Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)#[N:14].C(O)(=O)C[C:22](CC(O)=O)(C(O)=O)[OH:23]>CCCCCC.O1CCCC1.O.CN(C)C=O>[C:13]([C:15]1[O:16][C:17]([CH:22]=[O:23])=[CH:18][CH:19]=1)#[N:14]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: N#Cc1ccco1
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: N#Cc1ccc(C=O)o1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
165 ml (264 mmol) of a 1.6 molar solution of n-butyllithium in n-hexane were added over the course of 20 min to a solution of 26.7 g (264 mmol) of diisopropylamine in 600 ml of tetrahydrofuran cooled to -78° C. The solution was allowed to reach -20° C., again cooled to -75° C. and, at this temperature, a solution of 22.3 g (240 mmol) of 2-cyanofuran in 100 ml of tetrahydrofuran were slowly added dropwise. After stirring for 30 min, 93 ml of dimethylformamide were slowly added dropwise, and the mixture was stirred for a further 30 min. For workup, a solution of 40 g of citric acid in 200 ml of water was added at -70° C. After concentration in a rotary evaporator, 600 ml of saturated sodium chloride solution were added, and the mixture was extracted three times with 200 ml of diethyl ether each time. The combined organic extracts were dried over magnesium sulfate. The desiccant was filtered off and then the solvent was distilled off under water pump vacuum and the residue was purified by column chromatography (mobile phase dichloromethane). The eluate was concentrated and the residue was subjected to steam distillation (boiling range of the azeotrope with water: 60-65° C. at p=0.1 mm Hg). Extraction of the distillate with diethyl ether, drying of the organic phase and concentration of the solution resulted in 10.6 g (88 mmol, 36%) of the title compound. 1H-NMR (270 MHz, d6 -DMSO): δ=7.7 (d, 1H), 7.8 (d, 1H), 9.75 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([NH:13][CH2:14][C:15]2[C:16](=[O:23])[NH:17][C:18]([CH3:22])=[CH:19][C:20]=2[CH3:21])=[O:12])[C:5]2[CH:10]=[N:9][NH:8][C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH:31]=[C:32]([CH3:34])[CH3:33].O>CN(C=O)C.CO.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([NH:13][CH2:14][C:15]2[C:16](=[O:23])[NH:17][C:18]([CH3:22])=[CH:19][C:20]=2[CH3:21])=[O:12])[C:5]2[CH:10]=[N:9][N:8]([CH2:33][C:32]([CH3:34])=[CH2:31])[C:6]=2[N:7]=1
Reactant: CC(C)=CCl
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3[nH]ncc23)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)Cn1ncc2c(C(=O)NCc3c(C)cc(C)[nH]c3=O)cc(Br)nc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 46.5 %

Procedure:
To a stirred solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.4 g, 1.0 mmol) in DMF (4 mL), K2CO3 (0.152 g, 1.10 mmol) and 3 chloro-2-methylpropene (0.115 g, 1.27 mmol) were added. Resulting reaction mixture was stirred at 80° C. for 2 h. On completion of reaction, water was added to it and extraction was carried out using 20% MeOH/DCM; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and residue was purified by silica gel column chromatography to obtain the desired intermediate (0.2 g, 43.8%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C@H:4]([CH3:11])[CH2:5]OS(C)(=O)=O.[N-:13]=[N+:14]=[N-:15].[Na+].C(OC(=O)CC(C)=O)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:12])[C@H:4]([CH3:11])[CH2:5][N:13]=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@H](C)COS(C)(=O)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(=O)CC(C)=O
Product: COC(=O)[C@H](C)CN=[N+]=[N-]
Reaction time: 24 h
Yield: 32 %

Procedure:
(R)-3-methanesulfonyloxy-2-methyl-propionic acid methyl ester was dissolved in 100 mL of dimethylformamide, and then 8.2 g (126 mmol) of sodium azide was added thereto at 60° C., followed by stirring for 24 hours. After addition of 400 mL of ethylacetoacetate and washing with water, an organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and then the residue was purified by column chromatography to give 2 g (13.9 mmol) of the title compound in a yield of 32%.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:10]=2)[C:6](=[S:25])[NH:5][C:4](=[O:26])[C:3]=1[NH:27][C:28](=O)[C:29]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH3:31])[CH3:30].CC([O-])(C)C.[K+]>C(O)(C)C.ClCCl>[CH2:18]([O:17][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[O:15][CH3:16])[CH2:8][N:7]1[C:2]2[N:1]=[C:28]([C:29]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([CH3:30])[CH3:31])[NH:27][C:3]=2[C:4](=[O:26])[NH:5][C:6]1=[S:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COc1ccc(Cn2c(N)c(NC(=O)C(C)(C)OCc3ccccc3)c(=O)[nH]c2=S)cc1OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1ccc(Cn2c(=S)[nH]c(=O)c3[nH]c(C(C)(C)OCc4ccccc4)nc32)cc1OCc1ccccc1
Yield: 69.9 %

Procedure:
6-Amino-1-(3 -benzyloxy-4-methoxy-benzyl)-5-(2-benzyloxy-2-methyl-propionylamino)-2-thiouracil (46.54 g, 83 mmole) and 97% t-BuOK (38.41 g, 332 mmole) were heated under reflux in isopropanol (460 ml) for 50 minutes. The solvent was removed in vacuo, the residue dissolved in water (300 ml), treated twice with 5 g of charcoal, filtered, water added to a total volume of 500 ml and pH adjusted to neutral with a mixture of 5M HCl (60 ml) and sodium bicarbonate solution. The solid was collected at 10° C. to give 41.62 g of crude product, which was dissolved in dichloromethane (60 ml) and chromatographed over silicagel (126 g) using dichloromethane as eluant. Crystallization from methanol gave 3-(3-benzyloxy-4-methoxy-benzyl)-8-(1-benzyloxy-1-methyl-ethyl)-2-thioxanthine, (31.5 g, 69.9%) mp 290-302° C. (dec).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][C:5]1[NH:10][C:9](=O)[C:8]2[CH:12]=[CH:13][O:14][C:7]=2[CH:6]=1.P(Cl)(Cl)([Cl:18])=O.[OH-].[Na+]>>[Cl:18][C:9]1[C:8]2[CH:12]=[CH:13][O:14][C:7]=2[CH:6]=[C:5]([CH2:4][CH2:3][N:2]([CH3:15])[CH3:1])[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)CCc1cc2occc2c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Product: CN(C)CCc1cc2occc2c(Cl)n1
Temperature: 110 °C
Yield: 94.2 %

Procedure:
A mixture of 6-[2-(dimethylamino)ethyl]furo[3,2-c]pyridin-4(5H)-one (3.9 g, 18.9 mmole) and phosphorus oxychloride (5.0 g, 32.6 mmole) was heated, under an argon atmosphere, at 110° C. for 2.0 hours. The cooled blackish liquid was poured onto crushed ice and the solution made basic with sodium hydroxide solution. The alkaline mixture was extracted into methylene chloride (4×100 ml). The combined extracts were washed with water (1×25 ml), brine (2×25 ml) and dried (MgSO4). Solvent removal gave 4.0 g of an oil (88%, yield). The compound was used as is in the following step. A small sample was purified further using a preparative thin layer chromatography plate and eluting with a 25% methanol/74% chloroform/1.0% ammonium hydroxide mixture. The sample was removed from the plate using methylene chloride and treated with excess hydrogen chloride in ethanol. The ethanol was removed via vacuum and the resulting clear oil triturated with diethyl ether to give white crystals, mp: 212°-213° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([O:18][CH2:19][CH3:20])=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[C:23]1(C)C=CC=CC=1.S(OC)(OC)(=O)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:1]([O:8][C:9]1[C:17]([O:18][CH2:19][CH3:20])=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH3:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1
Reactant: CCOc1ccc2[nH]ccc2c1OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: CCOc1ccc2c(ccn2C)c1OCc1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
The 4-benzyloxy-5-ethoxyindole (1.8 g, 0.0067 mole) obtained in Example (lc), 50% caustic soda (8 ml ), toluene (5.4 ml ) and tetrabutylammonium hydrogen sulphate (180 mg) are successively introduced. The mixture is heated to 60° C. and dimethyl sulphate (1 g) is introduced. The mixture is left at 60° C. for 30 minutes, diluted with water and the two phases are separated. The organic phase is washed with water, dried and the solvent evaporated. A colourless oil of 4-benzyloxy-5-ethoxy-l-methylindole (1.6 g; yield = 95%) is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH3:15])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][CH2:32]Cl)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1.[F:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C(N(C(C)C)CC)(C)C>COCCO.ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH3:15])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][CH2:32][N:40]3[CH2:41][CH2:42][N:37]([CH2:36][CH2:35][F:34])[CH2:38][CH2:39]3)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1
Reactant: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCl)c(OC)cc23)c2c1OCO2
Reactant: FCCN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCO
Solvent: ClCCl
Product: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCN(CCF)CC4)c(OC)cc23)c2c1OCO2
Temperature: 110 °C
Yield: 46.7 %

Procedure:
N-[5-chloro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine (0.165 g) was dissolved in 2-methoxyethanol (5 ml) and then fluoroethyl piperazine (0.821 g) was added followed by diisopropylethylamine (0.83 ml) and the mixture heated to 110° C. for 15 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and then evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of dichloromethane and methanol with methanolic ammonia as eluent. There was thus obtained the title compound (0.092 g) as a white powder, contaminated with approximately 5 wt. % diisopropylethylamine; NMR Spectrum: (CDCl3) 2.15 (quin, 2H), 2.63 (m(broad), 12H, ), 2.69 (t, 1H), 2.76 (t, 1H), 3.46 (s, 3H), 3.99 (s, 3H), 4.35 (s, 2H), 4.52 (t, 1H), 4.64 (t, 1H), 6.07 (s, 2H), 6.96 (s, 1H), 7.07 (s, 1H), 7.12 (s, 1H), 7.28 (s, 1H), 8.62 (s, 1H); Mass Spectrum: M+H+ 586/588.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:43])[C@@:10]3([C@@H:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH3:33])([CH3:32])[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=O)[CH2:14][C:13](=[O:34])[NH:12][C@H:11]3[C:35]3[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=3[CH3:42])[C:5]2=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.CC(C[AlH]CC(C)C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:43])[C@@:10]3([C@@H:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH3:33])([CH3:32])[CH2:25][NH:27][S:28]([CH3:31])(=[O:29])=[O:30])[CH2:14][C:13](=[O:34])[NH:12][C@H:11]3[C:35]3[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=3[CH3:42])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1[C@@H]1NC(=O)C[C@H](c2cc(Cl)ccc2OC(C)(C)C(=O)NS(C)(=O)=O)[C@@]12C(=O)Nc1cc(Cl)ccc12
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1[C@@H]1NC(=O)C[C@H](c2cc(Cl)ccc2OC(C)(C)CNS(C)(=O)=O)[C@@]12C(=O)Nc1cc(Cl)ccc12
Reaction time: 0.5 h
Yield: 47.3 %

Procedure:
At 0° C., to a solution of chiral (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-methanesulfonylamino-1,1-dimethyl-2-oxo-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (20 mg, 0.03 mmol) prepared in Example 12b in THF (1 mL) was added a toluene solution (1 M) of DIBALH (0.18 mL, 0.18 mmol) in one portion. After stirred for 0.5 h, the mixture was quenched with water. Then the mixture was filtered and the filtrate was concentrated. The residue was purified by Prep-HPLC to give the title compound as a white solid (9 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:41][CH3:42])[C:9]([C@@H:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([C:21]([C:23]3[CH:39]=[CH:38][C:26]([O:27][CH2:28][CH2:29][C:30]([F:37])([F:36])[C:31]([O:33]CC)=[O:32])=[CH:25][CH:24]=3)=[O:22])[C@@H:13]([CH3:40])[CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[OH-].[Li+].CO.Cl>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:41][CH3:42])[C:9]([C@@H:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([C:21]([C:23]3[CH:24]=[CH:25][C:26]([O:27][CH2:28][CH2:29][C:30]([F:37])([F:36])[C:31]([OH:33])=[O:32])=[CH:38][CH:39]=3)=[O:22])[C@@H:13]([CH3:40])[CH2:12]2)=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(F)(F)CCOc1ccc(C(=O)N2c3ccccc3[C@@H](C(=O)N(CC)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCN(C(=O)[C@H]1C[C@H](C)N(C(=O)c2ccc(OCCC(F)(F)C(=O)O)cc2)c2ccccc21)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (±)-trans-ethyl 4-(4-{[4-{[(4-chlorophenyl)(ethyl)amino]carbonyl}-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenoxy)-2,2-difluorobutanoate (190 mg, 0.32 mmol) in THF (4.4 mL) was added a solution of lithium hydroxide (15.2 mg, 0.63 mmol) in water (2 mL). To the resulting mixture was added methanol (2 mL) and the reaction stirred 18 hours at room temperature. The reaction mixture pH was adjusted to 2 via addition of 1N hydrochloric acid and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated in vacuo to yield (±)-trans-4-(4-{[4-{[(4-chlorophenyl)(ethyl)amino]carbonyl}-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenoxy)-2,2-difluorobutanoic acid. 1H-NMR (CDCl3) δ: 0.96 (d, 3H), 1.08 (t, 3H), 1.61-1.74 (m, 1H), 2.34-2.56 (m, 3H), 3.52-3.68 (m, 1H), 3.72-3.88 (m, 2H), 4.00-4.14 (m, 2H), 4.93-5.11 (m, 1H), 6.42-6.51 (m, 1H), 6.65-6.82 (m, 4H), 6.83-6.92 (m, 1H), 7.16-7.29 (m, 2H), 7.37-7.50 (m, 4H). MS m/z: 571 (M+1).
Reaction SMILES: Br[CH:2]([C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12])[CH:3]=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]1[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:25]([CH3:32])[NH:24][C:23](=[S:33])[NH:22]1>O1CCCC1>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([Cl:11])[C:5]=1[C:2]1[S:33][C:23]2=[N:24][C:25]([CH3:32])=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][CH3:13])[N:22]2[CH:3]=1
Reactant: CCOC(=O)C1=C(C)NC(=S)NC1c1ccccc1OC
Reactant: O=CC(Br)c1c(Cl)cccc1Cl
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C)N=C2SC(c3c(Cl)cccc3Cl)=CN2C1c1ccccc1OC
Temperature: 25 °C
Reaction time: 17 h
Yield: 56.3 %

Procedure:
A mixture of 2.0 g (7.5 mmol) of α-bromo-2,6-dichlorophenyl-acetaldehyde and 2.08 g (6.8 mmol) of ethyl (RS)-4-(2-methoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylate in 40 ml of tetrahydrofuran was stirred at RT for 17 h. Subsequently, the mixture was cooled to 0° C. and the precipitated solid was filtered off, dissolved in 75 ml of conc. acetic acid and heated at reflux while stirring for 24 h. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (ethyl acetate). There were obtained 1.82 g (51%) of ethyl (RS)-2-(2,6-dichlorophenyl)-5-(2-methoxyphenyl)-7-methyl-5H-thiazolo[3,2-a]pyrimidine-6-carboxylate as a yellow foam.
Reaction SMILES: [C:1]([C:5]1[C:6]([C:11]([OH:13])=O)=[N:7][CH:8]=[CH:9][CH:10]=1)([O:3]C)=O.[F:14][C:15]1[CH:22]=[CH:21][C:18](C=O)=[CH:17][CH:16]=1.N#N>CC1C=CC(C(C)C)=CC=1>[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH:11]2[C:6]3=[N:7][CH:8]=[CH:9][CH:10]=[C:5]3[C:1](=[O:3])[O:13]2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1cccnc1C(=O)O
Reactant: O=Cc1ccc(F)cc1
Agent: N#N
Solvent: Cc1ccc(C(C)C)cc1
Product: O=C1OC(c2ccc(F)cc2)c2ncccc21
Temperature: 25 °C

Procedure:
A suspension of 3-carbomethoxypicolinic acid (15.0 g, 0.083 mol) and 4-fluorobenzaldehyde (90.8 g. 0.732 mol) in 250 mL of p-cymene is heated to reflux under a stream of N2 for 16 hours. The mixture is then allowed to cool to room temperature, filtered and the filtrate distilled in vacuo to remove p-cymene. A solution of the crude residue in CH2Cl2 is chromatographed on silica gel (using Et2O-hexane (2:1) as the eluent). Recrystallization from hexane-EtOAc gives pure 7-(4-fluorophenyl)-5-oxo-5,7-dihydrofuro[3,4-b]pyridine. M.P. 116°-117.5° C.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]([F:15])([F:14])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13].[Br:16][CH2:17][CH2:18]Br.Cl>>[Br:16][CH2:17][CH2:18][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([F:14])([F:15])[F:3]
Reactant: BrCCBr
Reactant: Oc1ccccc1OCC(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: FC(F)(F)COc1ccccc1OCCBr
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To an aqueous solution (15 ml) of sodium hydroxide (0.63 g) were added 2-(2,2,2-trifluoroethoxy)phenol (2.85 g) and 1,2-dibromoethane (1.68 ml), and the mixture was reacted with stirring at 120° C. for 8 hours. To the reaction mixture was added concentrated hydrochloric acid (1.3 ml), and the mixture was extracted with diethyl ether. The extract was washed with water, dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on silica gel using a mixture of hexane and diethyl ether (5/1) as eluent to give 1.78 g of 1-(2-bromoethoxy)-2-(2,2,2-trifluoroethoxy)benzene as an oil
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[SH:7][C:8]1[N:22]=[CH:21][CH:20]=[CH:19][C:9]=1[C:10]([NH:12][CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)=[O:11].Br[CH2:24][CH2:25][S:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(OCC)(=O)C.CCCCCC>CN(C=O)C.C(OCC)(=O)C.O>[CH:27]1([S:26][CH2:25][CH2:24][S:7][C:8]2[N:22]=[CH:21][CH:20]=[CH:19][C:9]=2[C:10]([NH:12][CH2:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[O:11])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: O=C(NCc1cccs1)c1cccnc1S
Reactant: BrCCSC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NCc1cccs1)c1cccnc1SCCSC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
607 mg (4.4 mmol) of K2CO3 were added to a solution of 500 mg (2.0 mmol) of 2-mercapto-N-(thiophen-2-ylmethyl)nicotinamide (V1) in DMF (5 ml), and the mixture was stirred for 1 h at RT. 446 mg of (2-bromoethyl)-(cyclohexyl)sulfane (crude product V2) were then added, and stirring was continued for a further 18 h at RT. The mixture was then diluted with ethyl acetate, and water was added. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. CC (ethyl acetate/n-hexane 1:1) with the residue yielded 268 mg (0.68 mmol, 34%) of 2-(2-(cyclohexylthio)ethylthio)-N-(thiophen-2-ylmethyl)nicotinamide. MS: m/z 393.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][OH:12])[N:6]=1)=[O:4].O>ClCCCl.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]=[O:12])[N:6]=1)=[O:4]
Reactant: COC(=O)c1cccc(CO)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCCl
Solvent: O
Product: COC(=O)c1cccc(C=O)n1
Yield: 79 %

Procedure:
A solution of 3 g of 6-hydroxymethylpyridine-2-carboxylic acid methyl ester (16.5 mmol) in 70 ml of 1,2-dichloroethane containing 15 g of manganese dioxide (165 mmol) is heated under reflux for 4 hours with removal of the water formed continuously. The solid is removed by filtration on celite and then the dichloromethane is evaporated off. The title product is isolated by chromatography on a silica column (eluent: dichloromethane/ethyl acetate; 70:30). 2.33 g of a yellow oil are recovered.
Reaction SMILES: FC(S([O:8][Si:9]([CH3:12])([CH3:11])[CH3:10])(=O)=O)(F)F.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[C:14]([CH3:16])=O.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:19]([O:18][C:13](=[O:17])[C:14]([O:8][Si:9]([CH3:12])([CH3:11])[CH3:10])=[CH2:16])[CH3:20]
Reactant: CCOC(=O)C(C)=O
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C(O[Si](C)(C)C)C(=O)OCC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
A solution of trimethylsilyl trifluoromethylsulfonate (9.52 mL, 52.5 mmol) in anhydrous methylene chloride (10 mL) was added to a stirred ice-cooled solution of ethyl pyruvate (5.56 mL, 50 mmol) and diisopropylethyl amine (9.6 mL, 55 mmol) in anhydrous methylene chloride (100 mL) over a period of 15 minutes. The reaction was stirred on ice for 1.5 hours and then at room temperature for 3 hours. The solvent was evaporated at room temperature and the residue treated with anhydrous pentane (200 mL) and cooled in ice. The precipitated solid was filtered off. The filtrate was collected and the pentane evaporated to give 2-trimethylsilanyloxyacrylic acid ethyl ester as a light brown liquid (90% yield). The crude product was used for the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.C[Al](C)C.C([O:14][C:15]([C:17]1[CH:22]=[C:21]([Br:23])[CH:20]=[C:19]([CH3:24])[N:18]=1)=O)C>O1CCOCC1.CCCCCC>[CH3:7][C:5]1[N:6]=[C:2]([NH:1][C:15]([C:17]2[CH:22]=[C:21]([Br:23])[CH:20]=[C:19]([CH3:24])[N:18]=2)=[O:14])[S:3][CH:4]=1
Reactant: Cc1csc(N)n1
Reactant: CCOC(=O)c1cc(Br)cc(C)n1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: CCCCCC
Product: Cc1cc(Br)cc(C(=O)Nc2nc(C)cs2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
To a solution of 3.72 g (32.6 mmol) of 2-Amino-4-methylthiazole in 40 ml of dry dioxane were added dropwise 15.9 ml (31.8 mmol, 4.0 equiv.) of a 2M solution of trimethylaluminium in hexane. The solution was stirred for 30 min at room temperature. Then a solution of 1.94 g (7.95 mmol) of 4-Bromo-6-methyl-pyridine-2-carboxylic acid ethyl ester in 6 ml of dry dioxane was added dropwise and the reaction was heated to 100° C. for 1.5 h. The reaction was quenched by cautious addition of 2.5 ml of water. Then approximately 10 g of anhydrous sodium sulfate were added to bind the water and the mixture was stirred vigorously for 5 min. The mixture was diluted by addition of 20 ml of methylene chloride and filtered over Speedex filteraid which was washed with methylene chloride. The filtrate was concentrated in vaccuo and the residue was purified by flash chromatography (heptane/ethyl acetate 4:1) to yield the title compound (1.95 g, 79%) as a yellow solid, MS (ISP): m/e=312.0, 314.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]Br.[P:18]([O:25]CC)([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]>>[Cl:1][C:2]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]
Reactant: COc1ccc(OCCCCCCBr)c(Cl)c1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CCCCCCOc1ccc(OC)cc1Cl)OCC
Yield: 30.4 %

Procedure:
A mixture of 10 g (0.0313 mole) of 6-(2-chloro-4-methoxyphenoxy)hexyl bromide and 5.2 g (0.313 mole) of triethyl phosphite was heated at 180°-190° C. for two hours. The reaction mixture was distilled in vacuo, and the fraction (4.6 g) collected at 183°-185° C. (0.03 mm) was redistilled to give 3.6 g of diethyl [6-(2-chloro-4-methoxyphenoxy)hexyl]phosphonate, b.p. 195°-197° C. (0.005 mm).