Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH:20](OCC)=[O:21].[H-].[Na+]>COCCOC>[CH:20]([CH:14]([CH2:13][C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:21]
Reactant: CCOC(=O)CCc1cc(OC)c(OC)c(OC)c1
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(C=O)Cc1cc(OC)c(OC)c(OC)c1
Yield: 44 %

Procedure:
Ethyl 3-(3,4,5-trimethoxyphenyl)propionate was reacted with ethyl formate and sodium hydride in 1,2-dimethoxyethane to give crude ethyl 2-formyl-3-(3,4,5-trimethoxyphenyl)propionate in 44% yield.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:5][CH:6]=1.BrC1[O:17][C:18]([CH2:21]C2C=CC(F)=CC=2)=[CH:19][CH:20]=1>>[F:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C:4]2[S:3][C:2]([C:20]#[C:19][CH:18]([OH:17])[CH3:21])=[CH:6][CH:5]=2)=[CH:9][CH:10]=1
Reactant: Fc1ccc(Cc2ccc(Br)o2)cc1
Reactant: Fc1ccc(Cc2ccc(Br)s2)cc1
Product: CC(O)C#Cc1ccc(Cc2ccc(F)cc2)s1
Yield: 71 %

Procedure:
4-[5-(4-fluorophenylmethyl)-2-thienyl]-3-butyn-2-ol (9.16 g, 71%) was prepared according to the method of Example 1, step 3, except substituting 2-bromo-5-(4-fluorophenylmethyl)thiophene (13.3 g, 49.0 mmol), prepared as in step 2, for 2-bromo-5-(4-fluorophenylmethyl)furan.
Reaction SMILES: N(OC(C)(C)C)=O.[Br:8][C:9]1[CH:15]=[CH:14][C:12](N)=[C:11]([S:16][CH3:17])[C:10]=1[CH3:18].[CH3:19][S:20]SC>[Cu]>[CH3:18][C:10]1[C:11]([S:16][CH3:17])=[C:12]([S:20][CH3:19])[CH:14]=[CH:15][C:9]=1[Br:8]
Reactant: CSc1c(N)ccc(Br)c1C
Reactant: CSSC
Agent: [Cu]
Agent: CC(C)(C)ON=O
Product: CSc1ccc(Br)c(C)c1SC
Temperature: 50 °C
Reaction time: 4 h

Procedure:
14.8 g (129 mmol) of tert-butyl nitrite and 20 g of copper powder are initially charged in 50 ml of dimethyl disulfide, and a solution of 20 g (86 mol) of 4-bromo-3-methyl-2-methylthioaniline in 100 ml of dimethyl disulfide is added dropwise at 50-55° C. The mixture is then stirred at 50° C. for 4 hours. For work-up, the solid is filtered off with suction and the solution is diluted with methylene chloride and extracted with dilute hydrochloric acid. The organic phase is washed with saturated aqueous NaHCO3 solution, dried over sodium sulfate, filtered off and concentrated using a rotary evaporator. Excess dimethyl disulfide is removed under oil pump vacuum.
Reaction SMILES: [CH:1]([OH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:17]=1[O:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([O-:23])=[O:22].[CH2:36]([N:44]=[C:45]=[O:46])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>N1C=CC=CC=1>[CH:1]([OH:14])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:36]([NH:44][C:45](=[O:46])[NH:15][C:16]1[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[CH:28][C:17]=1[O:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([O-:23])=[O:22])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: Nc1cc(C(F)(F)F)ccc1Oc1ccccc1C(=O)[O-]
Reactant: CCCCCCCCN=C=O
Agent: OC(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCNC(=O)Nc1cc(C(F)(F)F)ccc1Oc1ccccc1C(=O)[O-]
Reaction time: 3 h

Procedure:
Benzhydrol 2-(2-amino-4-trifluoromethylphenoxy)benzoate (700 mg, 0.0015 mol) was dissolved in pyridine and octylisocyanate (412 mg, 0.0027 mol) was added to the mixture at room temperature and stirred for three hours. The solvent was evaporated and the residue was flash chromatographed (silica gel, ethyl acetate/hexane) to give the title compound. 1H NMR (250 MHz, CDCl3) δ8.7 (s, 1H), 8.2 (s, 1H), 7.95 (d, 1H), 7.29 (m, 10H), 7.12 (s, 1H), 7.1 (d, 1H), 7.0 (s, 1H), 6.9 (d, 1H), 4.8 (s, 1H), 3.1 (dd, 1H), 1.28 (s, 14H), 0.85 (t, 3H).
Reaction SMILES: [CH:1]1([C:5]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:8]([C:9](O)=[O:10])=[C:7]([CH2:18][CH3:19])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[F:54][C:55]1([C:61]2[CH:68]=[CH:67][C:64]([C:65]#[N:66])=[CH:63][CH:62]=2)[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]1>CN(C)C=O>[C:65]([C:64]1[CH:67]=[CH:68][C:61]([C:55]2([F:54])[CH2:60][CH2:59][N:58]([C:9]([C:8]3[C:7]([CH2:18][CH3:19])=[CH:6][C:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)=[C:13]([CH:12]=3)[C:14]([O:16][CH3:17])=[O:15])=[O:10])[CH2:57][CH2:56]2)=[CH:62][CH:63]=1)#[N:66]
Reactant: N#Cc1ccc(C2(F)CCNCC2)cc1
Reactant: CCc1cc(C2CCC2)c(C(=O)OC)cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(C2CCC2)c(C(=O)OC)cc1C(=O)N1CCC(F)(c2ccc(C#N)cc2)CC1
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
To a round-bottom flask was added a solution of 4-cyclobutyl-2-ethyl-5-(methoxycarbonyl)benzoic acid (compound 215.4, 70.0 mg, 0.270 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL). HBTU (210 mg, 0.550 mmol, 2.07 equiv), DIEA (150 mg, 1.16 mmol, 4.35 equiv) were added to the reaction mixture at 0° C., and stirred for 30 min. This was followed by the addition of 4-(4-fluoropiperidin-4-yl)benzonitrile hydrochloride (compound 11.2 HCl salt, 80.0 mg, 0.330 mmol, 1.20 equiv). The resulting solution was stiffed for 15 h at 25° C., and then quenched with 20 mL of ice-water. The mixture was extracted with 2×50 mL of ethyl acetate. The combined organic layers were washed with 1×50 mL of brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:100-1:5) as eluent to yield 100 mg (84%) of methyl 5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzoate as a white solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[C:10]([NH:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)(=[O:12])[CH3:11]>>[C:10]([NH:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[N+:1]([O-:4])=[O:2])(=[O:12])[CH3:11]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(CNC(C)=O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(CNC(C)=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture (mixed acid) of fuming nitric acid (70 ml) and conc. sulfuric acid (70 ml) was added methyl 4-acetamidomethylbenzoate (54 g) at 7-15° C. for 1.5 hr. This reaction mixture was stirred at room temperature for 1 hr and poured into ice water (600 ml). The mixture was extracted with chloroform (300 ml×3). The extract was washed with water, saturated sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a yellow oil (75 g). The obtained yellow oil was crystallized from ethyl acetate (50 ml) and recrystallized from hexane/ethyl acetate (1:1, 600 ml) to give the title compound (45.5 g) as pale-yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24](=[O:29])[CH:23]=[C:22]3[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[NH:9][C:10]([NH:12][CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])=[S:11])=[CH:4][CH:3]=1.IC.[C:38](=O)([O-])[O-].[K+].[K+]>CC(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24](=[O:29])[CH:23]=[C:22]3[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[NH:9][C:10]([S:11][CH3:38])=[N:12][CH2:13][CH:14]([O:15][CH3:16])[O:17][CH3:18])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: COC(CNC(=S)NC(c1ccc(Cl)cc1)c1ccc2[nH]c(=O)cc(-c3ccccc3)c2c1)OC
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(CN=C(NC(c1ccc(Cl)cc1)c1ccc2[nH]c(=O)cc(-c3ccccc3)c2c1)SC)OC
Temperature: 25 °C
Yield: 113.2 %

Procedure:
A mixture of intermediate (6-a) (15.3 g), iodomethane (2.27 ml) and potassium carbonate (5 g) in 2-propanone (50 ml) was stirred at room temperature for one night. The mixture was evaporated, the residue was taken up in DCM and washed with K2CO3 10%. The organic layer was dried (MgSO4), filtered off and evaporated, yielding 17.8 g (100%) of (±)-methyl N-[(4-chlorophenyl)(1,2-dihydro-2-oxo-4-phenyl-6-quinolinyl)-methyl]-N'-(2,2-dimethoxy-ethyl)carbamimidothioate (interm. 6-b), which was used without further purification.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[C:35]([CH2:40][C@H:41]([N:46]([C:48](=[O:72])[C@H:49]([NH:64][C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[CH2:50][CH2:51][CH2:52][NH:53][C:54]([O:56][CH2:57][C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[O:55])[CH3:47])[C:42]([O:44][CH3:45])=[O:43])[CH:34]=2)=[CH:29][C:28]=1[CH2:73][C@H:74]([NH:84][C:85]([O:87][CH2:88][C:89]1[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=1)=[O:86])[C:75]([O:77]CC[Si](C)(C)C)=[O:76])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1.CN(C=O)C>[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[C:35]([CH2:40][C@H:41]([N:46]([C:48](=[O:72])[C@H:49]([NH:64][C:65]([O:67][C:68]([CH3:69])([CH3:71])[CH3:70])=[O:66])[CH2:50][CH2:51][CH2:52][NH:53][C:54]([O:56][CH2:57][C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=3)=[O:55])[CH3:47])[C:42]([O:44][CH3:45])=[O:43])[CH:34]=2)=[CH:29][C:28]=1[CH2:73][C@H:74]([NH:84][C:85]([O:87][CH2:88][C:89]1[CH:90]=[CH:91][CH:92]=[CH:93][CH:94]=1)=[O:86])[C:75]([OH:77])=[O:76])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)[C@H](Cc1cc(-c2ccc(OCc3ccccc3)c(C[C@H](NC(=O)OCc3ccccc3)C(=O)OCC[Si](C)(C)C)c2)ccc1F)N(C)C(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1cc(-c2ccc(OCc3ccccc3)c(C[C@H](NC(=O)OCc3ccccc3)C(=O)O)c2)ccc1F)N(C)C(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.9 ml of 1N tetrabutylammonium fluoride in THF are added dropwise to a solution of 980 mg (0.922 mmol) of 2-(trimethylsilyl)ethyl (2S)-3-(4-(benzyloxy)-3′-{(2S)-2-[{(2R)-5-{[(benzyloxy)carbonyl]amino}-2-[(tert-butoxycarbonyl)amino]pentanoyl}(methyl)amino]-3-methoxy-3-oxopropyl }-4′-fluorobiphenyl-3-yl)-2-{[(benzyloxy)carbonyl]amino}propanoate (Example 19O) in 20 ml of absolute DMF. After 60 min at RT, the mixture is cooled to 0° C., and ice-water is added. The mixture is immediately extracted with dichloromethane. The organic phase is dried over magnesium sulfate, concentrated in vacuo and dried under high vacuum. The crude product is reacted without further purification.
Reaction SMILES: C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[CH:28]1([C:31]2[C:32]([O:41][CH2:42][C:43]34[C:49]([F:51])([F:50])[CH:48]3[CH2:47][CH2:46][CH2:45][CH2:44]4)=[CH:33][C:34]([F:40])=[C:35]([CH:39]=2)[C:36]([OH:38])=O)[CH2:30][CH2:29]1.CS(N)(=O)=O.[CH:57]1([S:60]([NH2:63])(=[O:62])=[O:61])[CH2:59][CH2:58]1>>[CH:28]1([C:31]2[C:32]([O:41][CH2:42][C:43]34[C:49]([F:51])([F:50])[CH:48]3[CH2:47][CH2:46][CH2:45][CH2:44]4)=[CH:33][C:34]([F:40])=[C:35]([CH:39]=2)[C:36]([NH:63][S:60]([CH:57]2[CH2:59][CH2:58]2)(=[O:62])=[O:61])=[O:38])[CH2:30][CH2:29]1
Reactant: NS(=O)(=O)C1CC1
Reactant: O=C(O)c1cc(C2CC2)c(OCC23CCCCC2C3(F)F)cc1F
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Product: O=C(NS(=O)(=O)C1CC1)c1cc(C2CC2)c(OCC23CCCCC2C3(F)F)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-cyclopropyl-4-(((1RS,6SR)-7,7-difluorobicyclo-[4.1.0]heptan-1-yl)methoxy)-2-fluorobenzoic acid and to replace methanesulfonamide with cyclopropanesulfonamide, the title compound was obtained as a white gum (0.030 g, 23%): 1H NMR (300 MHz, DMSO-d6) δ11.82 (br s, 1H), 7.12 (d, J=8.3 Hz, 1H), 6.92 (d, J=12.9 Hz, 1H), 4.17-3.92 (m, 2H), 3.10-2.97 (m, 1H), 2.04-1.54 (m, 6H), 1.34-1.15 (m, 4H), 1.14-1.02 (m, 4H), 0.92-0.80 (m, 2H), 0.72-0.62 (m, 2H); MS (ES+) m/z 444.1 (M+1).
Reaction SMILES: [CH2:1]([Li])CCC.[Si:6]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Si:6]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[CH2:1])=[CH:16][CH:15]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: [Li]CCCC
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
p-OSi-St chain transfer agent was synthesized in two steps. In a 500 ml flask equipped with a magnetic stirring bar, 70.4 g of imidazole was mixed with 52.4 g (0.42 mol) of 4-hydroxybenzaldehyde and 77.4 g of t-butyldimethylsilyl chloride in THF solution. The mixture was stirred at ambient temperature for 4 hours before being poured into cold water. The organic layer was separated and extracted with ether, then dried with magnesium sulfate. After evaporating the solvent, 94 g of 4-(t-butyldimethylsilyloxy)benzaldehyde (90% yield), a deep yellow color liquid, was obtained. The second reaction step was performed under a nitrogen atmosphere. In a 500 ml flask equipped with a magnetic stirring bar, 123.6 g of methyltriphenylphosphonium bromide suspended in THF was treated with 149.6 ml of n-butyllithium (2.5M in hexane). After 1 hour, 80.0 g of 4-(t-butyldimethylsilyloxy)benzaldehyde was introduced dropwise into the red solution. The mixture was stirred overnight at room temperature and then poured into cold water. The organic layer was separated by ether extraction and dried with magnesium sulfate. Further purification was performed by distillation under vacuum (10 Torr) at elevated temperature (80° C.). 65 g of p-OSi-St was obtained with a yield of more than 90%. Its structure was confirmed by 1H NMR spectrum.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]12([NH2:16])[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2.N1C=CC=CC=1>C(OCC)C>[C:6]12([NH:16][C:3](=[O:4])[CH2:2][Cl:1])[CH2:13][CH:12]3[CH2:11][CH:10]([CH2:9][CH:8]([CH2:14]3)[CH2:7]1)[CH2:15]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: O=C(Cl)CCl
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(CCl)NC12CC3CC(CC(C3)C1)C2
Reaction time: 1 h
Yield: 34.1 %

Procedure:
A solution of chloroacetyl chloride (1.6 mL, 20 mmol) in anhydrous diethyl ether (10 mL) was added dropwise within 5 min to a solution of 1-adamantanamine (3.0 g, 20 mmol) and pyridine (1.63 mL, 20 mmol) in anhydrous diethyl ether (40 mL) at 0° C. The yellow suspension was stirred for 1 h at that temperature. The precipitate was removed by filtration and washed by diethyl ether (10 mL). The combined organic solution was washed with HCl (2 N, 2×15 mL), followed by sat. NaHCO3 (15 mL), sat. NaCl (15 mL) solutions and dried with Na2SO4. The solvent was removed at reduced pressure and the residue was recrystallized from diethyl ether-hexanes to afford N-(1-adamantyl)chloroacetamide (1.551 g, 34%) as a yellow solid.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].CCS[C:8]([C:10]([F:13])([F:12])[F:11])=[O:9]>CO>[F:11][C:10]([F:13])([F:12])[C:8]([NH:4][CH2:3][CH2:1][OH:2])=[O:9]
Reactant: CCSC(=O)C(F)(F)F
Reactant: NCCO
Solvent: CO
Product: O=C(NCCO)C(F)(F)F
Reaction time: 8 h

Procedure:
Ethanolamine (12 g) is dissolved in methanol (50 ml) and S-ethylthiotrifluoroacetate (35 g) is added dropwise. The reaction is permitted to stand overnight irrigated with a stream of argon to remove ethanethiol. The excess solvent is removed in vacuo to leave the title product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[C:10](C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)[CH3:11].C([Sn](CCCC)(CCCC)C=C)CCC.[Na].C(NN)=O>C1(C)C=CC=CC=1.CO>[CH:10]([C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1)=[CH2:11]
Reactant: N#Cc1ccc(Br)cn1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Agent: NNC=O
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CO
Product: C=Cc1ccc(C#N)nc1

Procedure:
A 5-vinylpicolinonitrile intermediate (1-2) was prepared by adding 5-bromopicolinonitrile (1-1), tetrakis(triphenylphosphine) (Pd(PPH3)4), and 2,6-di-t-butyl-4-methylphenol (BHT) in toluene, adding tributyl(vinyl)stannane thereto, and reacting the resulting mixture at 80° C. for 24 hours. The intermediate (1-2) was added to a methanol solution, in which sodium metal was dissolved, and reacted at 70° C. for 3 hours and then cooled. Formohydrazide (1-3) was added to the reaction solution and reacted at 70° C. for 15 minutes. Then, the temperature was lowered to 25° C. and the reaction solution was reacted for 24 hours until yellow crystals were formed. Upon completion of the reaction, the yellow crystals were collected by filtration, and 2-(4H-1,2,4-triazol-3-yl)-5-vinylpyridine (1-4) was purified by column chromatography using chloroform and methanol as solvents.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:5]P(=O)(OC)OC.[CH:20]([C:22]1[O:23][CH:24]=[CH:25][C:26](=[O:39])[C:27]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=O.C(O)(=O)C>C1COCC1>[O:3]=[C:4]([CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)/[CH:5]=[CH:20]/[C:22]1[O:23][CH:24]=[CH:25][C:26](=[O:39])[C:27]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: COP(=O)(CC(=O)CCc1ccccc1)OC
Reactant: CCOC(=O)CCCCCOc1c(C=O)occc1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)CCCCCOc1c(/C=C/C(=O)CCc2ccccc2)occc1=O
Reaction time: 1 h
Yield: 61.6 %

Procedure:
To a solution, under nitrogen, of 0.187 g (3.9 mmole) of sodium hydride (50% dispersion in mineral oil) in 10 ml of dry THF was added dropwise 1.2 g (4.95 mmole) of dimethyl (2-oxo-4-phenylbutyl)-phosphonate. The heterogeneous mixture was stirred for 1.0 hour then a solution of 1.0 g (3.54 mmole) of 2-formyl-3-(5-carboethoxypentyloxy)-4-pyrone, prepared by the procedure of Examples 1 and 2, in 5 ml of THF was added. The mixture was stirred for 15 min then was neutralized to pH 7 with glacial acetic acid. The neutralized solution was concentrated by rotary evaporation and the residue dissolved in methylene chloride. The organic solution was washed with saturated brine solution and dried over magnesium sulfate. Removal of the solvent left an oil which was purified by chromatography on silica gel using ether as the eluent. Concentration of the fractions containing product furnished 0.90 g (64%) of pure 2-(3-oxo-5-phenyl-trans-1-pentenyl)-3-(5-carboethoxypentyloxy)-4-pyrone, m.p. 38.5°-40°. NMR (CDCl3): δ1.26 (3H, t, J=7 Hz); 2.35 (2H, t, J=6.5 Hz).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[CH3:8][C:9]1[C:17]([CH3:18])=[C:16]2[C:12]([CH2:13][CH2:14][NH:15]2)=[CH:11][C:10]=1[OH:19]>C(O)=O>[OH:19][C:10]1[CH:11]=[C:12]2[C:16](=[C:17]([CH3:18])[C:9]=1[CH3:8])[N:15]([CH:1]=[O:3])[CH2:14][CH2:13]2
Reactant: Cc1c(O)cc2c(c1C)NCC2
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: Cc1c(O)cc2c(c1C)N(C=O)CC2
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 95.9 %

Procedure:
To formic acid (100 mL) was added acetic anhydride (23 mL, 0.24 mol) under ice-cooling, and the mixture was stirred at room temperature for 40 minutes. To this solution was added 2,3-dihydro-6,7-dimethyl-1H-indole-5-ol (20.0 g, 0.12 mol) under ice-cooling, and the mixture was stirred at room temperature for 75 minutes. The reaction mixture was concentrated under reduced pressure, and dissolved in the mixture of chloroform-methanol. To this was added an aqueous solution of sodium bicarbonate solution to neutralize, the organic layer was separated, and the aqueous layer was extracted with chloroform three times. The combined organic layers were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The solid was washed with diisopropyl ether to obtain 22.0 g of the title compound.
Reaction SMILES: [CH3:1][CH:2]([S:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[CH2:19](Br)[C:20]#[CH:21]>>[CH2:21]([O:15][C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([S:9][CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:7])[CH3:8])=[CH:18][CH:17]=1)[C:20]#[CH:19]
Reactant: CC(C)CCCC(C)Sc1ccc(C(=O)O)cc1
Reactant: C#CCBr
Product: C#CCOC(=O)c1ccc(SC(C)CCCC(C)C)cc1

Procedure:
By utilizing the procedure of Example 8, by reacting p-[(1,5-dimethylhexyl)thio]benzoic acid and propargyl bromide, there is obtained p-[(1,5-dimethylhexyl)thio]benzoic acid propargyl ester M.P. 130°-131°C/0.03 mmHg.
Reaction SMILES: [CH2:1]([O-:3])C.[Na+].[I:5][C:6]1[C:7](Cl)=[N:8][C:9]([Cl:12])=[N:10][CH:11]=1.O>CO>[Cl:12][C:9]1[N:8]=[C:7]([O:3][CH3:1])[C:6]([I:5])=[CH:11][N:10]=1
Reactant: Clc1ncc(I)c(Cl)n1
Reactant: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nc(Cl)ncc1I

Procedure:
Methanolic sodium ethanolate solution (88.00 mL, 15.31 mmol—from 0.7 g sodium and 100 ml dry methanol) is added dropwise with stirring at −5 to 0° C. to a solution of 5-iodo-2,4-dichloropyrimidine (4.00 g, 14.55 mmol) in dry methanol (50 mL). The reaction solution is warmed to RT overnight, during which the crude product precipitates. The product is isolated by filtration and then stirred thoroughly with water (ca 50 mL) for 30 mins, recrystallised from methanol and dried over phosphorus pentoxide in the desiccator under vacuum: 2.18 g (8.06 mmol, 55.39%) of a white product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[CH:11][C:10]=1[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC1C([N+]([O-])=O)=NC=CC=1.[F:28][C:29]1[CH:30]=[C:31]([C:36](=[O:38])[CH3:37])[CH:32]=[CH:33][C:34]=1F>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[CH:11][C:10]=1[O:17][C:34]1[CH:33]=[CH:32][C:31]([C:36](=[O:38])[CH3:37])=[CH:30][C:29]=1[F:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(F)c(F)c1
Reactant: CCc1ccc(O)c(OCc2ccccc2)c1
Agent: O=[N+]([O-])c1ncccc1F
Product: CCc1ccc(Oc2ccc(C(C)=O)cc2F)c(OCc2ccccc2)c1
Yield: 96 %

Procedure:
According to the procedure of example 21 (a3) except substituting 4-Ethyl-2-methoxy phenol by 2-(benzyloxy)-4-ethylphenol (1.3 g, 5.7 mmol) and 3-Fluoro-2-nitropyridine by 1-(3,4-difluorophenyl)ethanone (0.98 g, 6.27 mmol), the title compound was prepared as a clear oil in 96% yield (2 g) and used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].C(N(CC)CC)C.[Cl:20][CH2:21][C:22](Cl)=[O:23]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:22](=[O:23])[CH2:21][Cl:20]
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(CN)c(OC)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CNC(=O)CCl)c(OC)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
To a solution of 2,4-dimethoxybenzylamine (1.50 mL, 10.0 mmol) and triethylamine (2.00 mL, 14.3 mmol) in tetrahydrofuran (20 mL) at 0° C. was added chloroacetyl chloride (0.80 mL, 10 mmol). The reaction was then stirred at 0° C. for three hours. The crude reaction mixture was partitioned between ethyl acetate and water, and the organic layer dried over brine and magnesium sulfate, filtered, and evaporated in vacuo to yield 2.2074 g (91%) of N-(2,4-Dimethoxy-benzyl)-2-chloro-acetamide which was carried forward without purification. LCMS (Method E, ESI): RT=1.43 min, m+H=244.2