Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20](OC)(OC)[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1.[CH3:31][C@H:32]([OH:36])[C@@H:33]([OH:35])[CH3:34].CC1C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>CC1C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1([CH2:21][N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)[O:36][C@@H:32]([CH3:31])[C@H:33]([CH3:34])[O:35]1
Reactant: COC(Cn1cncn1)(OC)c1ccc(Cl)cc1Cl
Reactant: C[C@H](O)[C@H](C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C[C@@H]1OC(Cn2cncn2)(c2ccc(Cl)cc2Cl)O[C@H]1C
Yield: 31 %

Procedure:
A mixture of 7.1 parts of 1-[2-(2,4-dichlorophenyl)-2,2-dimethoxyethyl]-1H-1,2,4-triazole 4-methylbenzenesulfonate, 1.5 parts of (2S,3S)-(+)-2,3-butanediol, 0.7 parts of 4-methylbenzenesulfonic acid and 68 parts of methylbenzene is stirred and refluxed for 3 days. The reaction mixture is cooled and alkalized with a sodium hydroxide solution 20%. The whole is poured onto water and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using ethyl acetate as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 2,2'-oxybispropane and petroleumether (1:1 by volume). The product is filtered off and dried, yielding 1.5 parts (31%) of (+)-(4S,trans)-1-[2-(2,4-dichlorophenyl)-4,5-dimethyl-1,3-dioxolan-2-ylmethyl]-1H-1,2,4-triazole; mp. 82.7° C.; [α]D =+30.47° (c=0.5 % CHCl3).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH2:13][NH:12][CH2:11][CH2:10]3)[CH2:5][C@H:4]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[O:3]1.C(N(CC)CC)C.[CH2:33]([O:40][CH2:41][C:42](Cl)=[O:43])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[O:1]=[C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH2:13][N:12]([C:42](=[O:43])[CH2:41][O:40][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:11][CH2:10]3)[CH2:5][C@H:4]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[O:3]1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CN(c2ccc3c(c2)CCNC3)C(=O)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC[C@H]1CN(c2ccc3c(c2)CCN(C(=O)COCc2ccccc2)C3)C(=O)O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
A solution of 1,1-dimethylethyl [[(5S)-2-oxo-3-[1,2,3,4-tetrahydro-6-isoquinolinyl]-5-oxazolidinyl]methyl]carbamate (Example 6, Step 2, 347 mg, 0.999 mmol) and triethylamine (0.21 mL, 1.50 mmol) in dry CH2Cl2 at 0° C. under N2 is treated with benzyloxyacetyl chloride (0.19 mL, 1.20 mmol), and the resulting mixture is stirred at 0° C. for 1 hr and then allowed to warm to ambient temperature. The reaction mixture is then diluted with CH2Cl2 (20 mL), washed with H2O (10 mL) and brine (10 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue is chromatographed on a Flash 40S silica gel (40 g, 32-63 μm) cartridge, eluting with a gradient of MeOH/CH2Cl2 (1/99-2/98), and those fractions with an Rf=0.72 by TLC (MeOH/CHCl3, 10/90) are pooled and concentrated to give 425 mg (86%) of the title compound as an amorphous, glassy solid. MS (ESI+) for C27H33N3O6 m/z 496 (M+H)+.
Reaction SMILES: [S:1]1(=[O:14])(=[O:13])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=O)[CH2:4][CH2:3][CH2:2]1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N:15]1([C:5]2[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[S:1](=[O:14])(=[O:13])[CH2:2][CH2:3][CH:4]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C1CCCS(=O)(=O)c2ccccc21
Reactant: C1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: O=S1(=O)CCC=C(N2CCCC2)c2ccccc21
Yield: 102.5 %

Procedure:
A solution of 20.6 g (0.1 mol) of 3,4-dihydro-1-benzothiepin-5(2H)-one 1,1-dioxide, 9.6 g of pyrrolidine and 250 mg of p-toluenesulfonic acid in 250 ml of benzene was refluxed under a nitrogen atmosphere for 20 hours, using a Dean-Stark apparatus to remove the water which formed. Removal of the solvent under reduced pressure gave 27 g of a viscous oil which was used without further purification. The infrared spectrum showed the absence of a ketone band and the presence of a strong enamine band at 1620 cm-1.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].S(=O)(=O)(O)O.[NH2:10][C:11]1[S:12][C:13]([CH2:17][CH2:18]O)=[C:14]([CH3:16])[N:15]=1.[OH-].[Na+]>CCCCCC.O>[CH3:16][C:14]1[N:15]=[C:11]([NH2:10])[S:12][C:13]=1[CH2:17][CH2:18][O:2][N+:1]([O-:4])=[O:3]
Reactant: Cc1nc(N)sc1CCO
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: O
Product: Cc1nc(N)sc1CCO[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Subsequently, 4-methyl-5-(2-nitrooxy-ethyl)-thiazole-2-ylamine was prepared by drop-wise addition of 1.59 grams of nitric acid (70%) to 2.48 grams of cooled sulfuric acid (95-98%) at 0-5° C. over a time period of 20 minutes. Following, 4 grams (0.025 moles) of 2-(2-Amino-4-methyl-thiazol-5-yl)-ethanol were added over a time period of 45 minutes at 0-5° C. After the addition was completed, the reaction mixture was stirred for 3 hours at 25° C., and was then added carefully to 50 ml of cold water. The water solution was turned basic with an aqueous solution of 20% sodium hydroxide and the aqueous phase was extracted with three portions of 75 grams of ethyl acetate. The organic extracts were combined, dried over sodium sulfate, filtered and evaporated to dryness under vacuum. Chromatography of the crude product on silica gel (using a mixture of 8:2 ethyl acetate:hexane as eluent) gave 1.8 grams (35% yield) of the product as orange oil having a purity of 98.5% as determined by gas chromatography.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][C:3]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][N:22]=1)=[O:19]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:18]([C:3]2[C:2](=[O:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:4]=2)=[O:19])=[N:22][CH:23]=1
Reactant: Cc1ccc(NC(=O)C2=C(O)c3ccccc3N(c3ccccc3)C2)nc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(NC(=O)c2cn(-c3ccccc3)c3ccccc3c2=O)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
A solution of 12.30 g of 1,2-dihydro-4-hydroxy-N-(5-methyl-2-pyridyl)-1-phenyl-3-quinolinecarboxamide in 250 ml of chloroform was treated with 50.0 g of activated manganese dioxide and stirred at room temperature for two hours. The slurry was filtered and evaporated. Recrystallization of the residue from chloroform yielded 10.96 g (91%) of 1,4-dihydro-N-(5-methyl-2-pyridyl)-4-oxo-1-phenyl-3-quinolinecarboxamide, m.p. 248°-250° C.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][C:5]1[NH:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=1.[Br:16]N1C(=O)CCC1=O>CO>[Br:16][C:6]1[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][NH:9][C:5]=1[CH2:4][CH2:3][S:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CSCCc1cc(-c2ccccc2)n[nH]1
Solvent: CO
Product: CSCCc1[nH]nc(-c2ccccc2)c1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 62.4 %

Procedure:
To a solution of 5-(2-(methylthio)ethyl)-3-phenyl-1H-pyrazole (4.0 g, 18.32 mmol) in methanol (20 mL) was added N-bromosuccinimide (3.26 g, 18.32 mmol) slowly at 0° C. The reaction was stirred at 0° C. for 2 h. The mixture was concentrated and purified by silica gel column chromatography to give the title compound (3.4 g). LCMS m/z=297.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.11 (s, 3H), 2.79 (t, J=7.83 Hz, 2H), 2.83-2.97 (m, 2H), 7.32-7.56 (m, 3H), 7.67-7.88 (m, 2H), 13.20 (bs, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[C:13]3[CH2:14][CH2:15][CH2:16][C:17](=[O:18])[C:12]=3[O:11][N:10]=2)[CH:6]=[CH:5][C:4]=1[NH:19][CH:20]=[O:21].C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:29][C:30](=[O:32])[CH3:31].O>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[C:13]3[CH2:14][CH2:15][CH2:16][C:17](=[O:18])[C:12]=3[O:11][N:10]=2)[CH:6]=[CH:5][C:4]=1[N:19]([CH2:29][C:30](=[O:32])[CH3:31])[CH:20]=[O:21]
Reactant: COc1cc(-c2noc3c2CCCC3=O)ccc1NC=O
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: COc1cc(-c2noc3c2CCCC3=O)ccc1N(C=O)CC(C)=O
Temperature: 55 °C
Yield: 33.1 %

Procedure:
To a mixture of N-(2-methoxy-4-(7-oxo-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-yl)phenyl)formamide (2.66 g, 9.28 mmol), Cs2CO3 (5.37 g, 27.9 mmol), and KI (308 mg, 1.86 mmol) in dry DMF (40 ml) was added chloroacetone (7.72 g, 18.57 mmol) dropwise. The reaction was stirred at 55° C. over night. Reaction mixture was worked up with water and DCM, organic phase was washed with water and brine, dried over sodium sulfate and concentrated. The product was purified by chromatography on silica gel using a mixture of ethyl acetate and hexanes as the eluent to furnish 1.05 g of the title compound, MS(M+H)+=343.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH:15](=O)[C:16]([CH3:18])=[O:17].C1(C)C=CC(S([CH:29]([N+:37]#[C-:38])[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CCOCC.CCOC(C)=O.O>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([N:1]2[C:15]([C:16](=[O:17])[CH3:18])=[C:29]([C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)[N:37]=[CH:38]2)[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(=O)C=O
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: [C-]#[N+]C(c1ccc(F)cc1)S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)c1c(-c2ccc(F)cc2)ncn1C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1.75 h
Yield: 27.2 %

Procedure:
To a solution of t-butyl 4amino-piperidinecarboxylate (0.95 g, 4.75 mmol) in 40 mL of Et2O was added pyruvaldehyde (40% w/w solution in water, 0.94 mL, 1.11 g, 6.17 mmol) at room temperature. After 1.75 h, the solution was poured into a separatory funnel, diluted with 30 mL of Et2O and 10 mL of EtOAc, and washed with 2×10 mL of water. The organics were concentrated in vacuo and the residue was diluted in 10 mL of DMF and α-(p-toluenesulfonyl)-4-fluoro-benzylisonitrile (1.37 g, 4.75 mmol) and K2CO3 (0.72 g, 5.23 mmol) were added. After 16 h, the solution was diluted with 100 mL of water and extracted with 2×40 mL of EtOAc. The combined organics were washed with 3×40 mL of 10% HCl. The aqueous layers were combined and neutralized with excess solid NaHCO3, then basified with 20 mL of 10% KOH. The aqueous layer was transferred to a separatory funnel and extracted 3×30 mL of EtOAc. The combined organics concentrated in vacuo to yield the imidazole product (0.5 g, 27%); 1H NMR (CDCl3) δ 7.74, 7.44 (2H, m), 7.13 (2H, t, J=8.6 Hz), 4.97 (1H, tt, J=3.7, 12.0 Hz), 4.29 (2H, m), 2.88 (2H, m), 2.15 (2H, m), 2.1 (3H, s), 1.78 (2H, dq, 4.2, 12.2 Hz), 1.48 (9H, s).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=1)=[O:6].C(=O)([O-])[O-].[K+].[K+].[N:31]1[CH:36]=[CH:35][C:34]([C:37]([OH:50])([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:33][CH:32]=1>O.C(OCC)(=O)C.C1(C)C=CC=CC=1>[OH:50][C:37]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[CH:34]1[CH2:35][CH2:36][N:31]([CH2:2][CH2:3][CH2:4][C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=2)=[O:6])[CH2:32][CH2:33]1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccncc1
Reactant: CCOC(=O)C(Cc1ccc(C(=O)CCCCl)cc1)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 168 h
Yield: 97.3 %

Procedure:
Mix together [4-(4-chloro-1-oxobutyl)phenyl]methyl-propanedioic acid, diethyl ester (380 mg, 1.1 mmol), potassium carbonate (450 mg, 3.2 mmol), α-(4-pyridyl)benzhydrol (500 mg, 1.9 mmol), water (4 mL) and toluene (10 mL). Heat the mixture to reflux. After 7 days, cool to room temperature. Add ethyl acetate and water. Wash the organic phase with brine, dry over anhydrous magnesium sulfate and concentrate. Purify by flash chromatography (200 g of silica gel, 10% methanol/chloroform as eluent) to give the title compound (627 mg, 99%).
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@H:13]1[NH:25][C:26]([O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])=[O:27])=O)C1C=CC=CC=1.[H][H]>[Pd].C(O)(C)C>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@H:13]1[NH:25][C:26]([O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])=[O:27]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](NC(=O)OCC[Si](C)(C)C)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](NC(=O)OCC[Si](C)(C)C)C1
Yield: 61.8 %

Procedure:
A mixture of cis-tert-butyl 4-(benzyloxycarbonylamino)-3-((2-(trimethylsilyl)ethoxy)carbonylamino)piperidine-1-carboxylate (1.8 g, 3.6 mmol) and 10% palladium on carbon (180 mg) in isopropanol (60 mL) was stirred under 1 atm hydrogen atmosphere (hydrogen balloon) at room temperature for 3 hours. After that, the mixture was filtered through a pad of celite. The filtrate was concentrated and purified by silica gel column chromatography (methanol/dichloromethane=1/30 to 1/10) to afford the title compound (800 mg, 61%) as a yellow oil. MS (ES+) C16H33N3O4Si requires: 359, found: 360 [M+H]+.
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].CC([O:17][CH3:18])(C)C>>[S:9]([O-:11])(=[O:17])(=[O:10])[CH3:8].[C:18]([O-:17])(=[O:10])[CH2:6][CH3:7]
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)Cl
Reactant: COC(C)(C)C
Product: CCC(=O)[O-]
Product: CS(=O)(=O)[O-]
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
The alcohol/propionate mixture was dissolved in MTBE (100 ml) , and the solution was cooled to 5° C. Triethylamine (10.8 ml, 78 mmol) was added. The solution was cooled to 0-2° C. and methanesulfonyl chloride (3.75 ml, 48.5 mmol) was added over 30 minutes, maintaining the internal temperature at 0-2° C. The suspension was stirred at 0-2° C. for 15 minutes, and extra methanesulfonyl chloride (0.2 ml, 2.6 mmol) was then added. The suspension was stirred at 0-2° C. for 5 minutes, and then the reaction was quenched with water (85 ml). The aqueous layer was removed, and the organic layer was washed with saturated potassium hydrogen sulfate solution-water (1:1, 80 ml), saturated sodium bicarbonate solution (80 ml) and brine (40 ml). After drying (MgSO4), filtration and evaporation of the solvent, the mesylate/propionate mixture was obtained as a yellow oil (26 g). 1H nmr (200 MHz, CDCl3) δ ppm 7.27-6.92 (2 H total, m), 6.84-6.78 (1 H total, m) 5.74 (1 H propionate, td, J5.8, 2.3 Hz), 5.51 (1 H mesylate, td, J5.6, 2.4 Hz), 4.25 (2 H, mesylate, d, J 4.9, 4.19 (1 H propionate, d, J5.5 Hz), 3.16 (3 H mesylate, s), 2.79 (1 H mesylate, J2.4 Hz), 2.53 (1 H propionate, J2.1 Hz), 2.39 (2 H propionate, q, J7.6 Hz) and 1.16 (3 H propionate, t, J7.5 Hz)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]=[CH:6][C:7]1[C:8](Cl)=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1)[CH3:2].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]=[CH:6][C:7]1[C:8]([C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1)[CH3:2]
Reactant: OB(O)c1cccnc1
Reactant: CCOC(=O)C=Cc1ccc(C(F)(F)F)nc1Cl
Product: CCOC(=O)C=Cc1ccc(C(F)(F)F)nc1-c1cccnc1
Yield: 50 %

Procedure:
3-(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid ethyl ester (103 mg, 0.368 mmol) was reacted with 3-pyridine boronic acid (2 eq) to give 3-(2-pyridin-3-yl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid ethyl ester (60 mg, 50%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][C:3]1=[O:8].Cl[C:10]1[N:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][N:11]=1>ClCCl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:10]2[N:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][N:11]=2)[CH2:4][C:3]1=[O:8]
Reactant: CN1CCNCC1=O
Reactant: COC(=O)c1cnc(Cl)nc1
Solvent: ClCCl
Product: COC(=O)c1cnc(N2CCN(C)C(=O)C2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.5 %

Procedure:
A solution of 1-methylpiperazin-2-one (198 mg, 1.74 mmol) in dichloromethane (4.00 mL) was added to a stirred solution of methyl 2-chloropyrimidine-5-carboxylate (300 mg, 1.74 mmol) in dichloromethane (4.70 mL) at 25° C. The resulting solution was stirred at room temperature for 4 h under nitrogen. The reaction mixture was concentrated and dissolved in ethyl acetate (25 ml) and NaOH (50 ml, 1M aqueous solution). The organic layer was washed with ethyl acetate (25 ml). The organic layers were combined and washed with brine (50 ml), dried using MgSO4, filtered and evaporated to dryness to afford methyl 2-(4-methyl-3-oxopiperazin-1-yl)pyrimidine-5-carboxylate (246 mg, 57%) as a cream solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]#N.[CH2:7]([O:9][C:10](=[O:13])[CH2:11]Br)[CH3:8].Cl.C1C[O:18]CC1>>[CH2:7]([O:9][C:10](=[O:13])[CH2:11][C:5](=[O:18])[CH2:4][CH2:3][O:2][CH3:1])[CH3:8]
Reactant: C1CCOC1
Reactant: CCOC(=O)CBr
Reactant: COCCC#N
Agent: Cl
Product: CCOC(=O)CC(=O)CCOC
Reaction time: 0.5 h
Yield: 76 %

Procedure:
68 g (0.8 mol) of 3-methoxypropionitrile were dissolved in 1000 mL THF freshly distilled over LiAlH4 and treated with 150.3 g (2.2 mol) Zn/Cu pair under inert gas. With moderate reflux 267.2 g (1.6 mol) of 2-bromoacetic acid ethyl ester were added drop-by-drop to the vigorously stirred suspension within 75 minutes. After the reaction had started, the heat was turned off and the slight reflux adjusted via the drop velocity. To complete the reaction, the solution was stirred for 30 minutes at the boiling temperature of THF. Then, 420 mL of 10% HCl were added drop-by-drop within 30 minutes at 15° C. and stirred for another 30 minutes. The solution was filtered from the non-converted zinc and the filtrate was extracted three times with 300 mL of CHCl3 each. The organic phases were washed four times with water and once with 5% NaHCO3 solution and the solvent was removed following drying over MgSO4 under vacuum. The obtained reddish liquid was distilled under oil pump vacuum. The fraction at 85° C./0.5 torr yielded 106.8 g (0.62 mol) of 5-methoxy-3-oxopentanic acid ethyl ester as a colorless, fruity smelling oil with a refractive index nD22 =1.434. The yield was to 77.5% based on 3-methoxypropionitrile.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13](=[O:18])[NH:14][CH:15]1[CH2:17][CH2:16]1)=O)(C)(C)C.[ClH:19]>C1(C)C=CC=CC=1>[ClH:19].[CH:15]1([NH:14][C:13]([C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[O:18])[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NC1CC1
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C(NC1CC1)[C@@H]1CCCN1
Reaction time: 2 h

Procedure:
The crude (S)-2-Cyclopropylcarbamoyl-pyrrolidine-1-carboxylic acid tert-butyl ester from the preceding reaction step was dissolved in 20 ml of saturated ethanolic hydrochloric acid and stirred for 2 h. Then, the reaction mixture was diluted with 200 ml of toluene and the solvents were removed under reduced pressure. The residue was co-distilled additional 3 times with toluene and then, triturated with ether. The obtained crystalline white solid was filtered and dried. Yield: 8.2 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.FC1C=C(C(F)(F)F)C=CC=1C=CC(C(C)C)C(O)=O.[CH2:37]([C:44]1[N:49]=[C:48]([CH2:50]O)[CH:47]=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([O:13][CH2:50][C:48]2[CH:47]=[CH:46][CH:45]=[C:44]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:49]=2)=[O:12])=[CH:6][CH:7]=1
Reactant: CC(C)C(C=Cc1ccc(F)cc1)C(=O)O
Reactant: OCc1cccc(Cc2ccccc2)n1
Agent: CC(C)C(C=Cc1ccc(C(F)(F)F)cc1F)C(=O)O
Product: CC(C)C(C=Cc1ccc(F)cc1)C(=O)OCc1cccc(Cc2ccccc2)n1

Procedure:
Following the procedure of Example 1, the acid chloride of each of 4-(4-fluorophenyl)-2-isopropyl-3-butenoic acid, 4-(2-chloro-4-trfluoromethylphenyl)-2-isopropyl-3-butenoic acid and 4-(2-fluoro-4-trifluoromethylphenyl)-2-isopropyl-3-butenoic acid is reacted with (6-benzyl-2-pyridyl)methanol to give (6-benzyl-2-pyridyl)methyl 4-(4-fluorophenyl)-2-isopropyl-3-butenoate,
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1>>[OH:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:1]=2)=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: NC(=O)c1ccccc1N
Product: O=c1[nH]c(-c2ccc(O)cc2)nc2ccccc12

Procedure:
The entitled compound was obtained according to the method of Example 1-(2) but starting from 2-aminobenzamide and 4-hydroxybenzaldehyde.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][C:17]2[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:18]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=2)=[O:20])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C1(OC)C=CC=CC=1.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>ClCCl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:19](=[O:20])[C:18]2[CH:29]=[C:30]([I:33])[CH:31]=[CH:32][C:17]=2[NH:16][C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:15])=[N:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(I)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)cn1)c1cc(I)ccc1NC(=O)C1CCNCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
To a stirring solution of 2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-iodobenzamide (2.0 g, 3.45 mmol) in dichloromethane (65 mL) and anisole (2 mL, 18 mmol) was added trifluoroacetic acid (6.7 mL, 87 mmol). The reaction solution was stirred at room temperature for 4 h, concentrated in vacuo, treated with diethyl ether and concentrated (3×), treated with diethyl ether, sonicated, and filtered to give 1.86 g (90%) of a gray solid.