Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[NH:3][C:4](=[O:14])[C:5]2[CH:10]=[CH:9][N:8]([CH:11]3[CH2:13][CH2:12]3)[C:6]=2[N:7]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:11]1([N:8]2[C:6]3[N:7]=[C:2]([C:20]4[CH:21]=[CH:22][C:17]([C:16]([F:27])([F:26])[F:15])=[CH:18][CH:19]=4)[NH:3][C:4](=[O:14])[C:5]=3[CH:10]=[CH:9]2)[CH2:13][CH2:12]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=c1[nH]c(Cl)nc2c1ccn2C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: O=c1[nH]c(-c2ccc(C(F)(F)F)cc2)nc2c1ccn2C1CC1
Temperature: 150 °C
Yield: 55.8 %

Procedure:
A microwave reaction vial was charged with 2-chloro-7-cyclopropyl-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one (57 mg, 272 μmol), 4-(trifluoromethyl)phenylboronic acid (62.0 mg, 326 μmol), a 2M aqueous sodium carbonate solution (408 μL, 816 μmol), and tetrakis(triphenylphosphine)palladium(0) (15.7 mg, 13.6 μmol) in ethanol (1.09 mL). The reaction mixture was heated in a microwave at 150° C. for 8 min. At this time, the reaction was diluted with methylene chloride and was filtered through a pad of Celite®, washing with a 10% methanol/methylene chloride solution. The filtrate was dried over sodium sulfate, filtered, and concentrated in vacuo onto Celite®. Flash chromatography (12 g silica gel column, 25-50% ethyl acetate/hexanes) afforded 7-cyclopropyl-2-(4-trifluoromethyl-phenyl)-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one as a white solid (48.5 mg, 55.9%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.71-1.29 (m, 4H) 3.65 (d, J=4.90 Hz, 1H) 6.49 (d, J=3.58 Hz, 1H) 7.15 (d, J=3.39 Hz, 1H) 7.91 (d, J=8.67 Hz, 2H) 8.35 (d, J=7.91 Hz, 2H) 12.35 (br. s., 1H). LC-MS calcd. for C16H13F3N3O [(M+H)+] 320, obsd. 320.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:10][C:9]([F:12])([F:11])[C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:18]2[CH:19]=[CH:20][C:15]([C:14]([F:25])([F:24])[F:13])=[CH:16][CH:17]=2)[CH:3]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Nc1ncc(Br)cc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1ncc(-c2ccc(C(F)(F)F)cc2)cc1C(F)(F)F
Yield: 86.9 %

Procedure:
A mixture of 5-bromo-3-trifluoromethyl-pyridin-2-ylamine (11.5 g, 48 mmol) with 4-trifluormethylphenylboronic acid (9.97 g, 52 mmol), Pd(PPh3)4 (551 mg, 1 mol %) and 1M aq. Na2CO3 soln. (111 mL, 111 mmol) in DME (250 mL) at reflux for 1 h. Poured on icewater, extracted with EtOAc, dried over Na2SO4 and concentrated. Purified by column chromatography (heptane/AcOEt 2:1), then triturated the collected solids with heptane and a few drops of ether, ultrasound sonication for 10 min, filtrated and dried in to give the product as a white crystalline solid (12.77 g, 87%). MS (ISP) 307.2 [(M+H)+].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N+](N[C:23]1[NH:28][C:27](=[O:29])[C:26]([CH2:30][C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[CH:25][N:24]=1)([O-])=O>N1C=CC=CC=1>[CH2:6]([N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:23]1[NH:28][C:27](=[O:29])[C:26]([CH2:30][C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[CH:25][N:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCCCN(Cc1ccccc1)c1ccccn1
Reactant: O=c1[nH]c(N[N+](=O)[O-])ncc1Cc1ccncc1
Solvent: c1ccncc1
Product: O=c1[nH]c(NCCCN(Cc2ccccc2)c2ccccn2)ncc1Cc1ccncc1

Procedure:
2-[N-(3-aminopropyl)-N-benzylamino)pyridine (1.0 g) and 2-nitroamino-5-(pyrid-4-ylmethyl)pyrimid-4-one (0.68 g) were heated together under reflux in pyridine (2.5 ml) for 23 hr. After stripping the residue was twice crystallized from ethanol/water to give 2-[3-(N-benzyl-N-pyrid-2-ylamino)propylamino]-5-pyrid-4-ylmethylpyrimid-4-one 1.6 H2O, 0.86 g (68%) m.p. 87°-89° C.
Reaction SMILES: ClC(Cl)(Cl)[N:3]=[C:4]=[O:5].[OH:8][CH2:9][CH2:10][N:11]1[C:16]([C:17]([C:19]2[CH:20]=[C:21]([CH:24]=[C:25]([CH3:27])[CH:26]=2)[C:22]#[N:23])=[O:18])=[C:15]([CH:28]([CH3:30])[CH3:29])[C:14](=[O:31])[N:13]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[C:12]1=[O:41]>C(Cl)Cl>[C:22]([C:21]1[CH:20]=[C:19]([CH:26]=[C:25]([CH3:27])[CH:24]=1)[C:17]([C:16]1[N:11]([CH2:10][CH2:9][O:8][C:4](=[O:5])[NH2:3])[C:12](=[O:41])[N:13]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[C:14](=[O:31])[C:15]=1[CH:28]([CH3:30])[CH3:29])=[O:18])#[N:23]
Reactant: COc1ccc(Cn2c(=O)c(C(C)C)c(C(=O)c3cc(C)cc(C#N)c3)n(CCO)c2=O)cc1
Reactant: O=C=NC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(Cn2c(=O)c(C(C)C)c(C(=O)c3cc(C)cc(C#N)c3)n(CCOC(N)=O)c2=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.5 %

Procedure:
Trichloro-isocyanato-methane (39 uL, 0.33 mmol, 2.0 eq) was added to 3-[3-(2-hydroxy-ethyl)-5-isopropyl-1-(4-methoxy-benzyl)-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl]-5-methyl-benzonitrile (76 mg, 0.165 mmol) in 2 mL of DCM. The reaction mixture was stirred at room temperature for 10 minutes. HPLC and LC-MS showed complete reaction of the starting materials. Ammonia gas was bubbled into 3 mL DCM in a test tube (keep bubbling for 5 minutes). The ammonia solution was added to the above reaction mixture. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and concentrated down and purified (silica gel, 0-80% EtOAC/hexane) to give a white powder (42 mg, 51%). LC-MS shows 505.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH3:23])[CH2:10][CH2:9][C:8]2[C:11]([CH3:22])=[C:12]([O:17][CH2:18][CH2:19][CH2:20][OH:21])[C:13]([CH3:16])=[C:14]([CH3:15])[C:7]=2[O:6]1)=[O:4].[CH3:24][S:25](Cl)(=[O:27])=[O:26].S(=O)(=O)(O)O>C(Cl)Cl.C(N(CC)CC)C>[CH3:1][O:2][C:3]([C:5]1([CH3:23])[CH2:10][CH2:9][C:8]2[C:11]([CH3:22])=[C:12]([O:17][CH2:18][CH2:19][CH2:20][O:21][S:25]([CH3:24])(=[O:27])=[O:26])[C:13]([CH3:16])=[C:14]([CH3:15])[C:7]=2[O:6]1)=[O:4]
Reactant: COC(=O)C1(C)CCc2c(C)c(OCCCO)c(C)c(C)c2O1
Reactant: CS(=O)(=O)Cl
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1(C)CCc2c(C)c(OCCCOS(C)(=O)=O)c(C)c(C)c2O1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 0.3 g of racemic-3,4-dihydro-2,5,7,8-tetramethyl-6-(3-hydroxypropoxy)-2H-1-benzopyran-2-carboxylic acid methyl ester in 5 ml of anhydrous methylene chloride and 0.33 ml of triethylamine was added 0.17 ml of methanesulfonyl chloride. The mixture was stirred at room temperature for 45 minutes then treated with 1N sulfuric acid and worked-up with methylene chloride in the usual manner. There was obtained 0.461 g of racemic-3,4-dihydro-2,5,7,8-tetramethyl-6-(3-methanesulfonyloxypropoxy)-2H-1-benzopyran-2-carboxylic acid methyl ester as an oil which was used without further purification.
Reaction SMILES: [C:1]1(=[O:12])[O:7][C:5](=O)[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2]1.[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17].CO>C1(C)C=CC=CC=1.C(Cl)Cl>[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][N:17]1[C:1](=[O:12])[CH2:2][C:3]2[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5]1=[O:7]
Reactant: NCc1ccccc1F
Reactant: O=C1Cc2ccccc2C(=O)O1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: O=C1Cc2ccccc2C(=O)N1Cc1ccccc1F
Yield: 68.2 %

Procedure:
A mixture of 800 mg (4.9 mmol) homophthalic anhydride, 680 mg (5.4 mmol) 2-fluorobenzylamine and 500 mg 4 Å molecular sieves in 1.5 mL toluene was stirred and heated at reflux overnight. A solution of 30% MeOH in CH2Cl2 was added, the resulting hot mixture filtered and the tiltrate concentrated to give 900 mg 2-(2-fluorobenzyl)-4H-isoquinoline-1,3-dione, mp 140°-144° C. A 500 mg (1.86 mmol) portion of this product was combined with 570 mg (3.71 mmol) DBU in 5 mL CH2Cl2 under argon, and cooled to -10° C. Isopropylsulfonyl chloride (290 mg, 2.04 mmol) was added, and after stirring 15 min the reaction was allowed to warm to room temperature. After 4 hr the reaction was diluted with EtOAc and worked up as in Example 1 giving 329 mg of the title compound, mp 174°-181° C.
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1)([O:5][CH3:6])=[O:4].[Cl:17][C:18]1[CH:19]=[CH:20][C:21](O)=[C:22]([C:24](=[O:27])[CH2:25][CH3:26])[CH:23]=1.[OH-].[K+].Cl>ClCCl.N1C=CC=CC=1.O>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[O:13][C:12]([C:11]3[CH:15]=[CH:16][C:8]([CH2:7][P:3](=[O:4])([O:5][CH3:6])[O:2][CH3:1])=[CH:9][CH:10]=3)=[C:25]([CH3:26])[C:24](=[O:27])[C:22]=2[CH:23]=1
Reactant: COP(=O)(Cc1ccc(C(=O)Cl)cc1)OC
Reactant: CCC(=O)c1cc(Cl)ccc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COP(=O)(Cc1ccc(-c2oc3ccc(Cl)cc3c(=O)c2C)cc1)OC
Temperature: 50 °C
Reaction time: 10 h

Procedure:
A 39.4 g quantity of 4-[(dimethoxyphosphoryl)methyl]benzoyl chloride was dissolved in 150 ml of dry dichloromethane. Then 150 ml of a pyridine solution containing 27.7 g of 5'-chloro-2'-hydroxypropiophenone was slowly added dropwise to the reaction mixture with stirring under ice-cooling, and the stirring was continued at room temperature for 10 hours. After addition of 150 ml of water, the reaction mixture was extracted with chloroform. The chloroform layer was washed serially with 300 ml of a 10% aqueous HCl solution and 200 ml of water and dried over Glauber's salt. The solvent was distilled off under reduced pressure, and the residue thus obtained was dissolved in 150 ml of pyridine. A 14.0 g quantity of potassium hydroxide was added to the solution with stirring at room temperature, and the mixture was heated at 50° C. with stirring for 2 hours. After addition of 300 ml of a 10% aqueous HCl solution, the reaction mixture was extracted with chloroform. The chloroform layer was washed with 100 ml of water and dried over Glauber's salt. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography (eluent: chloroform:ethyl acetate=1:1). The resulting crude crystals were recrystallized from dichloromethane-n-hexane to provide 3.9 g of the title compound as colorless crystals. Table 1 shows the structure and physical property of the compound obtained.
Reaction SMILES: [CH2:1](O)[CH:2]([OH:6])[CH2:3][CH2:4][OH:5].C[O:9][C:10](OC)([CH3:12])[CH3:11].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH3:11][C:10]1([CH3:12])[O:9][CH:3]([CH:2]([OH:6])[CH3:1])[CH2:4][O:5]1
Reactant: COC(C)(C)OC
Reactant: OCCC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(O)C1COC(C)(C)O1
Reaction time: 0.08 h
Yield: 96.7 %

Procedure:
To a vigorously stirring suspension of 1,2,4-butanetriol (5.8 g, 54.6 mmol) in dichloromethane (20 mL) was added 2,2-dimethoxypropane (6.8 mL, 54.6 mmol) and catalytic p-toluenesulfonic acid. After 5 minutes, the solution became homogenous and was allowed to stir for an additional 30 minutes. The reaction mixture was then concentrated in vacuo to afford (2,2-Dimethyl-[1,3]dioxolan-4-yl)-ethanol (7.72 g, 96.7%). To a stirring solution of (2,2-Dimethyl-[1,3]dioxolan-4-yl)-ethanol (6.95 g, 47.5 mmol), triphenylphosphine (12.5 g, 47.5 mmol) and N-hydroxyphthalimide in freshly distilled tetrahydrofuran (200 mL) at 0° C. was slowly added (over 20 minutes) diethylazodicarboxylate. The dark red solution was allowed to stir for 2 hours at 0° C. and then allowed to warm to room temperature while stirring for 17 hours. The yellow solution was concentrated in vacuo and dissolved in chloroform (100 mL). The solids were filtered and filtrate concentrated. This filtration was repeated twice. The remaining yellow oil was purified on silica gel eluting with hexanes-ethyl acetate (4:1) to afford 2-[2-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-ethoxy]-isoindole-1,3-dione (8.1 g, 58.7%). To a stirring solution of 2-[2-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-ethoxy]-isoindole-1,3-dione (0.86 g, 2.95 mmol) in dichloromethane (10 mL) at 0° C. was added methylhydrazine (0.16 mL, 2.95 mmol). The resultant solution was allowed to warm to room temperature and stirred for 3 days. The resulting suspension was diluted with diethyl ether (20 mL) and filtered. The filtrate concentrated in vacuo to afford O-(2,2-dimethyl-[1,3]dioxolan-4-ylethyl)-hydroxylamine (0.36 g, 75.3%): 1H NMR (400 MHz; CDCl3) δ 4.18 (quint, 1H, J=5.9), 4.07 (dd, 1H, J=5.9, 7.8), 3.86 (t, 2H, J=6.2), 3.56 (t, 1H, J=7.6), 1.89 (m, 2H), 1.36 (s, 3H), 1.20 (s, 3H); MS(APCI+)=162.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:10][C@H:9]1[C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:32]([O-:35])(=[S:34])[CH3:33].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([S:34][C:32](=[O:35])[CH3:33])[CH2:10][C@H:9]1[C:24]([N:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1)=[O:25])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC([O-])=S
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2C[C@@H](C(=O)N3CCCCC3)N(C(=O)OC(C)(C)C)C2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1C[C@@H](C(=O)N2CCCCC2)N(C(=O)OC(C)(C)C)C1
Yield: 71.3 %

Procedure:
6.39 g (14.12 mmol) (2S,4R)-2-(Piperidine-1-carbonyl)-4-(toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester in 50 ml DMF were treated with 2.42 g (21.18 mmol, 1.5 eq) potassium thioacetate at 100° C. for 4 h. The solution was concentrated in vacuo and the residue was dissolved in EtOAc, NaHCO3 solution, the phases were separated and the inorganic layer was extracted with EtOAc. The combined organic phases were washed with water and brine, dried over Na2SO4. Column chromatography gave 3.59 g (71%) (2S,4S)-4-Acetylsulfanyl-2-(piperidine-1-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as light pink solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:4](=[O:20])[C:3]=1[C:21]#[N:22].[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].[H-].[Na+]>CN(C=O)C>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:4](=[O:20])[C:3]=2[C:21]#[N:22])[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: N#Cc1c(Cl)c2ccccc2n(Cc2ccc(F)cc2)c1=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2c(C#N)c(=O)n(Cc3ccc(F)cc3)c3ccccc23)CC1
Reaction time: 2 h

Procedure:
To a stirred solution of 4-Chloro-1-(4-fluoro-benzyl)-2-oxo-1,2-dihydro-quinoline-3-carbonitrile, compound C, (1 eq, 0.250 g, 0.80 mmole) in N,N′-dimethylformamide was added commercially available piperazine-1-carboxylic acid tert-butyl ester (1.1 eq, 0.164 g, 0.88 mmole) and treated with 60% NaH oil dispersion (1.5 eq, 0.029 g, 1.2 mmole). After stirring for 2 h, reaction was quenched with 10% HCl aq, (1 ml) then H2O (5 ml), A solid formed that was collected and dried. No further purification was necessary, afforded 4-[3-Cyano-1-(4-fluoro-benzyl)-2-oxo-1,2-dihydro-quinolin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester as a pale yellow solid (0.325 g, 88%, calc M+H 463, obs M+H 463).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[CH3:13].[O:14]=[C:15]1[CH2:20][O:19][C:18]2[CH:21]=[C:22]([CH:25]=[CH:26][C:27](O)=[O:28])[CH:23]=[N:24][C:17]=2[NH:16]1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CN(C)CCCN=C=NCC>CN(C=O)C.O>[CH3:1][N:2]([CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[CH3:13])[C:27](=[O:28])/[CH:26]=[CH:25]/[C:22]1[CH:23]=[N:24][C:17]2[NH:16][C:15](=[O:14])[CH2:20][O:19][C:18]=2[CH:21]=1
Reactant: CNCc1c(C)oc2ccccc12
Reactant: O=C(O)C=Cc1cnc2c(c1)OCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1oc2ccccc2c1CN(C)C(=O)/C=C/c1cnc2c(c1)OCC(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
To a solution of methyl-(2-methyl-benzofuran-3-ylmethyl)-amine (152 mg, 0.87 mmol) in DMF (5 mL) were added in sequential order 3-(3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-acrylic acid (175 mg, 0.79 mmol), 1-hydroxybenzotriazole (121 mg, 0.87 mmol), diisopropylethylamine (412 uL, 2.37 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (174 mg, 0.87 mmol). The mixture was stirred at room temperature overnight, cooled in an ice bath and treated with water under rapid stirring. The precipitated product was filtered and dried, triturated with diethyl ether to yield the title compound (125 mg, 42%) as a light brown solid and as a mixture of amide rotamers. 1H NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 8.21 (s, 1H), 7.89 (s, 1H), 7.50-7.59 (m, 3H), 7.19-7.26 (m, 3H), 4.74 (s, 2H), 4.70 (s, 2H), 3.06 (s, 3H), 2.52 (s, 3H); MS (ESI) m/e 378 (C21H19N3O4+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[CH3:10][CH:11]([CH3:29])[CH2:12][CH2:13][Si:14]1(C2C=CC=CC=2)[CH2:19][CH2:18][CH:17]([C:20](O)=[O:21])[CH2:16][CH2:15]1>>[CH3:10][CH:11]([CH3:29])[CH2:12][CH2:13][Si@H:14]1[CH2:15][CH2:16][C@H:17]([C:20]([O:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[O:21])[CH2:18][CH2:19]1
Reactant: CC(C)CC[Si]1(c2ccccc2)CCC(C(=O)O)CC1
Reactant: N#Cc1ccc(O)cc1
Product: CC(C)CC[Si@H]1CC[C@H](C(=O)Oc2ccc(C#N)cc2)CC1

Procedure:
The general procedure of Example 3 was repeated using (4-cyanophenol and 4-(3-methylbutyl)-4-phenyl-4-silacyclohexanecarboxylic acid, thereby obtaining the intended product.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[OH:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([O:16][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[C:12]([F:15])([F:14])[F:13])[CH:18]=1
Reactant: COC(=O)c1ccc(F)c(C(F)(F)F)c1
Reactant: Oc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2cccnc2)c(C(F)(F)F)c1

Procedure:
2 mmol of methyl 4-fluoro-3-trifluoromethyl-benzoate, 2 mmol of 3-hydroxypyridine and 4 mmol of K2CO3 are stirred in 15 ml of DMF (anhydrous) at 110° C. for 1.5 hours. The mixture is then poured onto 100 ml of water and extracted 3 times with 50 ml of EA each time. The extract is dried over Na2SO4, the solvent is removed in vacuo and the product is further reacted without additional purification. 500 mg of colorless oil. Rf (MTB)=0.33 MS (ES): 298 (M+1)
Reaction SMILES: Cl.[I:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]1)[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2=[O:24].C=O.O.[C:28]([BH3-])#N.[Na+]>CO>[I:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([CH3:28])[CH2:14]1)[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2=[O:24]
Reactant: CCOC(=O)c1cn(C2CCCNC2)c2ccc(I)cc2c1=O
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)c1cn(C2CCCN(C)C2)c2ccc(I)cc2c1=O
Temperature: 23 °C
Reaction time: 16 h
Yield: 81.2 %

Procedure:
Ethyl 6-iodo-4-oxo-1-(piperidin-3-yl)-1,4-dihydroquinoline-3-carboxylate hydrochloride (Intermediate 132, 500 mg, 1.08 mmol) was suspended in methanol (15 mL) then 37% formaldehyde in water (405 μl, 5.4 mmol) and sodium cyanoborohydride (612 mg, 9.7 mmol) were added. The reaction was stirred at 23° C. for 16 h. The volume of the reaction was reduced by half and water (25 mL) was added. The suspension was extracted with 2:1 ethyl acetate: tetrahydrofuran (3×10 mL). The organic phases were combined, dried over sodium sulfate, and the solvent was removed in vacuo. The residue was passed through a plug of silica gel (2 g) eluting with 10% methanol in dichloromethane to remove any remaining borohydride. The solid was then dried in a vacuum oven at 50° C. for 18 h to give 386 mg (81% yield) of ethyl 6-iodo-1-(1-methylpiperidin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate as an off white solid.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)=[CH:7][CH:6]=1.Cl>CO.[OH-].[Na+]>[CH3:22][O:21][C:19]1[CH:20]=[C:15]([CH:16]=[C:17]([O:25][CH3:26])[C:18]=1[O:23][CH3:24])[O:14][CH2:13][CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:4](=[O:27])[C:3]([OH:28])=[O:2])=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)c1ccc(OCCOc2cc(OC)c(OC)c(OC)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(OCCOc2ccc(C(=O)C(=O)O)cc2)cc(OC)c1OC
Yield: 72 %

Procedure:
A mixture of 4-[[2-(3,4,5-trimethoxyphenoxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (0.9 g) in methanol and 0.5N sodium hydroxide (8 mL) was heated on the steam bath for 0.5 hours, chilled, and 2N hydrochloric acid (5 mL) added. The resulting solids were filtered, washed with water and then boiled in benzene to dry. Filtration, evaporation and crystallization from diethyl ether-hexane provided 0.625 g of colorless 4-[[2-(3,4,5-trimethoxyphenoxy)ethyl]oxy]-alpha-oxobenzeneacetic acid, mp 118°-119° C.
Reaction SMILES: C1(C)C=CC=CC=1.Cl[C:9]1[N:10]=[N:11][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:13][CH:14]=1.[CH2:24]([O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][N:34]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C([O-])([O-])=O.[Na+].[Na+]>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:16]([O:15][C:12]1[N:11]=[N:10][C:9]([C:36]2[CH:35]=[N:34][C:33]([O:32][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:38][CH:37]=2)=[CH:14][CH:13]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCOc1ccc(Cl)nn1
Reactant: CCCCCCCCOc1ccc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1ccc(-c2ccc(OCCCCCCCC)nn2)cn1

Procedure:
40 ml of toluene are added under a protective gas to 1.41 g (5.8 mmol) of 3-chloro-6-octyloxypyridazine. A solution of 1.45 g (5.8 mmol) of 2-octyloxy-5-pyridineboronic acid in 20 ml of ethanol, followed by 1.23 g of Na2CO3 and finally 20 ml of water are added. Finally, mg (0.058 mmol) of tetrakis(triphenylphosphine)palladium(0) are added with stirring. The mixture is refluxed for 8 hours and cooled, the phases are separated, the organic phase is washed once with saturated aqueous NaHCO3 solution and dried over MgSO4, and the solvent is removed in vacuo. The residue is chromatographed on SiO2 using CH2Cl2 /ethyl acetate: 20/1. The product obtained can be further purified by recrystallization from n-heptane.