Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][C:5]=1[CH3:11])[CH3:2].OC1C=CC(I)=CC=1C.C(I)C.C([O-])([O-])=O.[K+].[K+].[C:30]([O:34][CH3:35])(=[O:33])[CH:31]=[CH2:32].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC(C)=O.CN(C=O)C>[CH3:35][O:34][C:30](=[O:33])/[CH:31]=[CH:32]/[C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([CH3:11])[CH:6]=1
Reactant: CCOc1ccc(I)cc1C
Reactant: C=CC(=O)OC
Agent: Cc1cc(I)ccc1O
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Solvent: CCI
Product: CCOc1ccc(/C=C/C(=O)OC)cc1C
Temperature: 25 °C

Procedure:
In a 250 mL RBF was charged 2-ethoxy-5-iodotoluene (5 g, 19.1 mmol, prepared from 2-hydroxy-5-iodotoluene by reacting with ethyl iodide in acetone in the presence of K2CO3), methyl acrylate (17 mL), P(o-tolyl)3 (1.16 g), DMF (25 mL) and TEA (25 mL). The mixture was degased under nitrogen. To the solution was added Pd(OAc)2 (0.43 g) and the mixture was heated to reflux under nitrogen for 20 hours. After cooling to room temperature, the reaction mixture was diluted with water (200 mL) and extracted with ether (2×250 mL). The ether extracts were washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography. Eluting with 5-20% ethyl acetate in hexanes afforded the desired product 11 (3.3 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](Cl)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:13][OH:14]>>[CH3:13][O:14][C:10](=[O:11])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: CO
Product: COC(=O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Benzyloxyacetyl chloride was added slowly to 10 vol of MeOH at 0-5° C. The mixture was stirred at room temperature for 20 h. MeOH was removed under vacuum to give quantitatively the desired product.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]4[CH:28]=[CH:27][C:26]([S:29]([CH3:31])=[O:30])=[CH:25][CH:24]=4)=[N:21][CH:22]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)[CH3:3].C(=O)=O.CO>C(Cl)(Cl)Cl>[CH3:3][CH:2]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]4[CH:28]=[CH:27][C:26]([S@:29]([CH3:31])=[O:30])=[CH:25][CH:24]=4)=[N:21][CH:22]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)[CH3:1]
Reactant: CC(C)c1noc(N2CCC(COc3ccc(-c4ccc(S(C)=O)cc4)nc3)CC2)n1
Agent: O=C=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)c1noc(N2CCC(COc3ccc(-c4ccc([S@](C)=O)cc4)nc3)CC2)n1
Yield: 9.7 %

Procedure:
The racemic sulfoxide 5-[({1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]-2-[4-(methylsulfinyl)phenyl]pyridine (prepared as in Example 171, 290 mg) was subjected to Chiral HPLC [column: Chiralcel OJ-H, column mobile phase: 80% CO2: 20% (80% MeOH: 20% CHCl3) (2 mL/min), pressure 140 bar, temperature 30° C., 254 nm] analysis and then separation to give two (R and S) enantiomers. The title compound (28 mg) was isolated a tan solid with Tr of 12.11 min (second eluting peak). The (S) absolute stereochemistry was assigned by Ab initio VCD analysis.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Cl:9][S:10]([OH:13])(=O)=[O:11]>>[CH3:1][C:2]1[C:7]([S:10]([Cl:9])(=[O:13])=[O:11])=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:10]([Cl:9])(=[O:13])=[O:11]
Reactant: Cc1ccc(C)cc1
Reactant: O=S(=O)(O)Cl
Product: Cc1cc(S(=O)(=O)Cl)c(C)c(S(=O)(=O)Cl)c1
Temperature: 25 °C

Procedure:
1,4-Dimethylbenzene (10.6 g, 0.1 mol) was added dropwise to chlorosulfonic acid (60 g, 0.51 mol ) at room temperature with stirring. After the addition was complete, the reaction mixture was heated to ˜100C for 1 hr, cooled to room temperature and poured onto ice-water-1,2-dichloromethane mixture with stirring. The organic layer was separated, washed with water (2×), dried over anhydrous MgSO4 and the solvent evaporated to give 2,5-dimethyl-1,3-benzenedisulfonyl chloride, 26 g (86%) as a viscous liquid that solidified on standing, mp 24-27° C. Reported 25-27C. (C. M. Suter, Organic Chemistry of Sulfur Compounds, Chapter 3).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].Cl[CH2:13][CH2:14][CH2:15][C:16](Cl)=O.[OH-].[Na+]>OS(O)(=O)=O>[CH2:14]1[CH:13]2[N:11]([S:8](=[O:9])(=[O:10])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1]2)[CH2:16][CH2:15]1
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: O=C(Cl)CCCCl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=S1(=O)c2ccccc2NC2CCCN21
Temperature: 100 °C

Procedure:
2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method E (using 4-chlorobutanoyl chloride. The reaction mixture was NOT subjected to NaOH catalyzed ring closure, but dissolved in H2SO4 and heated at 100° C. for 72 h and precipitated on ice). M.p. 149–154° C.
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[CH:8]1([S:14][CH2:15][CH2:16][NH2:17])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.Br[CH:19]([CH3:23])[C:20]([OH:22])=[O:21]>C(O)(C)(C)C>[CH:8]1([S:14][CH2:15][CH2:16][NH:17][C@H:19]([C:20]([OH:22])=[O:21])[CH3:23])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(Br)C(=O)O
Reactant: NCCSC1CCCCC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: C[C@H](NCCSC1CCCCC1)C(=O)O

Procedure:
To a stirred solution of 22.4 parts potassium tert-butoxide in 400 parts by volume of tert-butanol, under a nitrogen atmosphere, is added successively 19.62 parts of 2-(cyclohexylthio)ethylamine hydrochloride and 15.3 parts of 2-bromopropionic acid. The mixture is refluxed for 3 hours, then dried under reduced pressure. The material remaining is dissolved in 200 parts of water containing 10 parts of sodium hydroxide and extracted with ether. The aqueous solution is cooled in an ice bath and acidified to pH 5 with concentrated hydrochloric acid. The solid is collected by filtration and dried under reduced pressure to yield N-[2-(cyclohexylthio)ethyl] alanine.
Reaction SMILES: [Na].[Cl:2][C:3]1[N:11]=[C:10]2[C:6]([NH:7][CH:8]=[N:9]2)=[C:5]([N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[CH:17]([CH3:19])[CH3:18])[N:4]=1.[C:20]1([CH3:46])[CH:25]=[CH:24][C:23]([C:26]([O:28][C@@H:29]2[C@@H:33]([CH2:34][O:35][C:36]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=3)=[O:37])[O:32][C@H:31](Cl)[CH2:30]2)=[O:27])=[CH:22][CH:21]=1>CC#N.C(Cl)Cl>[Cl:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@@H:31]2[O:32][C@H:33]([CH2:34][O:35][C:36]([C:38]3[CH:39]=[CH:40][C:41]([CH3:44])=[CH:42][CH:43]=3)=[O:37])[C@@H:29]([O:28][C:26]([C:23]3[CH:22]=[CH:21][C:20]([CH3:46])=[CH:25][CH:24]=3)=[O:27])[CH2:30]2)=[C:5]([N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[CH:17]([CH3:19])[CH3:18])[N:4]=1
Reactant: Cc1ccc(C(=O)OC[C@H]2O[C@H](Cl)C[C@@H]2OC(=O)c2ccc(C)cc2)cc1
Reactant: CC(C)c1nccn1-c1nc(Cl)nc2nc[nH]c12
Agent: [Na]
Solvent: CC#N
Solvent: ClCCl
Product: Cc1ccc(C(=O)OC[C@H]2O[C@@H](n3cnc4c(-n5ccnc5C(C)C)nc(Cl)nc43)C[C@@H]2OC(=O)c2ccc(C)cc2)cc1

Procedure:
The sodium salt of 2-chloro-6-(2-isopropylimidazol-1-yl)purine (0.132 g, 0.5 mmol) in dried CH3CN (10 mL) was treated with 2-deoxy-3,5-di-O-(p-toluoyl)-α-D-erythro-pentofuranosyl chloride (0.334 g, 0.86 mmol) in CH2Cl2 (10 mL) by general method 2 for 1 h (reaction complete, TLC). Sampling of the reaction mixture at the end of the reaction time showed no α-nucleoside by 1H NMR (500 MHz). The residue was chromatographed (25 g silica gel, EtOAc/hexanes˜1:1) to give 2-chloro-9-[2-deoxy-3,5-di-O-(p-toluoyl)-β-D-erythro-pentofuranosyl]-6-(2-isopropylimidazol-1-yl)purine (quantitative). Recrystallization (EtOAc) gave the compound (0.22 g, 70%): UV (MeOH) max 223, 241, 285 nm (∈ 32 100, 35 400, 14 800), min 230, 265 nm (∈ 30 300, 9200); 1H NMR (500 MHz, CDCl3) δ 8.42 (d, J=1.0 Hz, 1H), 8.26 (s, 1H), 7.99 (d, J=7.8 Hz, 2H), 7.85 (d, J=8.3 Hz, 2H), 7.30 (d, J=7.8 Hz, 2H), 7.20 (d, J=8.8 Hz, 2H), 7.11 (d, J=1.0 Hz, 1H), 6.60 (t, J=6.8 Hz, 1H), 5.81 (br s, 1H), 4.78-4.83 (m, 1H), 4.67-4.71 (m, 2H), 4.08 (sept, J=6.8 Hz, 1H), 2.97-3.01 (m, 2H), 2.46 (s, 3H), 2.37 (s, 3H), 1.43 (d, J=6.8 Hz, 3H), 1.41 (d, J=6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 166.05, 165.99, 156.18, 154.20, 153.21, 148.15, 144.72, 144.40, 142.25, 129.88, 129.55, 129.36, 129.33, 128.82, 126.44, 126.26, 123.00, 120.38, 85.23, 83.59, 74.93, 63.87, 38.63, 28.81, 21.78, 21.61; HRMS 77/z 637.1931 (MNa+[C32H31ClN6O5Na=637.1942]).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N-:5]=[N+:6]=[N-:7].[Na+].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N:17]=[C:18]=[O:19])[C:12]=1[CH3:20].N([O-])=O.[Na+].Cl>O.CN(C)C=O>[CH3:20][C:12]1[C:11]([O:10][CH3:9])=[CH:16][CH:15]=[CH:14][C:13]=1[N:17]1[C:18](=[O:19])[NH:7][N:6]=[N:5]1
Reactant: COc1cccc(N=C=O)c1C
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Al+3]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(-n2nn[nH]c2=O)c1C
Temperature: 0 °C
Yield: 75.4 %

Procedure:
Under ice-cooling, to N,N-dimethylformamide 180 mL was added anhydrous aluminum chloride 16.0 g and the resulting mixtures were stirred for fifteen minutes. Thereto was added sodium azide 7.8 g and the resulting mixtures were stirred for fifteen minutes and thereto was then added 1-methoxy-3-isocyanato-2-methylbenzene 17.0 g and the resulting mixtures were heated at 80° C. for four and a half hours. After cooling the mixtures, to a mixture of sodium nitrite 25 g, water 2 L and ice 500 g was added the reaction solutions with stirring. The mixtures were acidified with 10% hydrochloric acid and were extracted with ethyl acetate. The organic layers were washed with water and saturated saline, and were dried over anhydrous magnesium sulfate and were then concentrated under reduced pressure to give 1-(2-methyl-3-methoxyphenyl)-1,4-dihydrotetrazole-5-one 16.2 g.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:17])=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[CH:12]=1.S(=O)(=O)(O)O>C(O)(=O)C>[CH3:5][O:6][C:7]1[C:8]([N+:1]([O-:4])=[O:2])=[CH:9][C:10]([CH3:17])=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[CH:12]=1
Reactant: COc1ccc(C)c(NC(C)=O)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COc1cc(NC(C)=O)c(C)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 56.8 %

Procedure:
Nitric acid (70%, 2.5 mL, 25.14 mmol) was added, dropwise, at a temperature ranging between 5 and 10° C., to a mixture of N-(5-methoxy-2-methyl-phenyl)-acetamide (3.0 g, 16.76 mmol) and concentrated sulfuric acid (10 mL) in glacial acetic acid (20 mL) and the resulting mixture was stirred for 3 hours. The reaction mixture was poured into ice-water and the solid formed was collected by filtration. The residue was dissolved in dichloromethane, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 2.135 g of N-(5-methoxy-2-methyl-4-nitro-phenyl)-acetamide as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH2:9][CH2:10][NH:11]C(=O)OC(C)(C)C)[CH:3]=1.[ClH:19]>CO>[ClH:19].[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH2:9][CH2:10][NH2:11])[CH:3]=1
Reactant: Cc1ccnc(CCCNC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: CO
Product: Cc1ccnc(CCCN)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl N-[3-(4-methyl-2-pyridyl)propyl]carbamate (522 mg, 2.085 mmol) was dissolved in methanol (1 ml). A solution of HCl in methanol (4N, 41.7 mmol, 10.43 ml) was added and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and triturated several times with diethyl ether. The residue was dried in vacuo to obtain a brown solid (409 mg, quantitative). MS(ESI) m/z=151.2 [M+1]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].S(=O)(=O)(O)O.[CH3:12][C:13]1[NH:14][C:15]2[C:20]([C:21]=1[CH:22]=[CH:23][N+:24]([O-])=O)=[CH:19][C:18]([O:27][CH3:28])=[C:17]([Cl:29])[C:16]=2[Cl:30].[OH-].[Na+]>O1CCCC1.C(Cl)(Cl)Cl>[CH3:12][C:13]1[NH:14][C:15]2[C:20](=[CH:19][C:18]([O:27][CH3:28])=[C:17]([Cl:29])[C:16]=2[Cl:30])[C:21]=1[CH2:22][CH2:23][NH2:24]
Reactant: COc1cc2c(C=C[N+](=O)[O-])c(C)[nH]c2c(Cl)c1Cl
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COc1cc2c(CCN)c(C)[nH]c2c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 1.25 h

Procedure:
The above nitrovinyl compound was reduced with lithium aluminum hydride according to the following procedure: 8.2 g of lithium aluminum hydride were stirred with 235 ml of tetrahydrofuran (THF) under a nitrogen blanket. 10.67 g of 18M sulfuric acid were added to 43 ml of THF which was cooled to about 0° C. during the addition. This solution was added to the lithium aluminum hydride mixture. Next, a solution of 2.20 g of 2-methyl-3-(2-nitrovinyl)-5-methoxy-6,7-dichloroindole in 43 ml of THF was added thereto in dropwise fashion at ambient temperature over a period of about 1.25 hours. The reaction mixture was stirred for an additional 1.25 hours, and was then diluted with ice, followed by the addition of cold 20% aqueous sodium hydroxide. Chloroform was added to the mixture, and the chloroform extract separated. The chloroform extraction process was repeated, and the chloroform extracts combined and dried. Removal of the solvent yielded a residue comprising 2-methyl-5-methoxy-6,7-dichlorotryptamine formed in the above reaction. The residue was dissolved with difficulty in hot boiling ethyl acetate. The ethyl acetate solution was cooled, and hexane added to the point of incipient precipitation. The recrystallization mixture was then chilled. Crystalline 2-methyl-5-methoxy-6,7-dichlorotryptamine thus formed was collected by filtration. The crystals melted at about 228°-230° C. Total yield, including second crop material, was 73%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:22]([F:25])([F:24])[F:23])=[CH:10][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][CH:14]=2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[O:26]1[CH:30]=[CH:29][CH2:28][CH2:27]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:22]([F:25])([F:23])[F:24])=[CH:10][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:19][CH:27]3[CH2:28][CH2:29][CH2:30][O:26]3)=[O:18])=[CH:15][CH:14]=2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C1=COCC1
Reactant: NC(=O)c1ccc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: O=C(C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(C(=O)NC2CCCO2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.7 %

Procedure:
To a solution of 0.25 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)benzoic acid amide that was synthesized under Synthetic Example 9 in 3 mL of dichloromethane, 68 mg of 2,3-dihydrofuran and a catalytic amount of p-toluenesulfonic acid monohydrate were added and the mixture was stirred for 18 hours at room temperature. The solvent was distilled off from the reaction solution under reduced pressure, and the resulting residue was purified using silica gel column chromatography that was eluted with ethyl acetate-hexane (2:3) followed by crystallization from a mixed solvent of hexane and a small amount of ethyl acetate to obtain 0.12 g of aimed product as yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](Cl)=[O:5].[Cl:8][C:9]1[CH:10]=[N:11][N:12]([OH:14])[CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH3:1][C:2]([CH3:7])=[CH:3][C:4]([O:14][N:12]1[CH:13]=[C:9]([Cl:8])[CH:10]=[N:11]1)=[O:5]
Reactant: On1cc(Cl)cn1
Reactant: CC(C)=CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)=CC(=O)On1cc(Cl)cn1
Reaction time: 12 h
Yield: 90.1 %

Procedure:
20 g of dimethylacrylyl chloride, dissolved in 100 g of acetonitrile, are added to 20 g of 4-chloro-1-hydroxypyrazole, 20 g of sodium carbonate and 150 g of acetonitrile at 25° C., while stirring. Stirring is continued for 12 hours at 25° C., after which the solid product is filtered off under suction and washed with 100 g of acetonitrile. The solution is evaporated down at 40° C. and under 20 mbar, the residue is taked up in 200 g of dichloromethane, the solution is extracted 3 times with 200 g of saturated aqueous sodium bicarbonate solution, the organic phase is dried with magnesium sulfate and evaporated down, and the residue is digested with 300 g of petroleum ether. 30.5 g (90% of theory) of 4-chloropyrazol-1-yl 3,3-dimethylacrylate of melting point 71° C. are obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:25])[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:11]2[C:6](=[CH:7][C:8]([OH:24])=[CH:9][CH:10]=2)[O:5]1.Cl[CH2:27][C:28]#[N:29]>CN(C)C=O>[C:28]([CH2:27][O:24][C:8]1[CH:7]=[C:6]2[C:11]([CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:23])[F:22])[CH:15]=3)[CH2:13][C:4]([CH3:25])([CH3:3])[O:5]2)=[CH:10][CH:9]=1)#[N:29]
Reactant: N#CCCl
Reactant: CC1(C)CC(c2cccc(C(F)(F)F)c2)c2ccc(O)cc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CC(c2cccc(C(F)(F)F)c2)c2ccc(OCC#N)cc2O1
Temperature: 60 °C

Procedure:
Sodium hydride (0.93g, 80% dispersion in oil) was added to a solution of 2,2-dimethyl-4-(3-trifluoromethylphenyl) chroman-7-ol (containing 1 mole of carbon tetrachloride of crystallisation) (7.5g) in dimethylformamide (25 ml). Chloroacetonitrile (1.76g) was added and the mixture heated at 60° C for 3 hours. The solvent was removed under reduced pressure and the resulting oil was poured into water. The aqueous solution was extracted with ether and the etheeal extracts were dried (MgSO4) and evaporated under reduced pressure to yield an oil. Chromatography on alumina with ether-petrol (40°-60° C), 1:3 as eluate gave the title compound which crystallised on standing.
Reaction SMILES: [C:1]1([C:18]([OH:20])=O)[C:14]2[CH2:13][C:12]3[CH:11]=[CH:10][CH:9]=[C:8]([C:15]([OH:17])=O)[C:7]=3[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[CH:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>CN(C)C=O.S(Cl)(Cl)=O>[C:18]([C:1]1[C:14]2[CH2:13][C:12]3[C:7](=[C:8]([C:15](=[O:17])[C:1]4[CH:14]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:9]=[CH:10][CH:11]=3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)(=[O:20])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)c1cccc2c1Cc1cccc(C(=O)O)c1C2
Reactant: c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(c1ccccc1)c1cccc2c1Cc1cccc(C(=O)c3ccccc3)c1C2
Temperature: 60 °C
Reaction time: 18 h
Yield: 27 %

Procedure:
A solution of 9,10-dihydro anthracene-1,5-dicarboxylic acid (52, 1 g, 3.73 mmol) in 200 μl of dimethyl formamide and 20 ml of thionyl chloride was refluxed for 3 hours. The resulting solution was evaporated to dryness under vacuum, 60 ml of benzene added, and warmed to 60° C. to obtain a solution. This solution was slowly added to a 250 ml round bottom flask containing a mixture of AlCl3 and 20 ml of benzene. The resulting mixture was stirred for 18 hours at room temperature and poured into 100 ml of an ice/water mixture containing 10 ml of conc. HCl. The organic layer was separated and the aqueous layer was washed twice with 100 ml portions of benzene. After drying over Na2SO4, the combined organic extracts were dried under vacuum to yield a brown colored crude product. This was further purified by flash column chromatography to obtain a dark yellow, oily product (0.39 g, 27%) (According to NMR studies the product is 80+% pure). 1H NMR (300 MHz, CDCl3): δ 4.04 (s, 4H), 7.20-7.86 (m, 16H), 7.51 (d, 2H, J=6 Hz), 7.70 (d, 2H, J=6 Hz), 13.00 (broad s, 2H). 13C NMR (300 MHz, CDCl3): δ 33.95, 125.48, 126.98, 128.51, 128.55, 129.94, 130.30, 133.24, 135.74, 137.88, 197.15.
Reaction SMILES: [Cl:1][CH:2]([C:7](=[O:29])[CH2:8][C:9]([CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)(O)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[C:14]([F:22])[CH:13]=1)[C:3]([O:5]C)=[O:4].CCCC[Sn](Cl)(O[Sn](Cl)(CCCC)CCCC)CCCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3](=[O:4])[O:5][C:9]([CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[C:14]([F:22])[CH:13]=2)[CH2:8][C:7]=1[OH:29]
Reactant: COC(=O)C(Cl)C(=O)CC(O)(CCc1ccc(OC(C)C)c(F)c1)C1CCCC1
Agent: CCCC[Sn](Cl)(CCCC)O[Sn](Cl)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(O)=C(Cl)C(=O)O2)cc1F
Yield: 49.2 %

Procedure:
A solution of methyl 2-chloro-5-cyclopentyl-7-(3-fluoro-4-isopropoxyphenyl)-5-hydroxy-3-oxoheptanoate (1.74 g, 4.1 mmol), and bis(dibutylchlorotin)oxide (1.38 g, 2.5 mmol), dissolved in toluene (20 mL) were heated at reflux for 30 mins. The resulting mixture was concentrated and purified by silica gel chromatography to give the title compound (0.80 g, 50% yield, two Steps). 1H NMR (300 MHz, CDCl3): δ 1.33 (d, J=6.03 Hz, 6H), 1.45-1.80 (m, 10H), 1.99-2.05 (m, 2H), 2.34-2.44 (m, 1H), 2.59-2.66 (m, 2H), 4.44-4.52 (m, 1H), 6.78-6.91 (m, 3H).
Reaction SMILES: FC1C=C(C[C@H](NC(=O)CN2C3CCCCC=3C(C(F)(F)F)=N2)C2N(C3C=CC(OC)=CC=3)C=CN=2)C=C(F)C=1.Cl.[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[O:50][C:51]([CH:54]([NH2:64])[CH2:55][C:56]3[CH:61]=[C:60]([F:62])[CH:59]=[C:58]([F:63])[CH:57]=3)=[CH:52][N:53]=2)=[CH:45][CH:44]=1.[CH3:65][O:66][C:67]1[N:72]=[C:71]2[C:73]([CH2:76][C:77](O)=[O:78])=[CH:74][NH:75][C:70]2=[CH:69][CH:68]=1>>[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[O:50][C:51]([CH:54]([NH:64][C:77](=[O:78])[CH2:76][C:73]3[C:71]4=[N:72][C:67]([O:66][CH3:65])=[CH:68][CH:69]=[C:70]4[NH:75][CH:74]=3)[CH2:55][C:56]3[CH:61]=[C:60]([F:62])[CH:59]=[C:58]([F:63])[CH:57]=3)=[CH:52][N:53]=2)=[CH:45][CH:44]=1
Reactant: NC(Cc1cc(F)cc(F)c1)c1cnc(-c2ccc(Cl)cc2)o1
Reactant: COc1ccc2[nH]cc(CC(=O)O)c2n1
Agent: COc1ccc(-n2ccnc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)cc1
Agent: Cl
Product: COc1ccc2[nH]cc(CC(=O)NC(Cc3cc(F)cc(F)c3)c3cnc(-c4ccc(Cl)cc4)o3)c2n1

Procedure:
The title compound (6.0 mg) was prepared according to the method presented for the synthesis of compound 5F of Example 5 utilizing 19E and 2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)acetic acid. 1H NMR (400 MHz, DMSO) δ 11.6 (br, 1H), 8.50 (d, J=8.5 Hz, 1H), 8.40 (s, 1H), 8.01 (s, 1H), 7.89 (d, J=8.5 Hz, 2H), 7.55 (d, J=8.6 Hz, 3H), 7.03 (s, 1H), 6.83 (d, J=7.8 Hz, 3H), 5.08 (d, J=5.3 Hz, 1H), 3.82 (s, 3H), 3.44 (s, 2H), 3.23-3.06 (m, 1H), 3.04-2.91 (m, 1H). MS (m/z) 523.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14].COCC1C=C(C(O)=O)C=CC=1C1C=CC=CC=1C.[OH-].[Na+].O>CCO>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14]
Reactant: COCc1cc(C(=O)OC)ccc1Br
Agent: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COCc1cc(C(=O)O)ccc1Br
Temperature: 60 °C
Yield: 87 %

Procedure:
To a solution of methyl 4-bromo-3-(methoxymethyl)benzoate (Intermediate 28, step 2), (7 g; 27.02 mmol) in EtOH (210 mL) was added NaOH (16.21 mL; 5 M; 81.05 mmol). The resulting reaction mixture was heated at 60° C. for one hour. It was then cooled to RT and concentrated under vacuum to give a yellow solid. Water was added and the aqueous phase was washed with EtOAc. The aqueous phase was then acidified with HCl (1 M) and extracted with EtOAc. Organic phase was dried over MgSO4, filtered and concentrated under vacuum to give the title compound as a yellow solid (5.81 g, 87%). 1H NMR (DMSO-d6, 300 MHz) 13.19 (br s, 1H), 8 (m, 1H), 7.77-7.76 (m, 2H), 4.49 (s, 2H), 3.40 (s, 3H). LC/MS (Method B): 245.0 (M−H)−. HPLC (Method A) Rt 3.63 min (purity: 97.4%).