Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([CH2:12][C:13]2[C:14](=[O:18])[O:15][CH2:16][CH:17]=2)=[CH:10][CH:9]=[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:7]=1[CH3:26])(=[O:3])[CH3:2].[H][H]>C(OCC)(=O)C.CO>[C:1]([O:4][CH2:5][C:6]1[C:11]([CH2:12][C@H:13]2[CH2:17][CH2:16][O:15][C:14]2=[O:18])=[CH:10][CH:9]=[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:7]=1[CH3:26])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)OCc1c(CC2=CCOC2=O)ccc(C(=O)OC(C)(C)C)c1C
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)OCc1c(C[C@H]2CCOC2=O)ccc(C(=O)OC(C)(C)C)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
3-(tert-butoxycarbonyl)-2-methyl-6-((2-oxo-2,5-dihydrofuran-3-yl)methyl)benzyl acetate (280 mg, 0.75 mmol) was dissolved in a mixture of ethyl acetate (10 mL) and methanol (10 mL). A catalytic amount of(−)-1,2-bis((2R,5R)-diethylphospholano)benzene(cyclooctadiene)rhodium(I) tetrafluoroborate was added to the mixture. Reaction vessel was placed on a Parr apparatus and charged with 50 psi of hydrogen gas. Reaction shook at room temperature for 16 hours. A fresh portion of (−)-1,2-bis((2R,5R)-diethylphospholano)benzene(cyclooctadiene)rhodium (I) tetrafluoroborate was added to the mixture. Reaction vessel was charged with 50 psi of hydrogen gas. Reaction shook at room temperature for 24 hours. Reaction mixture was concentrated in vacuo. Residue was passed through a plug of silica gel eluting 80% ethyl acetate-hexanes. Filtrate was concentrated in vacuo. Title compound was obtained as clear colorless oil in 69% yield. MS m/e (M−H)−=376.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Br[C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=1.CC1C=CC(S([O-])=O)=CC=1.[Na+].[H-].[Na+]>C1COCC1.O>[C:9]([CH:8]([C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=1)[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)#[N:10]
Reactant: Cc1cccnc1Br
Reactant: N#CCc1ccc(F)cc1
Agent: Cc1ccc(S(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccnc1C(C#N)c1ccc(F)cc1
Yield: 78.2 %

Procedure:
Under argon atmosphere, to a mixture of 4-fluorophenylacetonitrile (3.97 g), 2-bromo-3-methylpyridine (5.00 g) and sodium 4-methylphenylsulfinate (10.48 g) in THF (125 ml) was added sodium hydride (2.35 g, 60%) at 0° C. to the mixture, and the mixture was heated to reflux for 3.5 hours. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:3), to give 2-(α-cyano-4-fluorobenzyl)-3-methylpyridine (5.14 g) as brown oil.
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.Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18]([O:25][CH3:26])[N:17]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.CN(C=O)C>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([NH:1][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18]([O:25][CH3:26])[N:17]=2)[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1ccc([N+](=O)[O-])c(NC2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 60 °C

Procedure:
A mixture of 4-amino-1-Boc-piperidine (commercial; 6.7 g, 35 mmol), 2-chloro-6-methoxy-3-nitro-pyridine (1 eq.) and K2CO3 (1 eq.) in MeCN (100 mL) and DMF (30 mL) was heated at 60° C. for 3 h. The mixture was filtered and concentrated in vacuo. The residue was taken up in ether/water 1:1, the org. phase dried over MgSO4 and concentrated. The residue was triturated with EA and filtered to afford 4.5 g of pure product. The filtrate was concentrated and purified by CC (Hept/EA 9:1, 4:1, 2:1) to give another 4 g of product. In total 8.5 g (70% yield) of a yellow solid were obtained.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][C:14]1[CH:15]=[C:16]([C:44]2[C:45]([C:50]#[N:51])=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:22](=[O:43])[N:23]([C@H:33]2[CH2:36][C@@H:35]([O:37][CH2:38][C:39]([OH:42])([CH3:41])[CH3:40])[CH2:34]2)[C:24]2[N:25]([N:30]=[CH:31][N:32]=2)[C:26]=1[CH2:27][CH2:28][CH3:29]>O.C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[C:16]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[C:50]2[NH:3][C:4](=[O:7])[O:5][N:51]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:22](=[O:43])[N:23]([C@H:33]2[CH2:36][C@@H:35]([O:37][CH2:38][C:39]([OH:42])([CH3:40])[CH3:41])[CH2:34]2)[C:24]2[N:25]([N:30]=[CH:31][N:32]=2)[C:26]=1[CH2:27][CH2:28][CH3:29]
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@@H](OCC(C)(C)O)C2)c2ncnn12
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2F)c(=O)n([C@H]2C[C@@H](OCC(C)(C)O)C2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
A mixture of hydroxylammonium chloride (0.34 g), sodium hydrogen carbonate (0.55 g) and dimethyl sulfoxide (4 mL) was stirred at 40° C. for 30 min, 3′-fluoro-4′-({4-[cis-3-(2-hydroxy-2-methylpropoxy)cyclobutyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.17 g) was added, and the mixture was stirred at 90° C. for 15 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.064 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.059 mL) were added, and the mixture was stirred at room temperature for 1 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was acidified with 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.13 g, 70%).
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([C:18]#[N:19])[C:16]=1[OH:17])[CH:12]=O.N1CCCCC1>C(O)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:7]2[S:1][C:2](=[S:3])[NH:4][C:5]2=[O:6])[CH:14]=[C:15]([C:18]#[N:19])[C:16]=1[OH:17]
Reactant: O=C1CSC(=S)N1
Reactant: N#Cc1cc(C=O)cc(O)c1O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: N#Cc1cc(C=C2SC(=S)NC2=O)cc(O)c1O
Temperature: 100 °C

Procedure:
A solution containing 0.61 g of rhodanine, 0.72 g of 3,4-dihydroxy-5-cyanobenzaldehyde and 0.1 ml of piperidine in 10 ml of acetic acid was heated for 4 h at 100° C. The product was filtered and washed with 2-propanol. Yield 0.35 g, mp >350° C.
Reaction SMILES: [CH:1]1([CH:4]([N:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([C:14]#[N:15])[C:7]2=[O:16])[CH3:5])[CH2:3][CH2:2]1.[Br:17]N1C(=O)CCC1=O>CN(C)C=O>[Br:17][C:10]1[C:9]([O:12][CH3:13])=[C:8]([C:14]#[N:15])[C:7](=[O:16])[N:6]([CH:4]([CH:1]2[CH2:3][CH2:2]2)[CH3:5])[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccn(C(C)C2CC2)c(=O)c1C#N
Solvent: CN(C)C=O
Product: COc1c(Br)cn(C(C)C2CC2)c(=O)c1C#N
Temperature: 60 °C
Reaction time: 16 h
Yield: 81.8 %

Procedure:
A mixture of 1-(1-cyclopropylethyl)-4-methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step A of Example 163 (2.45 g), N-bromosuccinimide (3.00 g) and N,N-dimethylformamide (50 mL) was stirred at 60° C. for 16 hr. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.73 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[C:5]([NH2:17])=[CH:4][CH:3]=1.[CH:18](O)=O>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:17]=[CH:18][N:8]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=3)[C:6]=2[CH:7]=1
Reactant: O=CO
Reactant: Nc1ccc(Br)cc1NCc1cccc(F)c1
Solvent: CCOC(C)=O
Product: Fc1cccc(Cn2cnc3ccc(Br)cc32)c1

Procedure:
A mixture of Example 2B (299 mg, 1.013 mmol) in formic acid (500 μL, 13.25 mmol) was stirred at 90° C. for 1 hour. The cooled mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel flash chromatography (Isco®, Redi-Sep® column) eluting with 80% ethyl acetate/hexane afforded the title compound. MS (ESI) m/e 306 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[C:18]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=3)[S:17][C:10]=2[NH:11][C:12](=S)[CH:13]([CH3:15])[N:14]=1.O.[NH2:33][NH2:34].O1[CH2:39][CH2:38]CC1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[C:18]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=3)[S:17][C:10]=2[N:11]2[C:38]([CH3:39])=[N:33][N:34]=[C:12]2[CH:13]([CH3:15])[N:14]=1
Reactant: C1CCOC1
Reactant: NN
Reactant: CC(C)Cc1ccc(CCc2cc3c(s2)NC(=S)C(C)N=C3c2ccccc2Cl)cc1
Solvent: O
Product: Cc1nnc2n1-c1sc(CCc3ccc(CC(C)C)cc3)cc1C(c1ccccc1Cl)=NC2C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 9.1 g of 5-(2-chlorophenyl)-7-[2-(4-isobutylphenyl)ethyl]-3-methyl-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-thione in 150 ml of tetrahydrofuran is added 3.1 g of 100% hydrazine hydrate under ice-cooling and the mixture is stirred at room temperature for 2 hours. After the tetrahydrofuran is distilled off under reduced pressure, the residue is dissolved in 200 ml of chloroform and the solution is dried over anhydrous magnesium sulfate. After separating by filtration, the filtrate is concentrated under reduced pressure. To the residue is added 50 ml of ethyl orthoacetate and the mixture is heated at 70°-72° C. for an hour. The mixture is concentrated under reduced pressure, and the residue is subjected to chromatography on silica gel and eluted with chloroform-methanol (100:1 to 100:3) solvent. The eluate of the objective fraction is concentrated and the residue is crystallized from isopropyl ether to give 4.3 g of 4-(2-chlorophenyl)-2-[2 -(4-isobutylphenyl)ethyl]-6,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine as colorless crystals, melting at 129.5°-131.5° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([C:10]([C:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)=[O:11])[CH:7]=[CH:6][N:5]=1.[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br>CN(C)C=O>[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21](=[O:22])[C:12]([C:10]([C:8]2[CH:7]=[CH:6][N:5]=[C:4]([CH3:3])[CH:9]=2)=[O:11])=[CH:13]1
Reactant: Cc1cc(C(=O)c2c[nH]c3ccccc3c2=O)ccn1
Reactant: Cc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(Cn2cc(C(=O)c3ccnc(C)c3)c(=O)c3ccccc32)c1

Procedure:
Compound 4gg was prepared following the procedure outlined in Step 3 of Example 1 using 10.4 mg (0.26 mmol) of sodium hydride (60%), 53 mg (0.20 mmol) of 3-(2-methyl-pyridine-4-carbonyl)-1H-quinolin-4-one 3h, 3 mL of anhydrous dimethylformamide, and 48 mg (0.26 mmol) of 3-methylbenzylbromide. The crude product was purified by preparative HPLC to yield 27 mg of a colorless solid 4gg: LC-MSD, m/z for C24H20N2O2, [M+H]+=369.5, [M+2H]+=370.5; Reverse phase HPLC (gradient acetonitrile 0.1% TFA 20-95% in 4 min) retention time=1.605 min; 1H NMR (400 MHz, CDCl3/HCl): δ 2.35 (s, 3H), 2.61 (s, 3H), 5.40 (s, 2H), 7.00 (d, 2H), 7.15 (d, 1H), 7.25 (t, 1H), 7.35 (d, 1H), 7.39-7.46 (m, 3H), 7.60 (t, 1H), 8.40-8.46 (m, 2H), 8.60 (d, 1H).
Reaction SMILES: S(O)(O)(=O)=O.[C:6]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)(=[NH:8])[NH2:7].[OH-].[Na+].[C:24]([C:26](=[CH:32]OCC)[C:27](OCC)=[O:28])#[N:25]>C(O)C>[CH2:15]([N:12]1[CH2:13][CH2:14][N:9]([C:6]2[N:7]=[C:27]([OH:28])[C:26]([C:24]#[N:25])=[CH:32][N:8]=2)[CH2:10][CH2:11]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N=C(N)N1CCN(Cc2ccccc2)CC1
Reactant: CCOC=C(C#N)C(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1cnc(N2CCN(Cc3ccccc3)CC2)nc1O
Yield: 29.6 %

Procedure:
Mixed were 26.8 g of 1-amidino-4-benzylpiperazine sulfate and 133 ml of a 3% ethanol solution of sodium hydroxide, followed by an addition of 17.0 g of ethyl 2-cyano-3-ethoxyacrylate. After being refluxed for 5 hours, the reaction mixture was allowed to cool down. After distilling off ethanol from the reaction mixture, the residue was added with water and ethyl acetate. The resultant mixture was shaken. Precipitated colorless crystals of 2-(4-benzylpiperazino)-5-cyano-4-hydroxypyrimidine were collected by filtration, washed with water and then dried, thereby obtaining 7.4 g of 2-(4-benzylpiperazino)-5-cyano-4-hydroxypyrimidine (yield: 25%).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]([NH2:8])=[O:7])[CH2:4][OH:5].S=[C:10]1[CH2:14][S:13][C:12](=[O:15])[NH:11]1.C(N(C(C)C)C(C)C)C>C(O)C>[O:15]=[C:12]1[N:11]=[C:10]([NH:2][C@H:3]([C:6]([NH2:8])=[O:7])[CH2:4][OH:5])[CH2:14][S:13]1
Reactant: NC(=O)[C@@H](N)CO
Reactant: O=C1NC(=S)CS1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)[C@H](CO)NC1=NC(=O)SC1
Yield: 75.4 %

Procedure:
To a solution of L-serinamide hydrochloride (1.00 g) in ethanol (20 mL) were added 4-thioxo-1,3-thiazolidin-2-one (957 mg) and N-ethyl-N-(1-methylethyl)propan-2-amine (1.88 mL), and the mixture was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (methanol/ethyl acetate), and the obtained powder was washed with ethyl acetate to give the title compound (1.09 g).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=O.S(O)(O)(=O)=O.[CH3:21][S:22][C:23](=[NH:25])[NH2:24].[O-]CC.[Na+]>C(O)C>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:25]=[C:23]([S:22][CH3:21])[N:24]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccccn1
Reactant: CSC(=N)N
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CSc1nc(-c2ccccn2)cc(C(F)(F)F)n1
Temperature: 25 °C
Yield: 16.8 %

Procedure:
To a solution of 4,4,4-trifluoro-1-(pyridin-2-yl)butane-1,3-dione (1.0 g, 4.6 mmol) in ethanol (10 mL) was added 2-methyl-2-thiopseudourea sulfate (0.64 g, 4.6 mmol), followed by sodium ethoxide (3.0 mL of 21 wt. % solution in ethanol, 9 mmol). The mixture was heated at reflux for 9 h, then cooled to room temperature and extracted with EA. The EA was washed with water and the solvent removed under reduced pressure. The crude product was purified by column chromatography, eluting with 49:1 chloroform/MeOH, to give 4-trifluoromethyl-2-methylthio-6-(pyridin-2-yl)pyrimidine (0.21 g, 17% yield) as an off-white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=1[CH2:28][CH3:29])[CH2:10][C:9]2([CH3:31])[CH3:30])=[O:5])C.[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH2:28]([C:17]1[CH:18]=[CH:19][C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:21][C:16]=1[CH:11]1[CH2:10][C:9]([CH3:31])([CH3:30])[C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12]1)[CH3:29]
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cc(N3CCOCC3)ccc1CC)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCc1ccc(N2CCOCC2)cc1C1CC(C)(C)c2cc(C(=O)O)ccc2N1
Temperature: 60 °C
Reaction time: 12 h
Yield: 90.5 %

Procedure:
To a stirred mixture solution of 2-(2-ethyl-5-morpholin-4-yl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.6 g, 1.4 mmol) in methanol (10 mL) and tetrahydrofuran (20 mL) was added 30% sodium hydroxide in water (10 mL). The reaction mixture was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(2-ethyl-5-morpholin-4-yl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (0.5 g, 89%) as a light white solid which was used for next step without further purification: MS (ESI) M+1=395.2.
Reaction SMILES: C1C=CC(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)=CC=1.[CH2:18]=[C:19]([C:21]1[CH:22]=[C:23]([C@@H:27](O)[CH3:28])[CH:24]=[N:25][CH:26]=1)[CH3:20].C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.CCOC(C)=O>[N:15]([C@@H:27]([C:23]1[CH:24]=[N:25][CH:26]=[C:21]([C:19]([CH3:20])=[CH2:18])[CH:22]=1)[CH3:28])=[N+:16]=[N-:17]
Reactant: C=C(C)c1cncc([C@H](C)O)c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=C(C)c1cncc([C@@H](C)N=[N+]=[N-])c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
DPPA (0.55 mL, 2.55 mmol) was added to (S)-1-(5-(prop-1-en-2-yl)pyridin-3-yl)ethanol (347 mg, 2.13 mmol) in toluene (5 mL) and the reaction is cooled to 0° C. DBU (0.38 mL, 2.55 mmol) was added, the reaction was allowed to warm to room temperature and stirred overnight, diluted with EtOAc and washed with water. The organic layer was dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (35% EtOAc in hexanes) to provide 340 mg of (R)-3-(1-azidoethyl)-5-(prop-1-en-2-yl)pyridine.
Reaction SMILES: [CH:1](=O)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C[C:10]([OH:12])=[O:11].N1CCCC[CH2:16]1>N1C=CC=CC=1>[O:6]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:1](=[CH2:16])[C:10]([OH:12])=[O:11]
Reactant: C1CCNCC1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccco1
Solvent: c1ccncc1
Product: C=C(C(=O)O)c1ccco1

Procedure:
2-Furyl acrylic acid was prepared by reaction of furfural and malonic acid. Furfural (19.2 g.), malonic acid (41.6 g.), pyridine (100 ml.), and piperidine (2 ml.) were charged into a 250 ml. round bottom flask and refluxed for 31/2 hours. The reaction solution was worked up in the manner described in Example 41 to isolate 2-furyl acrylic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:11][C:10]=1[C:22]([O:24]CC)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O>C1COCC1.O>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:11][C:10]=1[C:22]([OH:24])=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc(C2CCCC2)n(C)c(=O)c1OCc1ccccc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(C2CCCC2)nc(C(=O)O)c(OCc2ccccc2)c1=O
Yield: 97 %

Procedure:
A mixture of ethyl 5-(benzyloxy)-2-cyclopentyl-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (prepared according to the procedure in Naidu, B. N. Synlett, 2008;) (1.1 g, 3.1 mmol) and LiOH.H2O (0.25 g, 6 mmol) in 2:1 THF/H2O (15 mL) was heated at 80° C. for 1 h then cooled. The reaction mixture concentrated and the residue acidified with 1 N aq. HCl and the resulting solid isolated by filtration to yield the title compound (0.98 g, 97% yield) as a white solid. 1HNMR (500 MHz, CDCl3) δ: 7.56-7.52 (2H, m), 7.36-7.28 (3H, m), 5.42 (2H, s), 3.59 (3H, s), 3.20-3.14 (1H, m), 2.08-2.01 (2H, m), 1.93-1.78 (4H, m), 1.74-1.67 (2H, m). HRMS (M+H) calcd for C18H21N2O4: 329.1501. found: 329.1489.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:8])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5].O[C:10](=[C:13]1C(=O)OC(C)(C)[O:15][C:14]1=O)[CH2:11][CH3:12].CCOCC>CCCCCC>[CH2:11]([C:10]1[NH:1][C:2]([CH3:8])=[C:3]([C:4]([O:6][CH3:7])=[O:5])[C:14](=[O:15])[CH:13]=1)[CH3:12]
Reactant: CCC(O)=C1C(=O)OC(C)(C)OC1=O
Reactant: COC(=O)/C=C(/C)N
Solvent: CCCCCC
Solvent: CCOCC
Product: CCc1cc(=O)c(C(=O)OC)c(C)[nH]1
Temperature: 120 °C
Reaction time: 18 h
Yield: 11.8 %

Procedure:
A mixture of methyl 3-aminocrotonate (5 g) and 5-(1-hydroxypropylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (10 g) (obtained as described in J. Org. Chem., 1978, 43, 2087) was heated at 120° C. for 1 hour. The residue was cooled to ambient temperature and treated with a mixture of ether and hexane (1:6 v/v; 35 ml) and allowed to stand for 18 hours. The solvent was removed by decanting and the insoluble residue purified by flash chromatography, eluting with methanol/dichloromethane (1:9 v/v) to give methyl 1,4-dihydro-6-ethyl-2-methyl-4-oxopyridine-3-carboxylate (1 g), as a yellow solid, m.p. 176°-180° C.; NMR (CDCl3): 1.2(t,3H); 2.45(s,3H), 2.45(q,2H), 3.8(s,3H), 6.3(s,1H); mass spectrum (chemical ionisation, ammonia): 196(M+H)+.
Reaction SMILES: CC([N:5]([C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=1)=[S:27])[C@H:6]([C:23]([OH:25])=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][CH:9]=1)(C)C.BrC1C=CC2N=C(N[C@H](C(O)=O)[CH2:46][C:47]3[CH:52]=CC(OCCCC(=O)NC4NCCCN=4)=C[CH:48]=3)SC=2C=1>ClC1C=CC=CC=1.C(OCC)(=O)C>[Br:35][C:32]1[CH:31]=[CH:30][C:29]2[N:28]=[C:26]([NH:5][C@H:6]([C:23]([O:25][C:47]([CH3:52])([CH3:48])[CH3:46])=[O:24])[CH2:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][CH:9]=3)[S:27][C:34]=2[CH:33]=1
Reactant: CCOC(=O)CCCOc1ccc(C[C@@H](C(=O)O)N(C(=S)Nc2ccc(Br)cc2)C(C)(C)C)cc1
Reactant: O=C(CCCOc1ccc(C[C@H](Nc2nc3ccc(Br)cc3s2)C(=O)O)cc1)NC1=NCCCN1
Solvent: CCOC(C)=O
Solvent: Clc1ccccc1
Product: CCOC(=O)CCCOc1ccc(C[C@H](Nc2nc3ccc(Br)cc3s2)C(=O)OC(C)(C)C)cc1
Reaction time: 2 h
Yield: 19.9 %

Procedure:
0.6 ml of SO2Cl2 in 5 ml of chlorobenzene is added to a solution of amino thiourea 8-1 (3 g, 5.3 mmol) in 60 ml of chlorobenzene at 0° C., agitation is carried out for 2 hours at ambient temperature, followed by diluting in ethyl acetate, washing, drying and evaporating the organic phase under reduced pressure, in order to obtain the crude product which is purified by chromatography eluting with a heptane/ethyl acetate mixture 80/20. 593 mg of expected product is obtained 8-2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.I[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][O:10][CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH3:17]
Reactant: OCCc1cccc(F)c1
Reactant: CCOC(=O)CI
Agent: [Ag+]
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=S(=O)([O-])C(F)(F)F
Product: CCOC(=O)COCCc1cccc(F)c1

Procedure:
In analogy to the procedure described in example 78.1, 2-(3-fluoro-phenyl)-ethanol was reacted with ethyl iodoacetate in the presence of silver trifluoromethanesulfonate and 2,6-di-tert-butylpyridin to give [2-(3-fluoro-phenyl)-ethoxy]-acetic acid ethyl ester as colorless liquid. MS: m/e=227.2 [M+H+].
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.[C:12]([O:17][CH2:18][CH3:19])(=[O:16])[C:13]#[C:14][CH3:15].C(N(CC)CC)C>C(OCC)C>[CH2:18]([O:17][C:12]([C:13]1[C:3]([C:4]2[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=2)=[N:2][O:1][C:14]=1[CH3:15])=[O:16])[CH3:19]
Reactant: O/N=C(\Cl)c1ccc(Cl)cc1
Reactant: CC#CC(=O)OCC
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2)noc1C
Temperature: 25 °C
Yield: 41.8 %

Procedure:
To a solution of (E)- and/or (Z)—N-hydroxy-4-chloro-benzenecarboximidoyl chloride (26.0 g, 137 mmol) in diethylether (323 mL) was added ethyl 2-butynoate (15.4 g, 16.1 mL, 137 mmol) at 0° C. followed by the dropwise addition of triethylamine (24.1 g, 22.9 mL, 164 mmol) and the resulting mixture allowed to warm up to room temperature overnight. The mixture was then poured onto ice-water, and extracted with diethylether. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (15.2 g, 42%) which was obtained as a light yellow solid. MS: m/e=266.1 [M+H]+.