Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=2)=[CH:12][CH:11]=1)([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl[C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[O:37])=[CH:34][N:33]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:36]([C:35]1[CH:38]=[CH:39][C:32]([N:18]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][C:27]([F:28])([F:29])[F:30])=[CH:24][CH:25]=2)[CH2:17][CH2:16][C:13]2[CH:14]=[CH:15][C:10]([O:9][C:2]([CH3:1])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:11][CH:12]=2)=[N:33][CH:34]=1)=[O:37]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCNCc2ccc(OC(F)(F)F)cc2)cc1
Reactant: O=Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(OC(F)(F)F)cc2)c2ccc(C=O)cn2)cc1
Yield: 67.5 %

Procedure:
A solution of ethyl 2-methyl-2-[4-(2-{[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]propanoate (3.0 g; 7.05 mmol) in 8 ml of DMF was treated with 6-chloronicotinaldehyde (0.91 g; 6.42 mmol) and K2CO3 (0.97 g; 7.05 mmol). The reaction mixture was heated at 150C for 4 hr. Upon cooling, the mixture was partitioned between ethyl acetate and 0.05N HCl. The organic phase was washed with 0.05N HCl and brine, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography using ethyl acetate-hexane mixtures (5–50%) afforded the title compound (2.3 g; 68% yield).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:25]([C:27]1[CH:40]=[CH:39][C:30]([CH2:31][N:32]2[C:36]([CH:37]=O)=[CH:35][N:34]=[CH:33]2)=[CH:29][CH:28]=1)#[N:26].CCOC(C)=O>ClCCCl>[C:25]([C:27]1[CH:28]=[CH:29][C:30]([CH2:31][N:32]2[C:36]([CH2:37][NH:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:35][N:34]=[CH:33]2)=[CH:39][CH:40]=1)#[N:26]
Reactant: NCCCc1ccccc1
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: N#Cc1ccc(Cn2cncc2CNCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 3-phenylpropylamine (0.202 mL, 1.42 mmol) in 5 mL of 1,2-dichloroethane at 0° C. was added 4Å powdered molecular sieves (0.38 g), followed by sodium triacetoxyborohydride (301 mg, 1.42 mmol g). The aldehyde 6 from Step 5 of Example 1 (200 mg, 0.947 mmol) was added, and the reaction was allowed to warm to room temperature. After 2 days, the reaction was poured into EtOAc, washed with sat. aq. NaHCO3, and the aqueous layer was extracted with EtOAc. The combined organics were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting product was taken up in 12 mL of 20% CH2Cl2 /propylamine, stirred for 12 hours, concentrated in vacuo, and purified by preparative HPLC. Thus, the product was taken up in water/MeOH solution and was injected directly onto a Delta-Pak (C-18, 100A, 15 mm, 40 mm×100 mm) prep HPLC column using a gradient with 0.1% trifluoroacetic acid/water and 0.1% trifluoroacetic acid/acetonitrile as solvents. A portion of the pure fractions was then partitioned between methylene chloride and water, and the organic phase was dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled product 10 as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:10]1(=O)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][C:12](=[O:20])[O:11]1>C(O)(=O)C>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([N:5]2[C:12](=[O:20])[CH2:13][C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]2=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1c(N)cccc1Br
Reactant: O=C1Cc2ccccc2C(=O)O1
Solvent: CC(=O)O
Product: Cc1c(Br)cccc1N1C(=O)Cc2ccccc2C1=O
Temperature: 100 °C
Yield: 35.5 %

Procedure:
Step 1 A mixture of 3-bromo-2-methylaniline (1 g, 5.37 mmol) and isochroman-1,3-dione (0.872 g, 5.37 mmol) in acetic acid (15 mL) was heated overnight at 100° C. in a sealed tube. The mixture was cooled to rt and concentrated, and the residue was purified by column chromatography (eluting with a gradient from 80:20 hexane-EtOAc to EtOAc) to give 2-(3-bromo-2-methylphenyl)isoquinoline-1,3(2H, 4H)-dione as a tan solid (630 mg, 36%). Mass spectrum m/z 330, 332 (M+H)+.
Reaction SMILES: CN(C)C=O.[CH:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C-]#N.[Na+].[C:17](#[N:20])[CH:18]=[CH2:19]>O>[C:6]([CH2:19][CH2:18][C:17]#[N:20])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=Cc1ccccc1
Reactant: C=CC#N
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCC(=O)c1ccccc1
Temperature: 30 °C
Reaction time: 0.25 h

Procedure:
320 ml of absolute dimethylformamide, 42.5 g (0.4 mol) of freshly distilled benzaldehyde and 9.8 g (0.2 mol) of sodium cyanide are introduced into a 500 ml 4-necked flask equipped with dropping funnel, stirrer, KOH drying tube and internal thermometer. A week exothermic reaction takes place after the addition of sodium cyanide to the reaction mixture and the temperature rises from 30° to 34° C. The reaction mixture is stirred for 15 minutes at a reaction temperature of 30° C and a solution of 15.9 g (0.3 mol) of freshly distilled acrylonitrile and 80 ml of absolute dimethylformamide is introduced dropwise into the reaction mixture in the course of one hour at the same temperature. Stirring is then continued for 1/4 hours at the same temperature. The reaction mixture, which is now very creamy, is poured on to 800 ml of water and vigorously shaken. The aqueous solution is extracted twice with 200 ml of chloroform and twice with 100 ml of chloroform. The combined chloroform solutions are vigorously washed with water and dried over MgSO4 and the chloroform is distilled off. Inoculating crystals are added to the residue. β-Benzoyl-propionitrile then crystallises at once. It is suction filtered and washed with ethanol. 26.6 g of β-benzoylpropionitrile are obtained. M.p.: 69° C.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:13][CH2:12][C:11]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:14]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][CH:20]=[CH:19]3)=[O:15])[CH2:10]1)=O)(C)(C)C>CO>[CH2:25]([C:11]1([C:14]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][CH:20]=[CH:19]3)=[O:15])[CH2:12][CH2:13][NH:9][CH2:10]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccccc2)(C(=O)c2ccc3[nH]ccc3c2)C1
Agent: Cl
Solvent: CO
Product: O=C(c1ccc2[nH]ccc2c1)C1(Cc2ccccc2)CCNC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 93 %

Procedure:
A solution of HCl (1.0 M in MeOH, 12 mL) was added to a solution of 3-benzyl-3-(1H-indole-5-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester enantiomer A (257 mg, 0.635 mmol) in MeOH (5 mL). The resulting pale yellow solution was stirred at room temperature for 6 hours, then cooled to 0° C. and quenched by addition of aqueous NaOH (1.0 M). The mixture was diluted with water and extracted with DCM. The combined organic layers were dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (5% to 10% of MeOH in DCM with 0.5% of NH4OH) to give 179 mg (93% yield) of (3-Benzyl-pyrrolidin-3-yl)-(1H-indol-5-yl)-methanone, which was dissolved in a mixture of DCM/MeOH. A solution of HCl (1 M in Et2O) was added, and the resulting mixture was evaporated under reduced pressure and the residue was triturated with Et2O to give 173 mg of (3-benzyl-pyrrolidin-3-yl)-(1H-indol-5-yl)-methanone hydrochloride enantiomer A as a white powder. MS=305 [M+H]+; [α]D=−26.3° (5.40 mg/10.0 mL of MeOH).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6](=[O:20])[C:7]([CH3:19])=[C:8]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[O:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:27](Cl)(=[O:31])[O:28][CH2:29][CH3:30]>CN(C)C=O>[OH:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6](=[O:20])[C:7]([CH3:19])=[C:8]([CH:13]3[CH2:18][CH2:17][N:16]([C:27]([O:28][CH2:29][CH3:30])=[O:31])[CH2:15][CH2:14]3)[O:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c(C2CCNCC2)oc2c(C)c(O)ccc2c1=O
Reactant: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCOC(=O)N1CCC(c2oc3c(C)c(O)ccc3c(=O)c2C)CC1
Reaction time: 48 h
Yield: 69.5 %

Procedure:
To a solution of 7-hydroxy-3,8-dimethyl-2-(piperidin-4-yl)-4H-chromen-4-one (68 mg, 0.25 mmol) obtained in Example 7-2 and pyridine (22 μL, 0.28 mmol) in dimethylformamide (2 mL), ethyl chlorocarbonate (24 μL, 0.25 mmol) was added dropwise under cooling with ice, and then the mixture was brought back to room temperature and stirred for 2 days. The reaction solution was concentrated, and the obtained residue was purified by reverse-phase HPLC to obtain 60 mg of the title compound (yield: 69%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[NH2:6].Br[CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].N1C(C)=CC=CC=1C>C(#N)C>[CH2:21]([O:20][C:18](=[O:19])[CH:17]([NH:6][C:5]1[CH:7]=[CH:8][C:9]([C:10]([F:11])([F:12])[F:13])=[C:3]([C:2]([F:14])([F:15])[F:1])[CH:4]=1)[CH3:23])[CH3:22]
Reactant: Nc1ccc(C(F)(F)F)c(C(F)(F)F)c1
Reactant: CCOC(=O)C(C)Br
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)C(C)Nc1ccc(C(F)(F)F)c(C(F)(F)F)c1
Yield: 49 %

Procedure:
In analogy to intermediate 40B, 3,4-bis(trifluoromethyl)aniline and ethyl 2-bromopropionate with 2,6-lutidine were heated for 20 h at 82° C., diluted with acetonitrile and treated with 1 equivalent of ethyl 2-bromopropionate and 2,6-lutidine and refluxed for 2 days, treated again with 1 equivalent of ethyl 2-bromopropionate and 2,6-lutidine and continued to reflux for 2 days. Workup and purification by flash silica gel column (n-heptane/ethyl acetate 9:1 to 2:1) yielded 49% of the titled compound as yellow oil. MS: 328.08 (M−H−).
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][C:12](=O)[CH:11]([C:16]([O:18][CH3:19])=[O:17])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[NH3:26]>C(O)C>[NH2:26][C:12]1[CH2:13][CH2:14][N:9]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:10][C:11]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: N
Reactant: COC(=O)C1CN(Cc2ccccc2)CCC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)C1=C(N)CCN(Cc2ccccc2)C1

Procedure:
855 g of methyl 1-benzyl-4-oxopiperidine-3-carboxylate hydrochloride, 176 g of sodium carbonate and 450 ml of 25% aqueous ammonia solution in 6.5 1 of ethanol were heated for 5 h at an internal temperature of 70° C., with stirring. After concentration under reduced pressure, the mixture was worked up by extraction with dichloromethane and water. The combined dichloromethane phases were dried over sodium sulfate and concentrated under reduced pressure to give 788 g of oily methyl 4-amino-1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylate as a crude product, which was used in Example 1b) without further purification.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15]CC)=O.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:13]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][CH:9]=[C:8]([CH3:12])[CH:7]=3)=[O:15])=[CH:21][CH:20]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2cc(C)ccc2c1O
Product: Cc1ccc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc2c1
Temperature: 200 °C
Reaction time: 1 h

Procedure:
A mixture of 0.50 g of ethyl 4-hydroxy-7-methyl-3-quinolinecarboxylate (J. Indian Chem. Soc., 31 (1954)) and 5.0 mL of 4-chlorobenzylamine is stirred 1 hour at 200° C. The mixture is cooled to 25° C. and it is diluted with 25 mL of hexanes. After stirring for an additional 1 h the solid precipitate is collected by filtration and washed with 10 mL of hexanes. It is dried in a stream of air and then it is suspended in 20 mL of glacial acetic acid. The mixture is heated until the solid is completely dissolved and the resulting solution is diluted with 200 mL of distilled water. The mixture is allowed to cool to 25° C. and the solid is collected by filtration. It is washed with a small volume of 10% aqueous acetic acid and then it is dried at torr and 45° C. for 18 h. The yield is 0.23 g.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C@@:5]([CH3:23])([O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH3:25][C:26]1[O:30][C:29]([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)=[N:28][C:27]=1[CH2:36][CH2:37]OS(C1C=CC(C)=CC=1)(=O)=O>>[CH2:1]([O:3][C:4](=[O:24])[C@@:5]([CH3:23])([O:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:37][CH2:36][C:27]2[N:28]=[C:29]([C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)[O:30][C:26]=2[CH3:25])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)[C@](C)(Cc1ccc(O)cc1)Oc1ccc(OC)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Product: CCOC(=O)[C@](C)(Cc1ccc(OCCc2nc(-c3cccs3)oc2C)cc1)Oc1ccc(OC)cc1

Procedure:
The title compound was prepared from (S)-3-(4-hydroxyphenyl)-2-methyl-2-(4-methoxyphenoxy)-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester to produce a colorless oil (32%). 1H NMR (300 MHz, CDCl3): δ 7.57 (d, 1H, J=3.5), 7.36 (d, 1H, J=5.1), 7.15 (d, 2H, J=8.6), 7.07 (dd, 1H, J=5.1, 3.5), 6.81 (d, 2H, J=6.6), 6.78 (d, 2H, J=8.6), 6.71 (d, 2H, J=6.6), 4.21 (q, 2H, J=7.2), 4.20 (t, 2H, J=6.4), 3.74 (s, 3H), 3.21 (d, 1H, J=13.7), 3.08 (d, 1H, J=13.7), 2.95 (t, 2H, J=6.4), 2.35 (s, 3H), 1.28 (s, 3H), 1.25 (t, 3H, J=7.2). MS [EI+] 522 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:14])[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[C@H:3]1[C:15]([OH:17])=[O:16].[C:19]([C@@H:21](O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=1)#[CH:20]>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:18])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:14])[O:8][CH2:9][C:10]([F:13])([F:11])[F:12])[C@H:3]1[C:15]([O:17][C@H:21]([C:19]#[CH:20])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=1)=[O:16]
Reactant: C#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1/C=C\C(=O)OCC(F)(F)F
Solvent: ClC(Cl)Cl
Product: C#C[C@@H](OC(=O)[C@@H]1[C@H](/C=C\C(=O)OCC(F)(F)F)C1(C)C)c1cccc(Oc2ccccc2)c1

Procedure:
Using the orocedure of Step F of Example 9, the acid of Step D of Example 1 and (R)α-ethynyl-3-phenoxy-benzyl alcohol were reacted to obtain (R)α-ethynyl-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3[(Z) 3-oxo-3(2,2,2-trifluoroethoxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+42°±1.5° (c=1% in CHCl3).
Reaction SMILES: C([O:4][C@H:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[C:8]=2[C@H:7]([CH3:27])[CH2:6]1)(=O)C.[Li+].[OH-]>C1COCC1>[OH:4][C@H:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[C:8]=2[C@H:7]([CH3:27])[CH2:6]1
Reactant: CC(=O)O[C@@H]1C[C@@H](C)c2c1ncnc2N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 6 h
Yield: 69.5 %

Procedure:
To a solution of tert-butyl 4-((5R,7R)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.144 g, 0.383 mmol) in THF (4 mL) was added LiOH (3M, 2 mL). The mixture was stirred at room temperature for 6 hours and then quenched with 2N HCl (3 mL). The solvent was removed and the residue was purified by silica gel chromatography, eluting with ethyl acetate to give tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (89 mg, 70%). %). 1H NMR (CDCl3, 400 MHz) δ 8.52 (s, 1H), 5.48 (br, 1H), 5.14 (m, 1H), 3.82-3.40 (m, 9H), 2.20 (m, 2H), 1.49 (s, 9H), 1.19 (d, J=6.8 Hz, 3H). MS (APCI+) [M+H]+335.
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=[C:8]([C:10]([OH:12])=O)[N:9]=1)([CH3:4])[CH3:3].[NH2:21][C@@H:22]([CH3:39])[CH2:23][N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:36]=[C:35]([F:37])[C:32]([C:33]#[N:34])=[C:31]([Cl:38])[CH:30]=2)=[N:25]1>>[Cl:38][C:31]1[CH:30]=[C:29]([C:26]2[CH:27]=[CH:28][N:24]([CH2:23][C@@H:22]([NH:21][C:10]([C:8]3[N:9]=[C:5]([C:2]([OH:1])([CH3:3])[CH3:4])[N:6]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=3)=[O:12])[CH3:39])[N:25]=2)[CH:36]=[C:35]([F:37])[C:32]=1[C:33]#[N:34]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: CC(C)(O)c1nc(C(=O)O)cn1COCC[Si](C)(C)C
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cn(COCC[Si](C)(C)C)c(C(C)(C)O)n1

Procedure:
The title compound was prepared using the procedure described in Example 32(e) starting from 2-(2-hydroxypropan-2-yl)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-imidazole-4-carboxylic acid (400 mg, 1.33 mmol) and (S)-4-(1-(2-amino-propyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (370 mg, 1.33 mmol). The product was purified with flash-chromatography. Yield 305 mg. LC-MS: [M+1]=561.17.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C([O-])(O)=O.[Na+].Cl[CH2:18][C:19](Cl)=[O:20]>CC(C)CC(=O)C.O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:19](=[O:20])[CH2:18][O:11][C:3]=2[CH:4]=1)([O-:10])=[O:9]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=C1COc2cc([N+](=O)[O-])ccc2N1
Temperature: 0 °C
Reaction time: 60 h

Procedure:
Mix 2-amino-5-nitro-phenol (10.0 g, 64.9 mmol) and NaHCO3 (13.1 g, 155.7 mmol) in 4-methyl-pentan-2-one (40 mL) and water (40 mL). Cool the mixture to 0° C. and slowly add chloroacetyl chloride (6.0 mL, 75.3 mmol) with stirring. After the addition is complete, reflux the mixture for 5 h. Cool the mixture to room temperature and let stand for 2.5 days. Collect the light yellow solid, wash with water and dry in a vacuum oven at 80° C. for 3 h. MS (ES−) 193.1 (M−1)−. 1H NMR (400 MHz, DMSO-d6): δ 11.31 (s, 1H), 7.90 (dd, 1H, J=8.8, 2.2 Hz), 7.76 (d, 1H, J=2.6 Hz), 7.06 (d, 1H, J=8.8 Hz), 4.72 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:25][OH:26].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:25]\[OH:26])=[CH:4][CH:3]=1
Reactant: NO
Reactant: CCCCC(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCCC(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 151, step 3, 5-[3-(4-bromo-phenyl)-heptanoyl]-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing 4% of the corresponding Z isomer as a colorless foam, MS (ESI+): m/z=391.3 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:19])[O:18][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[C:9]([CH3:17])=[CH:8]3.[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C)C=O>[N:20]([CH2:2][C:3]1([CH3:19])[O:18][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[C:9]([CH3:17])=[CH:8]3)=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc2c3c(cc(C)c2[nH]c1=O)CC(C)(CBr)O3
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c3c(cc(C)c2[nH]c1=O)CC(C)(CN=[N+]=[N-])O3
Temperature: 150 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
To 2-bromomethyl-2,5,8-trimethyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (3.93 g, 12.2 mmol) and sodium azide (5.15 g, 79.3 mmol), dimethylformamide (85 ml) was added, and the mixture was stirred for 3 hours in a bath at 150° C. After cooling, post-treatment and recrystallization (chloroform-n-hexane) were performed in a manner similar to that described in Example 278 to obtain 3.28 g of the title compound as colorless crystals (94.7%).
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([OH:9])[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][N:4]=1.[CH2:15]([NH2:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C(O)C>[CH2:15]([NH:23][C:3]1[N:8]=[C:7]([OH:9])[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][N:4]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCOC(=O)c1cnc(SC)nc1O
Reactant: CCCCCCCCN
Solvent: CCO
Product: CCCCCCCCNc1ncc(C(=O)OCC)c(O)n1

Procedure:
2-Methylthio-5-ethoxycarbonyl-4-hydroxypyrimidine (2.5 mmol, 535 mg) was refluxed overnight in ethanol with n-octylamine (4 mmol, 650 μl). The product was filtered off and washed with ethanol. Yield 402 mg (54.5%)
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:30][C:31](=[O:34])[CH:32]=[CH2:33]>C1C=CC=CC=1>[O:34]=[C:31]1[CH2:32][CH2:33][C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:5][CH2:4]2)[CH:1]=[CH:30]1
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: C=CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: O=C1C=CC2(CC1)CCN(C(=O)OCc1ccccc1)CC2
Temperature: 70 °C
Yield: 62.5 %

Procedure:
To a benzene (700 mL) solution of benzyl 4-formylpiperidine-1-carboxylate (90.0 g, 363.9 mmol) stirring in a 2 L 3-neck flask fitted with a Dean-Stark trap was added p-toluenesulfonic acid (6.92 g, 36.4 mmol). The reaction was heated to 70° C., 3-buten-2-one (61.8 mL, 753 mmol) was added and mixture was heated at reflux for 24 hours collecting expelled water in the trap. The reaction was cooled to room temperature and washed with 500 mL saturated aqueous sodium bicarbonate. The organic phase was dried over sodium sulfate, filtered and concentrated. The resultant dark brown oil was taken up in 200 mL dichloromethane and filtered through a silica pad (600 mL silica), eluting with 2 L heptane followed by 3 L 50% ethyl acetate/heptane and then 3 L ethyl acetate, collecting by 1 L fractions. Fractions containing clean product were combined and concentrated to yield 68.1 g of the title compound as a thick brown oil. The fractions containing impure product were combined and concentrated and purified by flash chromatography (10-80% ethyl acetate/heptane, 340 g silica gel) to yield an additional 23.6 g of the title compound as a thick brown oil. Combined yield of 91.7 g, (94.1%) was realized. 1H NMR (400 MHz, CDCl3) δ ppm 7.27-7.43 (m, 5H), 6.79 (d, J=10.3 Hz, 1H), 5.95 (d, J=10.3 Hz, 1H), 5.13 (s, 2H), 3.56-3.71 (m, 2H), 3.39-3.55 (m, 2H), 2.38-2.50 (m, 2H), 1.96 (t, J=6.7 Hz, 2H), 1.70-1.52 (m, 4H).
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13]([C:14]([O:16]C)=O)=[N:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](OCC)(=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].CC(C)([O-])C.[K+]>>[CH2:20]([C:19]1[C:18](=[O:24])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2=[N:9][CH:10]=[CH:11][N:12]=[C:13]2[C:14]=1[OH:16])[CH2:21][CH2:22][CH3:23]
Reactant: CCCCCC(=O)OCC
Reactant: COC(=O)c1nccnc1Nc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCCc1c(O)c2nccnc2n(-c2ccccc2)c1=O

Procedure:
A mixture of 3.5 g. of methyl 2-phenylamino-3-pyrazine carboxylate, 30 ml. of ethyl caproate and 4 g. of potassium tertiary butoxide is stirred and heated under nitrogen at 150°-160° for one and a half hours. The reaction mixture is poured on ice, extracted with ethyl acetate and the ethyl acetate extracts washed with water. The combined aqueous layers are acidified to pH 5.5 with dilute hydrochloric acid and the solid filtered. Recrystallization from ethyl acetate-hexane yields the product of this example as a colorless solid; m.p. 183°-185° C.