Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]([CH2:7][O:8]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:4][C:3]1=[O:19].[CH2:20]([C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[O-])[CH3:21].[K+]>>[CH3:1][N:2]1[CH2:6][CH:5]([CH2:7][O:8][C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[CH2:20][CH3:21])[CH2:4][C:3]1=[O:19]
Reactant: Cc1ccc(S(=O)(=O)OCC2CC(=O)N(C)C2)cc1
Reactant: CCc1ccccc1[O-]
Agent: [K+]
Product: CCc1ccccc1OCC1CC(=O)N(C)C1

Procedure:
The compound is prepared from 1-methyl-4-tosyloxymethyl-pyrrolidin-2-one described in Example 17, and potassium 2-ethyl-phenoxide, as described in Example 17. B.p.(0.3 mm Hg)=186° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]=[CH:8]2)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][N:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]=[CH:8]2
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cnn2cnc3ccccc3c12
Agent: [Pd]
Solvent: CCO
Product: Nc1cnn2cnc3ccccc3c12
Yield: 79.8 %

Procedure:
21.4 g (0.1 mole) of 1-nitropyrazolo[1,5-c]quinazoline are treated with hydrogen in ethanol and in the presence of palladium/carbon at room temperature and atmospheric pressure. When the hydrogen consumption ceases, the solution is filtered and evaporated. 14.7 g (80%) of 1-aminopyrazolo[1,5-c]quinazoline are obtained. M.p.: 168°-170° C.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:19]([CH2:27][CH:28]([CH3:55])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[C:41]([S:42]([NH:45][C:46]3[C:51]([O:52][CH3:53])=[N:50][C:49]([CH3:54])=[CH:48][N:47]=3)(=[O:44])=[O:43])=[CH:40][CH:39]=[CH:38][N:37]=2)=[CH:32][CH:31]=1)[Si](C(C)(C)C)(C)C>C1COCC1.O>[OH:19][CH2:27][CH:28]([CH3:55])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[C:41]([S:42]([NH:45][C:46]3[C:51]([O:52][CH3:53])=[N:50][C:49]([CH3:54])=[CH:48][N:47]=3)(=[O:44])=[O:43])=[CH:40][CH:39]=[CH:38][N:37]=2)=[CH:32][CH:31]=1
Reactant: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(CC(C)CO[Si](C)(C)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(CC(C)CO)cc1
Reaction time: 0.75 h
Yield: 80.5 %

Procedure:
Tetrabutylammonium fluoride (0.4 ml of a 1.0M solution in THF) was added to a solution of 2-[4-(2-((tert-butyldimethylsiloxy)methyl)propyl)phenyl]-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (118 mg) in THF (5 ml) at ambient temperature. More tetrabutylammonium fluoride solution was added after 0.25 hour (0.4 ml), after 0.75 hour (1.0 ml) and finally after 1.5 hours (0.2 ml). The reaction mixture was stirred for a further 0.5 hour, diluted with water (10 ml) and the reaction mixture was extracted with dichloromethane (4×10 ml). The combined organic extracts were dried over MgSO4 and evaporated to give an amber oil. This was purified by gradient elution with 0-50% methanol/dichloromethane through a silica gel Mega Bond Elut column to give 2-[4-(3-hydroxy-2-methylpropyl)phenyl]-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (75 mg) as a white crystalline solid, m.p.118°-119° C.; 1H NMR (DMSO-d6): 0.95 (d, 3 H), 1.35 (m, 1 H), 2.0 (m, 1 H), 2.3 (s, 3 H), 2.5 (m, 1 H), 2.9 (m, 1 H), 3.5 (m, 2 H), 3.8 (s, 3 H), 6.65 (s, 1 H), 7.2 (m, 4 H), 7.35 (s, 1 H), 7.5 (m, 1 H), 8.7 (d, 1 H), 8.8 (dd, 1 H); mass spectrum (+ve ESP): 429 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:17]([O:19]CC)=[O:18])=[CH:8][N:9]2[C@@H:13]2[CH2:15][C@@H:14]2[F:16])=[CH:4][CH:3]=1.Cl>C(O)(=O)C>[F:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:17]([OH:19])=[O:18])=[CH:8][N:9]2[C@@H:13]2[CH2:15][C@@H:14]2[F:16])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(C)c(F)ccc2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: Cc1c(F)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 0 °C
Yield: 92.7 %

Procedure:
Ethyl 7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylate (1.40 g, 4.56 mmol) was dissolved in acetic acid (4 ml), and after adding concentrated hydrochloric acid (4 ml) thereto, it was heated under reflux for 3 hours. After cooling, the reaction solution was poured into ice water (50 ml) and the precipitated crystals were filtered out. After washing the filtered-out crystals with an excess amount of water, washing in cold ethanol and washing in diethyl ether were performed in that order, and after drying under a reduced pressure, 1.18 g (93%) of the title compound was obtained in the form of a white powder.
Reaction SMILES: C(OC([NH:8][C@H:9]([CH:13]=[CH:14][CH2:15][CH2:16][CH2:17][P:18]([O:24]C(C)C)([O:20]C(C)C)=[O:19])[C:10]([OH:12])=[O:11])=O)(C)(C)C.C[Si](C)(C)Br>ClCCl>[NH2:8][C@H:9]([CH:13]=[CH:14][CH2:15][CH2:16][CH2:17][P:18]([OH:24])([OH:20])=[O:19])[C:10]([OH:12])=[O:11]
Reactant: CC(C)OP(=O)(CCCC=C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)OC(C)C
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: N[C@H](C=CCCCP(=O)(O)O)C(=O)O
Temperature: 25 °C
Reaction time: 30 h
Yield: 95 %

Procedure:
A solution of 3.1 g of acid 7 and 3 ml of N,O-bis-trimethylsilylacetamide in 200 ml of dry dichloromethane is stirred at room temperature for one hour. 3.5 ml of trimethylbromosilane are added, and the mixture is stirred at room temperature for 30 hours. The volatile portions are evaporated off, the residue is taken up in 50 ml of dichloromethane, and 250 ml of water are added at 0°-2°. The aqueous phase is separated off and concentrated to 10 ml under a high vacuum. Chromatography on 20 ml of Dowex® 50 W×8 using water as eluant, and lyophilisation of the eluate yield 1.04 g of 8 H2O); 13C-NMR (75 MHz, D2O): 172.8 (CO2H); 140.3 (C(4)); 122.2 (C(3)); 56.4 (C(2)); 33.3 (d, J=17, C(5)); 27.3 (d, J=134, C(7 )); 22.6 (d, J=4, C(6)). In order to analyse the purity of the enantiomer, a sample is derivatised to the amide trimethyl ester with (R)-(+)-methoxytrifluoromethylphenylacetic acid chloride followed by diazomethane. 1H-NMR analysis (300 MHz) by integration of the OCH: signals gives ≥95% (2R)-isomer (3.54 ppm) and ≤5% (2S)-isomer (3.37 ppm).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:20](=[O:26])[CH:21](OCC)O)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.Cl[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]([NH2:38])([CH3:37])[CH3:36])=[C:30]([C:39]([F:42])([F:41])[F:40])[CH:29]=1.FC(F)(F)C([O-])=O>>[CH3:37][C:35]([NH:38][CH2:21][CH:20]([C:11]1[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=[C:9]([OH:8])[CH:10]=1)[OH:26])([CH3:36])[CH2:34][C:31]1[CH:32]=[CH:33][CH:28]=[CH:29][C:30]=1[C:39]([F:40])([F:41])[F:42]
Reactant: CCOC(O)C(=O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Reactant: CC(C)(N)Cc1ccc(Cl)cc1C(F)(F)F
Agent: O=C([O-])C(F)(F)F
Product: CC(C)(Cc1ccccc1C(F)(F)F)NCC(O)c1cc(O)cc2c1OCC(=O)N2

Procedure:
357 mg (1 mmol) 6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 252 mg (1 mmol) 2-(4-chloro-2-trifluoromethyl-phenyl)-1,1-dimethyl-ethylamine are reacted and worked up analogously to the method described for Example 2c). White solid. Yield: 165 mg (31%, trifluoroacetate); mass spectroscopy [M+H]+=425.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.[Br-].[CH2:10]([O:12][C:13](=[O:17])[CH2:14][CH2:15][Zn+])[CH3:11].[Cl-].[NH4+].C(=O)(O)[O-].[Na+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[N:3]=[CH:4][C:5]([CH2:15][CH2:14][C:13]([O:12][CH2:10][CH3:11])=[O:17])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC[Zn+]
Reactant: Brc1cc(I)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(Br)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Palladium tetrakis (1.64 g, 1.41 mmol) was added to a solution of 2-bromo-4-iodopyridine (4.00 g, 14.1 mmol) in THF (28.2 ml) under an argon atmosphere. The mixture was cooled to 0° C., 3-ethoxy-3-oxopropylzinc bromide (36.6 mL, 18.3 mmol) was slowly added to the reaction mixture and stirred for 1 hour. The mixture was then allowed to warm to room temperature overnight. An aqueous ammonium chloride was added to the reaction mixture and stirred for 5 minutes. pH was then adjusted to ˜8 with aqueous sodium bicarbonate and product was extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/hexanes) to afford ethyl 3-(6-bromopyridin-3-yl)propanoate. MS ESI calc'd for C10H13BrNO2 [M+H]+ 258 and 260. found 258 and 260.
Reaction SMILES: C(O)C.Cl[C:5]1[S:6][C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([C:10]([F:13])([F:12])[F:11])[N:9]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>O>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:19][C:5]1[S:6][C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([C:10]([F:13])([F:12])[F:11])[N:9]=1
Reactant: CCOC(=O)c1sc(Cl)nc1C(F)(F)F
Reactant: Nc1ccccn1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1sc(Nc2ccccn2)nc1C(F)(F)F
Temperature: 80 °C
Yield: 24.6 %

Procedure:
A reaction vessel was charged with 100 ml ethanol, 13.0 g (50 mmol) ethyl 2-chloro-4-trifluoromethyl-5-thiazolecarboxylate and 9.41 g (100 mmol) 2-aminopyridine. The reaction mixture was heated at a temperature of about 80° C. for 80 hours. The mixture was cooled to room temperature. This mixture was diluted with water and extracted three times with ethyl ether. The combined ether extracts were washed with large amounts of water, dried over magnesium sulfate, and concentrated under reduced pressure to give 19.1 g of a brown, wet, solid material. This material was recrystallized from a 1:1 ethanol:water solution over a 36-hour period. The recrystallized material was suction filtered to give 3.9 g of a dark brown solid material which was triturated in warm hexane to give 2.3 g of brown solid product (m.p. 07°-111° C.) identified in Table I.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[C:10]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]([C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=3)[N:19]=2)[N:3]=1.N1C=CC=CC=1.[CH3:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>C(Cl)Cl>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([S:14]([N:44]3[CH2:45][CH2:46][N:41]([CH3:40])[CH2:42][CH2:43]3)(=[O:16])=[O:15])[CH:9]=2)[N:5]=[C:4]([C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][C:30]([F:31])([F:32])[F:33])=[CH:27][CH:28]=3)[N:19]=2)[N:3]=1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CN1CCNCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(S(=O)(=O)N2CCN(C)CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)benzene-1-sulfonyl chloride (50 mg, 0.1 mmol) in DCM (5 mL) were added pyridine (0.05 ml) and 1-methylpiperazine (20 mg, 0.2 mmol). The mixture was stirred at RT for 1 h, then diluted with DCM and washed with H2O (100 mL). The aqueous layer was separated and extracted with DCM (2×100 mL), the combined organic layers were washed with brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by prep-HPLC (Mobile phase: A=0.1% formic acid/H2O, B=MeCN; Gradient: B=36%-95% in 18 min; Column: XBridge C18, 5 um, 30 mm×150 mm) to give the title compound as a white solid; MS (ES+) C21H19F3N6O4S requires: 508. found: 509 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ ppm 8.28 (d, J=8 Hz, 2H), 7.86 (bs, 1H), 7.84 (m, 1H), 7.64 (m, 2H), 7.50 (d, J=7.5 Hz, 2H), 5.67 (s, 2H), 3.98 (m, 2H), 3.61 (m, 2H), 3.26 (m, 2H), 2.90 (s, 3H), 2.74 (m, 2H), 2.69 (s, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:24]=[CH:25][C:26]=1[CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:12]=1)=[O:9].C(N(CC)CC)C.[NH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.C(N(C(C)C)C(C)C)C>ClCCl.C(#N)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8](=[O:9])[C:7]2[CH:24]=[CH:25][C:26]([CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])=[C:5]([O:4][CH2:3][CH2:2][N:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)[CH:6]=2)=[CH:12][C:13]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: C1CCNCC1
Reactant: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1OCCBr
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClCCl
Product: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1OCCN1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.9 %

Procedure:
3-(2-Bromoethoxy)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide (50 mg, 0.095 mmol) was dissolved in dichloromethane (1.0 ml), treated with triethylamine (20 μl, 0.15 mmol) and piperidine (11 μl, 0.11 mmol), and stirred 2.0 hours at room temperature. Acetonitrile (0.25 ml) and N-ethyl-N-isopropylpropan-2-amine (25 μl, 0.19 mmol) were added, and the reaction was stirred for an additional 45 hours. The reaction was quenched in water and extracted with dichloromethane twice. The dichloromethane extracts were washed with water once, brine once, dried with MgSO4, and evaporated to an solid which was purified by reverse phase HPLC to yield 17 mg N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)-3-(2-(piperidin-1-yl)ethoxy)benzamide. MS (Q1) 528 (M)+.
Reaction SMILES: [C:1]1(=O)[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1.[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22]>O.OP(O)(O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O>[OH:22][C:17]1[CH:18]=[CH:19][C:20]([C:13]2([C:1]3[CH:2]=[CH:3][C:17]([OH:22])=[C:16]([CH3:21])[CH:15]=3)[C:5]3[CH:4]=[CH:9][CH:8]=[CH:7][C:6]=3[C:11]3[C:12]2=[CH:18][CH:19]=[CH:20][CH:10]=3)=[CH:21][C:16]=1[CH3:15]
Reactant: Cc1ccccc1O
Reactant: O=C1C=CC=C2C1=Cc1ccccc12
Agent: O=[W](=O)=O
Agent: O=P(O)(O)O
Solvent: O
Product: Cc1cc(C2(c3ccc(O)c(C)c3)c3ccccc3-c3ccccc32)ccc1O
Temperature: 80 °C
Yield: 83.4 %

Procedure:
A reaction was carried out by (a) feeding 23 g of fluorenone, 0.57 g of tungstophosphoric acid, and 161 g of 2-methyl phenol into a 500 ml glass reactor vessel equipped with a stirrer, a condenser and a thermometer, and (b) stirring a mixture under a reduced pressure of 1.3×103 Pa at 70° C. for 4 hours while removing generated water out of the system. The amount of remaining fluorenone was determined by HPLC, and found to be 0.1% or less. To an obtained reaction mixture liquid, 0.6 g of 29% sodium hydroxide aqueous solution was added, and 103.5 g of 2-methyl phenol was recovered from an organic phase by concentration under reduced pressure. To a concentrated liquid, 161 g of toluene and 46 g of water were added, and the mixture liquid was stirred at 80° C. Thereafter, an aqueous phase was separated and removed, and a target substance partitioned in an organic phase was recovered. The organic phase was further washed twice with 46 g of water, and cooled to 10° C. Then, precipitated crystals were subjected to filtration and drying to obtain 40.3 g of 9,9-bis(4-hydroxy-3-methylphenyl)fluorene (yield: 83.5%, LC purity: 99.3%). Obtained 9,9-bis(4-hydroxy-3-methylphenyl)fluorene was dissolved by heat at 230° C. for 2 hours. The 9,9-bis(4-hydroxy-3-methylphenyl)fluorene thus dissolved show a hue of 1 or less in Gardner. The total amount of toluene used was 4 parts by weight relative to 1 part by weight of the 9,9-bis(4-hydroxy-3-methylphenyl)fluorene.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:8]2[O:13][CH:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][C:10](=[O:19])[C:9]=2[CH:20]=1)([CH3:4])([CH3:3])[CH3:2].[Se](=O)=O>CCOCC>[C:1]([C:5]1[CH:6]=[C:7]([C:21]([CH3:22])([CH3:24])[CH3:23])[C:8]2[O:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][C:10](=[O:19])[C:9]=2[CH:20]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CC(=O)c2cc(C(C)(C)C)cc(C(C)(C)C)c2O1
Agent: O=[Se]=O
Solvent: CCOCC
Product: CCOC(=O)c1cc(=O)c2cc(C(C)(C)C)cc(C(C)(C)C)c2o1

Procedure:
A mixture of 3.32 parts of 6,8-di-t-butyl-2,3-dihydro-4-oxo-4H-1-benzopyran-2-carboxylic acid, ethyl ester and 3.33 parts of selenium dioxide was refluxed in 35 parts of xlene for eight hours. The reaction mixture was cooled, ether was added and the insoluble inorganic products were removed by filtration. Evaporation of the volatile components of the filtrate gave abrown residue which crystallised from light petroleum (b.p. 40°-60° C) to give 1.54 parts of 6,8-di-t-butyl-4-oxo-4H-1-benzopyran-2-carboxylic acid, ethyl ester, m.p. 130°-131.5° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:12][N:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14](Cl)=[O:15]>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:14](=[O:15])[N:13]([CH3:12])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccc(S(C)(=O)=O)cc1)c1ccccc1

Procedure:
The title product was prepared from 4-methylsulfonylphenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (50%, white solid). HPLC-MS: m/z=306.1 (M+1); Rt: 3.22 min.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C[O:16][C:17](=[O:30])[CH2:18][C:19]1[C:23]2[CH:24]=[CH:25][C:26]([OH:29])=[C:27]([CH3:28])[C:22]=2[O:21][CH:20]=1>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:29][C:26]3[CH:25]=[CH:24][C:23]4[C:19]([CH2:18][C:17]([OH:30])=[O:16])=[CH:20][O:21][C:22]=4[C:27]=3[CH3:28])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: ClCc1cccnc1SC1CCCC1
Reactant: COC(=O)Cc1coc2c(C)c(O)ccc12
Product: Cc1c(OCc2cccnc2SC2CCCC2)ccc2c(CC(=O)O)coc12
Yield: 83.9 %

Procedure:
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (21 mg, 0.09 mmol) obtained in Step C of Preparation Example 8 and (6-hydroxy-7-methyl-benzofuran-3-yl)-acetic acid methyl ester (21 mg, 0.09 mmol) obtained in Preparation Example 54 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (30 mg, 83%).
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[C:14]([CH:18]3OCC[O:19]3)[CH:15]=[CH:16][CH:17]=2)=[CH:6][CH:5]=1.C1COCC1.Cl>O>[F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=2)[CH:18]=[O:19])=[CH:6][CH:5]=1
Reactant: FC(F)Oc1ccc(C#Cc2cccc(C3OCCO3)c2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cccc(C#Cc2ccc(OC(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 432.5 %

Procedure:
Into a mixture of 2-(3-{[4-(difluoromethoxy)phenyl]ethynyl}phenyl)-1,3-dioxolane, (1.0 g, 3.1 mmol) and THF (5 mL) was added HCl (2N, 1 mL). The mixture was stirred at room temperature for 2 hours, poured into water and extracted with EtOAc/ethyl ether 1/1. The organic extracts were dried over MgSO4. Evaporation and purification on silica gel (ISCO) using hexanes/EtOAc (3/1) as the eluting solvents gave 3-{[4-(difluoromethoxy)phenyl]ethynyl}benzaldehyde as a yellow oil (3.65 g, 95% yield), MS m/e M+ 272; 1H NMR (400 MHz, DMSO-d6) 3.9-4.05 (m, 4H), 5.72 (s, 1H), 7.1-7.3 (m, 4H), 7.62 (m, 2H), 7.8-7.9 (m, 2H), 8.03 (s, 1H), 9.99 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[C:11](O)(=[O:15])[C:12]([CH3:14])=[CH2:13]>>[CH3:13][CH:12]1[CH2:14][C:3]2[C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]=2[NH:1][C:11]1=[O:15]
Reactant: C=C(C)C(=O)O
Reactant: CC1(C)CC(=O)C=C(N)C1
Product: CC1CC2=C(CC(C)(C)CC2=O)NC1=O

Procedure:
Prepared analogously to Example G from 1-amino- 5,5-dimethylcyclohexen-3-one and methacrylic acid in an autoclave at 180° C. over a period of one hour.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:14])[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]([O:25][CH3:26])=[O:24]>CC(C)=O>[C:1]([NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1Cc2ccc(O)cc2C1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc2c(c1)CC(NC(C)=O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
1.05 g of 2-acetylamino-5-hydroxyindan are dissolved in 15 ml of acetone, and 1.14 g of powdered potassium carbonate and 1.01 g of methyl bromoacetate are added to the solution. The mixture is stirred overnight at room temperature and the reaction mixture is evaporated to remove solvent. The residue is extracted with ethyl acetate and the extract is washed successively with water and an aqueous sodium chloride solution, dried and evaporated to remove solvent. The residue is recrystallized from ethyl acetate-isopropyl ether-n-hexane to give 1.243 g of methyl (2-acetylaminoindan-5-yl)oxyacetate as colorless prisms. Yield: 86%
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5]Cl.[CH2:11]([NH:18][CH2:19][CH2:20][OH:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH2:11]([N:18]([CH2:19][CH2:20][OH:21])[CH2:5][C:4]1[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: OCCNCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCN(Cc1ccccc1)Cc1ccc(Cl)c(Cl)c1
Yield: 57.5 %

Procedure:
To a solution of 13 g of 3,4-dichlorobenzyl chloride and 9.15 g of N-benzylethanolamine in 150 ml of dimethylformamide (DMF), 9 g of anhydrous potassium carbonate was added and the mixture was vigorously stirred. After stirring for 24 hours, the reaction mixture was acidified by adding 10% HCl and extracted with isopropyl ether. The aqueous phase was made basic with 10% sodium hydroxide solution and extracted with isopropyl ether. The extract was dried and the solvent was evaporated to produce the object compound (10.8 g, yield 57%).