stirred at ambient temperature overnight. The solvent was evaporated in vacuo, the residue was diluted with water and extracted with diethyl ether. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a brown oil that was subjected to flash column chromatography over silica gel (230-400 mesh) using 20% ethyl acetate in hexane as the eluent to afford the title compound (0.0246 g, 13%).
Reaction SMILES: [C:1]1([CH2:11][C:12]#[N:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Na].CO.[C:17](=O)([O:20]C)[O:18][CH3:19]>>[C:1]1([CH:11]([C:17]([O:18][CH3:19])=[O:20])[C:12]#[N:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: N#CCc1cccc2ccccc12
Reactant: COC(=O)OC
Agent: [Na]
Solvent: CO
Product: COC(=O)C(C#N)c1cccc2ccccc12

Procedure:
0.1 mol of 2-(1-naphthyl)acetonitrile is dissolved in 120 cm3 of dimethyl carbonate, and the solution is heated to reflux. 0.1 mol of sodium is then added in small portions over 30 min, during which time the methanol evaporates off. The reaction medium is kept refluxing for 1 hour, and the excess dimethyl carbonate is then evaporated off to dryness. The residue is taken up with 100 cm3 of an 18% solution of acetic acid in water.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.Br[CH2:10][CH2:11][CH3:12].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][CH3:12])=[CH:4][N:3]=1
Reactant: CCCBr
Reactant: Oc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCOc1ccc(Br)nc1

Procedure:
10.0 g (57.5 mmol) 2-bromo-5-hydroxypyridine, 28.3 g (230 mmol) 1-bromopropane and 19.9 g (143.7 mmol) K2CO3 are added to 1 L ACN and stirred at reflux over night. Afterwards the reaction is quenched by the addition of water and extracted with TBME. The org. layers are combined, dried over MgSO4, filtered and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, PE/EtOAc).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]1([CH:15]([CH3:17])[CH3:16])[C:6]([S:11]([O-:14])(=[O:13])=[O:12])=[CH:7][CH:8]=[CH:9][CH:10]=1.[Na+].[CH:19](Cl)(Cl)Cl>CN(C=O)C>[C:5]1([CH:15]([CH3:17])[CH3:16])[C:6]([S:11]([O:14][CH3:19])(=[O:13])=[O:12])=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)c1ccccc1S(=O)(=O)[O-]
Reactant: ClC(Cl)Cl
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COS(=O)(=O)c1ccccc1C(C)C
Yield: 44 %

Procedure:
594.9 g (5.0 mol) of thionyl chloride were initially introduced together with 1 g of DMF, and 222.2 g (1.0 mol) of sodium cumenesulfonate were slowly added in portions starting at room temperature. The mixture was stirred at reflux for 16 hours and 250 ml of chloroform were added after cooling. Following filtration, excess thionyl chloride was stripped off together with the chloroform under reduced pressure. 250 ml of methanol were added, and a pH of 7.0 was established using 25% strength sodium hydroxide solution at 25° C. The mixture was then stirred out with dichloromethane, the organic phase was concentrated on a rotary evaporator, and the residue obtained was subjected to fractional distillation under reduced pressure. At 102° C. and 0.03 mbar, 96.9 g (0.44 mol) of methyl cumenesulfonate were isolated in the form of a clear liquid, corresponding to a yield of 44%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([NH:17][C:18]([C:20]2([NH2:23])[CH2:22][CH2:21]2)=[O:19])[CH2:12][CH2:11]3)[CH:7]=1.[CH3:31][O:32][C:33]1[CH:37]=[C:36]([C:38](O)=[O:39])[O:35][N:34]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([NH:17][C:18]([C:20]2([NH:23][C:38]([C:36]4[O:35][N:34]=[C:33]([O:32][CH3:31])[CH:37]=4)=[O:39])[CH2:21][CH2:22]2)=[O:19])[CH2:12][CH2:11]3)[CH:7]=1
Reactant: COc1cc(C(=O)O)on1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(N)CC2)no1
Product: COc1cc(C(=O)NC2(C(=O)N[C@H]3CCc4cc(-c5cc(Cl)cc(F)c5-c5noc(C)n5)ccc43)CC2)on1

Procedure:
In analogy to the procedures described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(S)-5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-indan-1-yl}-amide (example 24) was coupled with 3-methoxy-isoxazole-5-carboxylic acid to yield the title compound as light yellow solid. MS: 552.2 (MH+, 1Cl).
Reaction SMILES: Cl[C:2]1[C:3](=[O:14])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1Cl)=[CH:8][CH:7]=[CH:6][CH:5]=2.C([O-])([O-])=O.[K+].[K+].[CH3:21][NH:22][C:23]([NH2:25])=[S:24]>C(O)(C)C>[CH3:21][NH:22][C:23]1[S:24][C:11]2[C:10](=[O:13])[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[C:3](=[O:14])[C:2]=2[N:25]=1
Reactant: CNC(N)=S
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CNc1nc2c(s1)C(=O)c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 0.9 %

Procedure:
A mixture of 2,3-dichloronaphthalene-1,4-dione 10.0 g (0.044 mol,), 18.0 g K2CO3 (0.13 mol, 3.0 eq) and 1-methylthiourea (0.056 mol, 1.2 eq) in 100 ml isopropanol was stirred at room temperature under N2 for 20 h. After removing all solvents under reduced pressure, the residue was diluted with CH2Cl2 and the K2CO3 was removed by filtration, the organic layer was concentrated, the residue was purified by chromatography to afford 0.1 g 2-(methylamino-) naphtho[2,3-d]thiazole-4,9-dione as black solid in a yield of 0.93%. 1HNMR (300 MHz, DMSO) δ3.59 (s, 3H); 7.78-7.81 (m, 2H); 7.89-7.93 (m, 1H); 7.98-8.01 (m, 1H); 9.06 (br, 1H) ppm. MS-ESI: cal. 244; found: 285 (M+Na+H2O).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[F:15][C:16]([F:26])([F:25])[O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.C(N(CC)CC)C>C(O)CCC>[Cl:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=[C:2]([NH:22][C:21]2[CH:23]=[CH:24][C:18]([O:17][C:16]([F:15])([F:25])[F:26])=[CH:19][CH:20]=2)[CH:7]=1
Reactant: Clc1cc(Cl)nc(-c2ccccc2)n1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: FC(F)(F)Oc1ccc(Nc2cc(Cl)nc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Yield: 48.8 %

Procedure:
A mixture of compound 4,6-dichloro-2-phenyl-pyrimidine (27 g, 112 mmol), 4-trifluoromethoxy aniline (21 g, 119 mmol) and triethylamine (33 mL, 225 mmol) in n-butanol (300 mL) was refluxed for 20 hours under nitrogen atmosphere. The reaction mixture was then cooled to room temperature and concentrated under vacuum. The crude compound was passed through the silica gel by using 5-6% ethylacetate in petroleum ether to afford the compound (6-chloro-2-phenyl-pyrimidin-4-yl)-(4-trifluoromethoxy-phenyl)-amine (20 g, 46%) as off-white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][N:12]3[C:17]([C:18]=2[CH3:19])=[C:16]([CH:20]2[CH2:22][CH2:21]2)[CH:15]=[C:14]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:13]3=[O:28])[CH:6]=[CH:7][CH:8]=1.[CH3:29][NH2:30]>O1CCCC1>[CH:20]1([C:16]2[CH:15]=[C:14]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:13](=[O:28])[N:12]3[C:17]=2[C:18]([CH3:19])=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][NH:30][CH3:29])[CH:4]=2)[CH:10]=[CH:11]3)[CH2:21][CH2:22]1
Reactant: CN
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3cccc(CBr)c3)ccn2c1=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3cccc(CNC)c3)ccn2c1=O
Reaction time: 10 h

Procedure:
31.2 mg of ethyl 8-(3-bromomethylphenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (Example 57) was dissolved in 2 ml of tetrahydrofuran. 0.1 ml of a solution of 2.0 M of methylamine in tetrahydrofuran was added to the obtained solution, and they were stirred for 10 hours. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by the silica gel column chromatography (eluent: chloroform/methanol=5/1) to obtain 18.1 mg of ethyl 1-cyclopropyl-9-methyl-8-(3-methylaminomethylphenyl)-4-oxo-4H-quinolizine-3-carboxylate.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:19])=[O:18])=[C:13]([F:20])[CH:12]=2)[CH2:6]1)=[N+:2]=[N-:3].N(C[C@H]1OC(=O)N(C2C=CC(SC[CH2:39][F:40])=C(F)C=2)C1)=[N+]=[N-].ClC1C=C(C=CC=1)C(OO)=O>>[N:1]([CH2:4][C@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH2:19][CH2:39][F:40])=[O:18])=[C:13]([F:20])[CH:12]=2)[CH2:6]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC[C@@H]1CN(c2ccc(SCCF)c(F)c2)C(=O)O1
Reactant: CS(=O)c1ccc(N2C[C@@H](CN=[N+]=[N-])OC2=O)cc1F
Agent: O=C(OO)c1cccc(Cl)c1
Product: [N-]=[N+]=NC[C@@H]1CN(c2ccc(S(=O)CCF)c(F)c2)C(=O)O1

Procedure:
This compound was prepared analogously to the synthesis of 5-(S)-azidomethyl-3-[4′-methylsulfinyl-3′-fluorophenyl]oxazolidine-2-one from 5-(S)-azidomethyl-3-[4′-(2″-fluoroethyl)thio-3′-fluorophenyl]oxazolidine-2-one (0.280 g, 0.891 mmol) and m-chloroperoxybenzoic acid (77%, 0.200 g, 0.891 mmol). Yield 0.280 g (95%). MS (m/z): [M+H]+=331.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[CH3:19])=[CH:7][CH:6]=1)=[O:4].[Li+].[OH-]>O1CCOCC1.O>[CH3:19][C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([CH3:17])[C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(-c2c(C)cc(C)cc2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C)c(-c2ccc(C(=O)O)cc2)c(C)c1
Temperature: 60 °C
Yield: 16 %

Procedure:
Combine 1-iodo-2,4,6-trimethylbenzene (2.966 g, 12.05 mmol), 4-carboxyphenylboronic acid (1.0 g, 6.026 mmol), Pd(OAc)2 (0.0067 g, 0.005 mmol), tetrabutylammonium bromide (0.388 g, 1.206 mmol), and potassium phosphate (2.557 g, 12.05 mmol). Purge the reaction vessel with argon and add anhydrous DMF (20 mL) to the reaction mixture. Heat the sealed reaction vessel to 120° C. with stirring until completion as determined by TLC. Cool reaction mixture to room temperature. Add methyl iodide (1.0 mL, 36.63 mmol) to reaction mixture with continued stirring until completion. Dilute the reaction with ethyl acetate and filter though a short plug of celite with additional ethyl acetate. Wash the organics with water, dry over MgSO4, filter and evaporate. Purification by flash column chromatography yields 2′,4′,6′-trimethylbiphenyl-4-carboxylic acid methyl ester as a yellow solid. Dissolve the purified ester in dioxane (45 mL) and water (5 mL) containing 5 eq of LiOH with stirring at 60° C. Upon completion, evaporate the solvent, acidify the reaction mixture with hydrochloric acid, and extract with ethyl acetate. Dry the organics over MgSO4, filter, and evaporate to yield 0.023 g (16%) of the title compound. MS (ES): m/z 239.1 (M−H).
Reaction SMILES: [C:1]1([NH2:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH:12]1[CH2:16][CH2:15][N:14]=[C:13]1S(O)(=O)=O>CC#N>[C:1]1([N:11]=[C:13]2[NH:14][CH2:15][CH2:16][NH:12]2)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cccc2c1CCCC2
Reactant: O=S(=O)(O)C1=NCCN1
Solvent: CC#N
Product: c1cc2c(c(N=C3NCCN3)c1)CCCC2
Temperature: 155 °C
Yield: 13.7 %

Procedure:
5,6,7,8-Tetrahydro-1-naphthylamine (Aldrich, 159 mg, 1.06 mmol), imidazoline-2-sulfonic acid (147.0 mg, 1.0 mmol, Compound 7 obtained as described above) and CH3CN (5ml) were placed in a thick-walled cap which was sealed with a TEFLON™ screw and heated to 155° C. for 1.25 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in CHCl3 and washed with aq. 1N NaOH (to pH 13). The organic layer was separated, washed with brine, dried over Na2CO3 and concentrated in vacuo to yield a brown oil. The crude material was purified by flash chromatography (SiO2 ; 80:20 CHCl3 /CH3OH saturated with NH3) to yield 29.5 mg (14%) of the title compound as a white solid: mp 138°-141° C.; 1H NMR (300 MHz, CDCl3) & 7.05 (t, 1H) 6.82 (m, 2 H); 5.41 (br, 2H); 3.50 (s, 4H); 2.79 (m, 2H); 2.62 (m, 2H); 1.80 (m, 4H); Mass spectrum m/e 214.1339 (C13H16N3 requires 214.1344). Alternatively and preferably alcohols, most preferably isobutanol, are used instead of CH3CN in this reaction.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9]([OH:10])=[C:8]([C:11]([O:13]CC)=[O:12])[CH:7]=[N:6][N:5]2[CH:16]=1.[OH-].[Na+]>CO.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9]([OH:10])=[C:8]([C:11]([OH:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:16]=1
Reactant: CCOC(=O)c1cnn2cc(F)cc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cnn2cc(F)cc2c1O
Temperature: 65 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
To a solution of ethyl 6-fluoro-4-hydroxypyrrolo[1,2-b]pyridazine-3-carboxylate (700 mg, 3.12 mmol) in MeOH (3 mL) and THF (3 mL) was added 3 N aq. sodium hydroxide (5.20 mL, 15.61 mmol) and the resulting mixture was stirred at 65° C. for 3 h. The mixture was cooled and concentrated to remove the MeOH and THF and the obtained residue was cooled in an ice bath and 3N aq. HCl was added dropwise with stirring until pH of the mixture was ˜2. The resulting slurry was stirred for 30 min, and filtered to collect the solid. The solid was rinsed with water and dried to afford 550 mg (90%) of the title compound as a white solid. HPLC (condition B): retention time=2.37 min. LCMS (condition B): m/z 197 +ve.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Br[CH2:10][CH:11]([O:14][CH3:15])[O:12][CH3:13].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.C(Cl)Cl>[CH3:13][O:12][CH:11]([O:14][CH3:15])[CH2:10][N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: ClCCl
Product: COC(Cn1cc([N+](=O)[O-])cn1)OC
Temperature: 85 °C

Procedure:
To a solution of 4-nitro-1H-pyrazole (1.50 g, 13.27 mmol) in MeCN (30 mL), 2-bromo-1,1-dimethoxyethane (2.34 mL, 19.90 mmol) and Cs2CO3 (6.48 g, 19.90 mmol) was added. The resulting mixture was refluxed (85° C.) for 20 h, then the reaction mixture was allowed to reach rt. The mixture was diluted with DCM, filtered, the filter cake was washed with DCM and the filtrate was concentrated in vacuo. The residue was partitioned between water and DCM, then the aq. layer was extracted with DCM (2×) and the comb. org. layers were dried (MgSO4), filtered and the solvent was removed under reduced pressure to yield 1-(2,2-dimethoxyethyl)-4-nitro-1H-pyrazole as a yellow oil which was used in the next step without further purification. LC-MS conditions B: tR=0.50 min, [M+H]+=no ionization.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].C(=O)([O-])O.[Cs+].Cl[CH2:16][CH2:17][O:18][C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20]>CN1C(=O)CCC1>[C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O:6][CH2:16][CH2:17][O:18][C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])=[O:5]
Reactant: CC(C)OC(=O)OCCCl
Reactant: COC(=O)/C=C/C(=O)O
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COC(=O)/C=C/C(=O)OCCOC(=O)OC(C)C
Yield: 90.9 %

Procedure:
Following general procedure A, methyl hydrogen fumarate (0.39 g, 3.0 mmol) in NMP (8 mL) was reacted with CsHCO3 (0.69 g, 3.6 mmol) and methylethyl (chloroethoxy)formate (0.70 g, 4.2 mmol) to afford 0.71 g (91% yield) of the title compound (40) after isolation and purification. 1H NMR (CDCl3, 400 MHz): δ 6.89 (d, J=15.6 Hz, 1H), 6.84 (q, J=5.2 Hz, 1H, superimposed), 6.82 (d, J=15.6 Hz, 1H, superimposed), 4.90 (heptet, J=6.2 Hz, 3H), 3.81 (s, 3H), 1.57 (d, J=5.2 Hz, 3H), 1.32 (d, J=6.2 Hz, 3H), 1.31 (d, J=6.2 Hz, 3H). MS (ESI): m/z 261.02 (M+H)+.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:36](Br)[CH:37]=[CH2:38]>O1CCCC1>[CH2:38]([C@H:11]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:10][C@H:9]([NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:37]=[CH2:36]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 2 h

Procedure:
26.96 g (75 mmol) of di-tert-butyl Boc-glutamate (Journal of Peptide Research (2001), 58, 338) were dissolved in 220 mL of tetrahydrofuran (THF) and cooled to −70° C. 165 mL (165 mmol) of a 1M solution of lithium bis(trimethylsilyl)amide in THF were added dropwise over a period of two hours at this temperature and the mixture was stirred at −70° C. for another 2 hours. 27.22 g (225 mmol) of allyl bromide were then added dropwise, and after 2 h at this temperature, the cooling bath was removed and 375 mL of 2N aqueous hydrochloric acid and 1.25 L of ethyl acetate were added. The organic phase was separated off, washed with water until neutral, dried over sodium sulphate and filtered, and the filtrate was concentrated. The crude product obtained in this manner was chromatographed in silica gel using a hexane/ethyl acetate gradient, and the appropriate fractions were combined and concentrated.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(N(CC)CC)C.C[O:17][C:18](=O)[N:19]=[C:20](SC)[C:21]([C:35]1[CH:36]=[C:37]([O:45][CH3:46])[C:38]2[O:42][CH2:41][CH2:40][C:39]=2[C:43]=1[F:44])=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1>CN(C=O)C>[F:44][C:43]1[C:39]2[CH2:40][CH2:41][O:42][C:38]=2[C:37]([O:45][CH3:46])=[CH:36][C:35]=1[CH:21]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1)[C:20]1[NH:19][C:18](=[O:17])[N:1]([C:3]2[N:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: NNc1ncccn1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c2c(c1F)CCO2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c(F)c2c1OCC2
Temperature: 85 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
After adding 22 mg of 2-hydrazinopyrimidine and 50 ul of triethylamine to a solution of 105 mg of {2-(4-fluoro-7-methoxy-2,3-dihydrobenzofuran-5-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 2 ml of DMF, the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 5 ml of methanol and 0.5 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the reaction mixture, it was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol-ethyl acetate) to give 5-{(4-fluoro-7-methoxy-2,3-dihydrobenzofuran-5-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one (76 mg) as a light brown solid.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:22]([CH2:24]Br)=[O:23])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F-].[K+].C(=O)([O-])[O-].[K+].[K+].[CH2:34]([OH:36])[CH3:35]>>[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:22]([CH2:24][O:36][CH2:34][CH3:35])=[O:23])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCc1ccccc1)C(=O)CBr
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: [F-]
Agent: [K+]
Product: CCOCC(=O)[C@H](CCc1ccccc1)NC(=O)[C@@H](N)Cc1ccccc1
Reaction time: 3 h

Procedure:
In a 100 ml round bottom flask equipped with an argon line was placed Nu-Phe-HPhe-CH2-Br (300 mg, 0.582 mmol), potassium fluoride (150 mg, 2.4 mmol), and potassium carbonate (150 mg, 1.2 mmol), and 8 ml of 200 proof ethanol. The reaction was stirred 3 hours, filtered and the solvents were removed under vacuum and the residue chromatographed on a short silica gel column (CHCl3:MLEOH 95:5) and then recrystallized from ether.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][N:5]=1)(=O)[CH3:2].Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>C(O)C.O>[C:1](=[N:17][OH:18])([C:4]1[N:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: CC(=O)c1nccc(OCC(F)(F)F)n1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=NO)c1nccc(OCC(F)(F)F)n1
Yield: 69.7 %

Procedure:
2-Acetyl-4-(2,2,2-trifluoroethoxy)-pyrimidine (0.47 g) was dissolved in a mixture of ethanol (10 ml) and water (5 ml) and heated to 40° C. for 1 hour with hydroxylamine hydrochloride (0.16 g) and sodium acetate (0.43 g). The reaction mixture was poured into water and extracted with ethyl acetate (3×50 ml). The combined extracts were dried and concentrated. The residue was washed with hexane to give 2-acetyl-4-(2,2,2-trifluoroethoxy)-pyrimidine oxime (0.35 g, 70% yield) as a white solid, m.p. 179°-181° C.; 1H NMR (270 MHz): δ2.39(3H,s), 4.87(2H,q), 6.88(1H,d), 8.60(1H,d) ppm.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12](=[O:14])[C:11]([CH2:21][C:22](O)=[O:23])([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:10]=2[CH:25]=1>C1C=CC=CC=1>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12](=[O:14])[C:11]([CH2:21][C:22]([Cl:3])=[O:23])([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:10]=2[CH:25]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CC1(c2ccccc2)C(=O)Oc2ccc(Cl)cc21
Solvent: c1ccccc1
Product: O=C(Cl)CC1(c2ccccc2)C(=O)Oc2ccc(Cl)cc21
Yield: 96.8 %

Procedure:
23.7 g of double-distilled thionyl chloride are added dropwise to a solution, stirred and heated to 70° C., of 30.2 g of 2-(5-chloro-2,3-dihydro-2-oxo-3-phenyl-3-benzofuranyl)acetic acid in 250 ml of anhydrous benzene. When the addition is complete, the mixture is heated to reflux until the evolution of gas has completely ceased. The medium is concentrated under vacuum, the residue washed with 200 ml of anhydrous benzene and the solvent evaporated off. This operation is repeated twice and the product is left to crystallize at room temperature. The crystals are washed with petroleum ether and filtered off, and 31 g of pure product are obtained.