Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[C:12]([CH2:13][CH3:14])=[CH:11][C:10]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:9][C:8]=1[CH2:22][CH3:23].C[O:25][B:26](OC)[O:27]C.Cl>O1CCCC1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:10]2[CH:11]=[C:12]([CH2:13][CH3:14])[C:7]([B:26]([OH:27])[OH:25])=[C:8]([CH2:22][CH3:23])[CH:9]=2)=[CH:16][CH:17]=1
Reactant: COB(OC)OC
Reactant: CCc1cc(-c2ccc(Cl)cc2)cc(CC)c1Br
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCc1cc(-c2ccc(Cl)cc2)cc(CC)c1B(O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 44.9 %

Procedure:
tert-Butyllithium (1.6 M solution in hexane, 13 ml, 0.02 mol) is added dropwise to a solution of 4-bromo-4′-chloro-3,5-diethylbiphenyl (4.5 g, 0.0139 mol) in dry tetrahydrofuran (50 ml) at −78° C. under an atmosphere of nitrogen. The reaction mixture is stirred at −78° C. for 30 minutes, then trimethylborate (9.3 ml, 0.083 mol) is added. The resulting mixture is stirred at −78° C. for 1 hour and then allowed to warm to room temperature over 3 hours. The reaction mixture is acidified with 0.1 N aqueous hydrochloric acid solution and the mixture is stirred at room temperature overnight. The mixture is extracted with ethyl acetate (3×100 ml). The organic layers are combined, dried over anhydrous sodium sulfate, filtered and the filtrate is evaporated. The residue is purified by column chromatography on silica gel to give 4′-chloro-3,5-diethylbiphen-4-ylboronic acid as a white powder (1.8 g).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]([CH2:9]Br)=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1.[CH:14]1([NH2:17])[CH2:16][CH2:15]1>C1COCC1>[CH:14]1([N:17]2[CH2:2][CH2:3][N:4]3[N:5]=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[C:8]3[CH2:9]2)[CH2:16][CH2:15]1
Reactant: NC1CC1
Reactant: O=[N+]([O-])c1cc(CBr)n(CCBr)n1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc2n(n1)CCN(C1CC1)C2
Temperature: 30 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
A mixture of 1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole 101c (4 g, 12.9 mmol) and cyclopropanamine (7.35 g, 129 mmol) in THF (40 mL) was stirred at 30° C. overnight. After the completion of the reaction, the mixture was filtered off and the solid was washed with THF (100 mL). The filtrate was concentrated under reduced pressure to give 135a (2.68 g, 99%). MS: [M+H]+ 209.
Reaction SMILES: [C:1]([N:8]1[CH2:15][S:14][CH2:13][C@H:9]1[C:10](O)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(C(C)C)C(C)C.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.O>[C:4]([O:3][C:1]([N:8]1[C@H:9]([CH2:10][OH:11])[CH2:13][S:14][CH2:15]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CSC[C@H]1C(=O)O
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CSC[C@H]1CO
Temperature: 0 °C
Reaction time: 24 h
Yield: 53.1 %

Procedure:
A solution of 4.66 g (20 mmol) of N-Boc-thioproline and 3.84 mL (22 mmol) DIEA dissolved in 10 mL THF was cooled to 0_C and treated with 2.1 mL (22 mmol) of ethyl chloroformate. After 30 min at RT the white precipitate is filtered off, the solution cooled to 0° C. and a solution of 8.32 g (220 mmol) sodium borohydride in 30 mL H2O is added dropwise. The reaction was stirred for 24 h, then cooled to 0° C. and quenched by dropwise addition of acetic acid. The product was then extracted with EtOAc, the combined organics were washed successively with sodium bicarbonate and citric acid, dried with magnesium sulfate, filtered and solvents removed in vacuo to provide 2.33 g of the title compound: MS (ES+) m/e 242 (M+23), 120 (M-Boc+1).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][N:20]([C:23]4(SC)[N:28]=[CH:27][C:26]([F:29])=[CH:25][NH:24]4)[CH2:19][CH2:18]3)[O:13][CH2:12][CH2:11][O:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C>[Ni].O.CCO>[ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:14][CH2:15][CH2:16][N:17]3[CH2:18][CH2:19][N:20]([C:23]4[N:24]=[CH:25][C:26]([F:29])=[CH:27][N:28]=4)[CH2:21][CH2:22]3)[O:10][CH2:11][CH2:12][O:13]2)=[CH:5][CH:4]=1
Reactant: CSC1(N2CCN(CCCC3(c4ccc(F)cc4)OCCO3)CC2)N=CC(F)=CN1
Agent: [Ni]
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: Fc1ccc(C2(CCCN3CCN(c4ncc(F)cn4)CC3)OCCO2)cc1
Yield: 23.9 %

Procedure:
1-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-4-(5-fluoro-2-methylthio-2-pyrimidinyl)piperazine hydrochloride (7.45 g, 0.0.17 mole), triethylamine (3.05 g, 0.034 mole) and 2 teaspoons of Raney Nickel in water were mixed in EtOH (125 mL) and refluxed 18 h. The hot reaction mixture was filtered and the filtrate was concentrated in vacuo to about 1/5 volume. A crude crystalline product was obtained by filtration and its recrystallization from 20-25 mL EtOH gave 1.6 g of solid, m.p. 220°-222° C. This solid was converted to the hydrochloride salt in EtOH using ethanolic HCl. Filtration and drying gave 1.6 g of product, m.p. 242°-244° C.
Reaction SMILES: [OH:1][CH:2]([CH:6]1[CH2:11][N:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:3]([OH:5])=[O:4].[N+](=[CH2:28])=[N-].C(O)(=O)C>CO.CCOCC>[OH:1][CH:2]([CH:6]1[CH2:11][N:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:3]([O:5][CH3:28])=[O:4]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)C(O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C(O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1

Procedure:
To a solution of 452 mg of 2-hydroxy-2-(1,4-dibenzylpiperazin-2-yl)acetic acid in 5 ml of methanol is added a solution of diazomethane in ether. After the excess amount of diazomethane is decomposed with acetic acid, the mixture is evaporated to dryness under reduced pressure. The residue is dissolved in ether. The resulting solution is washed with 10% aqueous sodium sulfate and water, dried over sodium sulfate and evaporated under reduced pressure to yield 468 mg of methyl 2-hydroxy-2-(1,4-dibenzylpiperazin-2-yl)acetate as a mixture of erythro and threo.
Reaction SMILES: C(=O)([O-])O.[K+].[NH2:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][CH2:8]1.Br[CH2:22][CH2:23][CH2:24][CH2:25]Br>CN(C=O)C>[N:6]1([C@@H:7]2[CH2:12][CH2:11][C@H:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][CH2:8]2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: BrCCCCBr
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
25 mg of potassium hydrogen carbonate are added to a solution of tert-butyl cis-4-aminocyclohexanecarbamate (10 g, 46 mmol) and 1,4-dibromobutane (12.1 g, 56 mmol) in 400 ml of DMF, and the mixture is stirred at RT for 24 h. The reaction mixture is then evaporated and the residue is taken up in diethyl ether; this solution is washed with water. The organic phase is dried and evaporated in vacuo. Yield: 12 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=O)[CH3:11])=[CH:5][C:4]=1[S:13]([NH2:16])(=[O:15])=[O:14].[N:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[NH:23][C:24]([NH2:26])=[S:25].II>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:25][C:24]([NH:23][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][N:17]=3)=[N:26][C:10]=2[CH3:11])=[CH:5][C:4]=1[S:13]([NH2:16])(=[O:15])=[O:14]
Reactant: NC(=S)Nc1cnccn1
Reactant: COc1ccc(CC(C)=O)cc1S(N)(=O)=O
Agent: II
Solvent: c1ccncc1
Product: COc1ccc(-c2sc(Nc3cnccn3)nc2C)cc1S(N)(=O)=O
Yield: 22.2 %

Procedure:
2-Methoxy-5-(2-oxo-propyl)-benzenesulfonamide (S. Sakurai et al. Chem. Pharm. Bull. 40(6) 1443-1451 (1992)) (0.3 g, 1.23 mmol), pyrazin-2-yl-thiourea (0.19 g, 1.23 mmol), iodine (0.31 g, 1.23 mmol) in pyridine (2.5 ml) is stirred at 60° C. for 20 hours. The mixture is concentrated. To the residue is added water, the precipitate is collected and recrystallised from ethanol to give the titled compound (0.103 g). m.p. 378.2° C.
Reaction SMILES: Cl[C:2]([C@:4]12[CH2:39][CH2:38][C@@H:37]([CH:40]([CH3:42])[CH3:41])[C@@H:5]1[C@@H:6]1[C@@:19]([CH3:22])([CH2:20][CH2:21]2)[C@@:18]2([CH3:23])[C@@H:9]([C@:10]3([CH3:36])[C@@H:15]([CH2:16][CH2:17]2)[C:14]([CH3:25])([CH3:24])[C@@H:13]([C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=2)[CH2:12][CH2:11]3)[CH2:8][CH2:7]1)=[O:3].[NH2:43][CH2:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=1>ClCCCl.CN(C1C=CN=CC=1)C.O>[CH:40]([C@H:37]1[C@@H:5]2[C@@H:6]3[C@@:19]([CH3:22])([CH2:20][CH2:21][C@@:4]2([C:2](=[O:3])[NH:43][CH2:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=2)[CH2:39][CH2:38]1)[C@@:18]1([CH3:23])[C@@H:9]([C@:10]2([CH3:36])[C@@H:15]([CH2:16][CH2:17]1)[C:14]([CH3:25])([CH3:24])[C@@H:13]([C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1)[CH2:12][CH2:11]2)[CH2:8][CH2:7]3)([CH3:42])[CH3:41]
Reactant: NCCc1ccccn1
Reactant: COC(=O)c1ccc([C@H]2CC[C@]3(C)[C@H]4CC[C@@H]5[C@H]6[C@H](C(C)C)CC[C@]6(C(=O)Cl)CC[C@@]5(C)[C@]4(C)CC[C@H]3C2(C)C)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: O
Product: COC(=O)c1ccc([C@H]2CC[C@]3(C)[C@H]4CC[C@@H]5[C@H]6[C@H](C(C)C)CC[C@]6(C(=O)NCCc6ccccn6)CC[C@@]5(C)[C@]4(C)CC[C@H]3C2(C)C)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 70 %

Procedure:
To a flask containing methyl 4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-3a-(chlorocarbonyl)-1-isopropyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (77 mg, 0.13 mmol) in DCE (2 mL) was added Hunig'sBase (0.068 mL, 0.390 mmol), DMAP (1 mg, 8.19 μmol), and 2-(2-Aminoethyl)pyridine (0.031 mL, 0.260 mmol). The mixture was stirred for 2.5 hours at rt. The reaction was diluted with 5 mL of water and was extracted with dichloromethane (3×5 mL). The combined organic layers were dried with Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by Biotage flash chromatography using a 0-75% ethyl acetate in hexanes gradient. The fractions containing the expected product were combined and concentrated. The expected product, methyl 4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3a-(2-(pyridin-2-yl)ethylcarbamoyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (0.062 g, 0.091 mmol, 70.0% yield), was isolated as a white foam. LCMS: m/e 679.7 (M−H)−, 3.09 min (method 3).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[S:12][C:13]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:5][CH:4]=1.[CH3:23]C1C=CC(S(C)(=O)=O)=CC=1.[C:34]1([CH3:45])[CH:39]=[CH:38][C:37]([S:40]([O:43]C)(=[O:42])=[O:41])=[CH:36][CH:35]=1>>[C:34]1([CH3:45])[CH:35]=[CH:36][C:37]([S:40]([O-:43])(=[O:41])=[O:42])=[CH:38][CH:39]=1.[CH3:1][N:2]([CH3:22])[C:3]1[CH:4]=[CH:5][C:6]([N:9]=[N:10][C:11]2[S:12][C:13]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:14]=3[N+:15]=2[CH3:23])=[CH:7][CH:8]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1ccc(S(C)(=O)=O)cc1
Reactant: COc1ccc2nc(N=Nc3ccc(N(C)C)cc3)sc2c1
Product: COc1ccc2c(c1)sc(N=Nc1ccc(N(C)C)cc1)[n+]2C
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Reaction time: 0.17 h

Procedure:
A mixture of 17.3 pounds (25.2 moles) of 2-(p-dimethylaminophenylazo)-6-methoxybenzothiazole and 51.6 pounds of dextrine were blended in a 4.6 ft. Littleford-Lodige precision blender, heated to about 80°-85° C, and 10.3 pounds (25.1 moles) of methyl p-toluene sulfonate added thereto portion wise over a period of about 10 minutes so that the temperature did not exceed about 90° C. The reaction mixture was then blended for an additional 30 minutes at 85°-90° C. The product was obtained in high yield and contained less than 1% of the dye base and less than 0.5% of methyl p-toluenesulfonate.
Reaction SMILES: [Cl:1][C:2]1[C:19]([C:20]2([C:23]#[N:24])[CH2:22][CH2:21]2)=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([OH:13])[C:10]([F:14])=[CH:9][C:8]=1[F:15])=[O:5].Cl[C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:19]([C:20]2([C:23]#[N:24])[CH2:22][CH2:21]2)=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][N:27]=2)[C:10]([F:14])=[CH:9][C:8]=1[F:15])=[O:5]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: N#CC1(c2cccc(C(=O)Nc3cc(O)c(F)cc3F)c2Cl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc([N+](=O)[O-])cn4)c(F)cc3F)c2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A suspension of 2-chloro-3-(1-cyanocyclopropyl)-N-(2,4-difluoro-5-hydroxyphenyl)benzamide (4.20 g, 12 mmol), 2-chloro-5-nitropyridine (1.9 g, 12 mmol) and potassium carbonate (1.66 g, 12 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature overnight. The reaction mixture was poured into water (200 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→50/50), and crystallized from diethyl ether to give the title compound (5.20 g, 92%) as a yellow powder.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])([CH2:7][CH3:8])[CH3:6].CN(C)C(N(C)C)=O>>[CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:1]([Cl:4])=[O:2])([CH2:7][CH3:8])[CH3:6]
Reactant: CCC(C)c1ccccc1O
Reactant: O=C(Cl)Cl
Solvent: CN(C)C(=O)N(C)C
Product: CCC(C)c1ccccc1OC(=O)Cl
Temperature: 100 °C
Yield: 97 %

Procedure:
In a round flask provided with stirrer, thermometer, an introduction tube for phosgene and a reflux cooler operating at about -30° C a mixture of 150 g of o-sec.-butylphenol and 4 g of N,N,N',N',-tetramethyl urea was heated at 100° C and phosgene was introduced to such a degree that the phosgene reflux in the deep-freezing cooler did not increase so much as to reduce the sump temperature. After a reaction time of about 5 hours and a phosgene consumption of about 190 g the reflux cooler was replaced by a descending cooler so that the greatest part of the excess phosgene could be separated from the reaction mixture by distillation. The rest of phosgene was blown out with dry nitrogen. Thus, a yield of about 97% of chloroformic acid-o-sec.-butyl-phenyl-ester was obtained which was practically free from the starting product (GC).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C@@H:11]([NH:14][C:15]3[N:23]=[CH:22][N:21]=[C:20]4[C:16]=3[N:17]=[CH:18][N:19]4C3CCCCO3)[CH2:12][CH3:13])[N:8]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:7]=2[CH:36]=1>O1CCOCC1.CO>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C@@H:11]([NH:14][C:15]3[N:23]=[CH:22][N:21]=[C:20]4[C:16]=3[NH:17][CH:18]=[N:19]4)[CH2:12][CH3:13])[N:8]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:7]=2[CH:36]=1
Reactant: CC[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)cc2n1-c1ccccc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC[C@H](Nc1ncnc2nc[nH]c12)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.7 %

Procedure:
HCl (0.22 mL of a 4M solution in dioxane) was added to a solution of [(S)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)propyl]-[9-(tetrahydropyran-2-yl)-9H-purin-6-yl]amine (82 mg, 0.17 mmol) in MeOH (2 mL) and the reaction was stirred at RT for 10 min. The reaction mixture was passed through a 2 g Isolute® SCX-2 cartridge, eluting with 2M NH3/MeOH. The basic fraction was concentrated in vacuo to give 360 (65 mg, quant.) as a white solid. LCMS (Method K): RT 3.58 min [M+H]+ 388.1. 1H NMR (CD3OD, 400 MHz): δ 8.06 (1H, s), 8.04 (1H, br s), 7.61 (1H, dd, J=8.8, 4.6 Hz), 7.57-7.43 (5H, m), 7.02 (1H, ddd, J=9.6, 8.8, 2.7 Hz), 6.76 (1H, dd, J=8.7, 2.7 Hz), 5.44 (1H, br s), 2.14 (1H, dqd, J=14.8, 7.4, 6.5 Hz), 2.05 (1H, dqd, J=14.8, 7.4, 6.5 Hz), 0.95 (3H, t, J=7.4 Hz)
Reaction SMILES: [C:1]([O:7][C@H:8]([CH2:20][C@H:21]1[C@H:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:23](=[O:31])[O:22]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:6])[CH2:2][C:3]([OH:5])=O.CN(C(O[N:40]1N=N[C:42]2C=CC=[CH:46][C:41]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)(C)C>C(#N)C>[CH2:25]([C@@H:24]1[C:23](=[O:31])[O:22][C@H:21]1[CH2:20][C@@H:8]([O:7][C:1](=[O:6])[CH2:2][C:3]([NH:40][CH:41]([CH3:46])[CH3:42])=[O:5])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCC[C@@H](C[C@@H]1OC(=O)[C@H]1CCCCCC)OC(=O)CC(=O)O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CC(C)N
Product: CCCCCCCCCCC[C@@H](C[C@@H]1OC(=O)[C@H]1CCCCCC)OC(=O)CC(=O)NC(C)C
Yield: 84.9 %

Procedure:
A solution of 33.5 mg of (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl hydrogen malonate (Example N) in 2 ml of acetonitrile was treated with 60 mg of HBTU and 75 mg of iso- propylamine. After stirring the reaction mixture was filtered, the filtrate was concentrated and the residue was chromatographed on silica gel with hexane/methylene chloride/ethyl acetate (2:2:1). There were obtained 31.1 mg of (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl-N-isopropylmalonamate, m.p. 59°.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])#[N:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:17]1[N:22]=[CH:21][N:20]=[C:19]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2/[C:30](=[CH:35]\[O:36][CH3:37])/[C:31]([O:33][CH3:34])=[O:32])[CH:18]=1>CO>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][C:17]1[N:22]=[CH:21][N:20]=[C:19]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2/[C:30](=[CH:35]\[O:36][CH3:37])/[C:31]([O:33][CH3:34])=[O:32])[CH:18]=1)#[N:2]
Reactant: N#Cc1ccccc1O
Reactant: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(Oc2ccccc2C#N)ncn1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A mixture of 2-cyanophenol (12.6 g), potassium carbonate (8.28 g) and (E)-methyl 2-[2-(6-chloropyrimidin4-yloxy)phenyl]-3-methoxypropenoate (33.0 g) was heated at 120° C. for 3 hours. The mixture was then cooled to 100° C. after which methanol (40 ml) was added to help cooling to 65° C. The resulting mixture was cooled to 0-5° C. and kept at this temperature for 1 hour. The mixture was filtered to leave (E)-methyl 2-[2-(6-(2-cyanophenoxy)pyrimidin-4-yloxy)phenyl]-3-methoxypropenoate as the residue (87.5%
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:10][N:11]1[C:15]2[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=2[N:13]([C@H:22]2[CH2:26][CH2:25][NH:24][CH2:23]2)[C:12]1=[O:27].C(N(CC)CC)C>C(Cl)(Cl)Cl.CN1CCN(C)C1=O>[Cl:6][C:7]1[CH:8]=[C:9]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:10][N:11]1[C:15]2[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=2[N:13]([C@H:22]2[CH2:26][CH2:25][N:24]([C:2]([O:4][CH3:5])=[O:3])[CH2:23]2)[C:12]1=[O:27]
Reactant: COc1ccc(Cn2c(=O)n([C@H]3CCNC3)c3ccc(C#N)cc32)cc1Cl
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CN1CCN(C)C1=O
Product: COC(=O)N1CC[C@H](n2c(=O)n(Cc3ccc(OC)c(Cl)c3)c3cc(C#N)ccc32)C1
Reaction time: 2 h
Yield: 59.7 %

Procedure:
A solution of methyl chloroformate (25.7 mg) in chloroform (1 ml) was added dropwise to a mixture of 3-(3-chloro-4-methoxybenzyl)-5-cyano-1-[(S)-pyrrolidin-3-yl]-2,3-dihydro-1H-benzimidazole-2-one (80 mg) and triethylamine (31.7 mg) in a mixture of chloroform (1.6 ml) and 1,3-dimethyl-2-imidazolidinone (0.8 ml) under cooling on an ice bath. The reaction mixture was stirred at same temperature for 2 hours and quenched by addition of 3-(N,N-diethylamino)propylamine (0.1 ml). The mixture was poured into water and extracted with chloroform. The organic layer was washed with 1N-hydrochloric acid, water, an aqueous saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by a preparative thin layer chromatography (10% methanol in chloroform) to give 3-(3-chloro-4-methoxybenzyl)-5-cyano-1-[(S)-1-methoxycarbonylpyrrolidin-3-yl]-2,3-dihydro-1H-benzimidazole-2-one (55 mg).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1.C(N(CC)C(C)C)(C)C.[N:32]1[C:41]2[C:36](=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:16][C:6]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:2]([C:37]2[CH:38]=[CH:39][CH:40]=[C:41]3[C:36]=2[CH:35]=[CH:34][CH:33]=[N:32]3)[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:5]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1Cl
Reactant: OB(O)c1cccc2ncccc12
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1cccc2ncccc12
Yield: 66.9 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-(piperidin-1-yl)pyrimidin-5-yl)pentanoate (0.081 g; 0.25 mmol), tetrakis(triphenylphosphine) palladium(0) (0.029 g; 0.025 mmol), N,N-diisopropylethylamine (0.172 mL; 1.00 mmol) and quinolin-5-ylboronic acid (0.086 g; 0.500 mmol) in DME-water (1 mL) for 20 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (5-40%) in heptane furnished 0.070 g (67%) of the title compound.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:14])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[NH2:12].[CH3:15][C:16](O)=O.[C:19](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:20].[Na+]>ClCCl>[CH3:1][O:2][N:3]([CH3:14])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[NH:12][CH2:19][CH2:20][CH2:16][CH3:15]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CON(C)C(=O)c1ccc(F)cc1N
Reactant: CC(=O)O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCNc1cc(F)ccc1C(=O)N(C)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-methoxy-N-methyl-2-amino-4-fluorobenzoic acid amide (0.35 g, 1.75 mmol), butyrylaldehyde (0.23 mL, 2.62 mmol), and AcOH (0.15 mL, 2.62 mmol) in dichloromethane (20 mL) was added sodium triacetoxyborohydride (0.74 g, 3.49 mmol) at 5° C. The mixture was stirred for 5 hours at the same temperature and overnight at room temperature. The reaction was quenched by adding water. The organic layer was washed with saturated aqueous NaHCO3 solution and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound quantitatively.
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12]CC)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O.[NH2:18][NH2:19]>>[C:2]1([C:1]2[NH:19][NH:18][C:10](=[O:12])[CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1cc(-c2ccccc2)[nH][nH]1
Yield: 81 %

Procedure:
A vigorously stirred solution of ethyl benzoylacetate (30 g 150 mmol), of 5% aqueous sodium hydroxide (312 mL), and hydrazine hydrate (14.6 mL 468 mmol) was heated to 75° C. for sixteen hours. The resultant precipitate was filtered, washed with water and dried and gave 5-Phenyl-1,2-dihydro-pyrazol-3-one (20.3) in 81% yield as a white solid. C9H8N2O: 1H NMR (d6-DMSO): δ 7.62 (d, 2H, J=7.0 Hz), 7.36 (t, 2H, J=7.0 Hz), 7.26 (t, 1H, J=7.0 Hz), 5.85 (s, 1H) ppm.