Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1>C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:17])[C:14]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)=[O:16])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Reactant: Nc1ccc(O)cc1
Solvent: CCOCC
Product: O=C(Nc1ccc(O)cc1)C(=O)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from [4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetic acid (Example 1b) and 4-amino-phenol (Aldrich) according to the method described in Example 1c. Melting Point: 98-100° C. (diethylether)
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][CH3:24])=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:25]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH:38]=O)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>C(Cl)Cl>[C:25]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]/[CH:38]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26]
Reactant: CC(C)(C)OC(=O)NCCCCCC=O
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: COC(=O)/C=C/CCCCCNC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
A solution of 35.28 g (105.5 mmole) methyl (triphenylphosphoranylidene)acetate in 70 mL methylene chloride was added to a solution of 11.36 g (52.76 mmoles) of (7) in 20 mL methylene chloride. After 2 h at room temperature, the solution was concentrated in vacuo to remove most of the solvent and the residue was diluted with ether. The solid was removed by filtration and the filtrate was concentrated and the residue chromatographed (Flash, hexane - ethyl acetate 7:3). The product fraction amounted to 10.7 g of a colorless oil (8).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([Br:17])=[C:15]([Br:18])[S:14][C:13]=2[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=[O:23].OO.S(=O)(O)[O-].[Na+]>ClCCl.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([Br:17])=[C:15]([Br:18])[S:14](=[O:23])[C:13]=2[CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Brc1sc2cc(OCc3ccccc3)ccc2c1Br
Agent: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=S1C(Br)=C(Br)c2ccc(OCc3ccccc3)cc21
Reaction time: 0.17 h
Yield: 62 %

Procedure:
Dissolve 6-benzyloxy-2,3-dibromo-benzo[b]thiophene (20 g, 50 mmol) in dichloromethane (88 mL) and add trifluoroacetic acid (88 mL). Stir for 10 minutes, then add 30% aqueous solution of hydrogen peroxide (5.1 mL, 50 mmol) and stir for 4 hours. Add solid sodium bisulfite (2.2 g, 21 mmol), dilute with water (30 mL), stir for 15 minutes, and then concentrate in vacuo. Partition residue between dichloromethane (150 mL) and saturated aqueous sodium bicarbonate (150 mL), separate layers, wash organic layer with additional saturated aqueous sodium bicarbonate (150 mlT) and brine (100 mL). Dry with sodium sulfate, filter, and concentrate in vacuo; Chromatograph on a SiO2 column eluting with 100% dichloromethane to give 12.8 g of 6-benzyloxy-2,3-dibromo-benzo[b]thiophene 1-oxide (62%).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:15]([OH:19])(=[O:18])[CH:16]=[CH2:17].Cl>C1COCC1>[C:1]1([S:7][CH2:17][CH2:16][C:15]([OH:19])=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: C=CC(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)CCSc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
To a solution of thiophenol (8.87 g, 80.6 mmol) in THF (20 ml) and triethylamine (8.6 g, 11.9 ml, 85 mmol) was added dropwise, with ice cooling, acrylic acid (5.8 g, 5.5 ml, 81 mmol). The reaction mixture was stirred at 0° C. for 1 h and then at RT overnight, acidified with 2N hydrochloric acid and extracted with diethyl ether (2×100 ml). The combined organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. The desired 3-phenylsulfanylpropionic acid product (13.67 g, 93% of theory) was obtained as a white solid (m.p. 51-54° C.)
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[CH:24][C:23]([CH2:26]O)=[CH:22][N:21]4[C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS([Cl:47])(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[CH:24][C:23]([CH2:26][Cl:47])=[CH:22][N:21]4[C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(CO)cn4c3-c3ccccc3)cc2)CCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(CCl)cn4c3-c3ccccc3)cc2)CCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of {1-[4-(6-hydroxymethyl-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (200 mg) in DCM (1.9 mL), was treated with triethylamine (0.062 mL), cooled to 0° C. (ice bath), treated with methanesulfonyl chloride (0.028 mL, 0.358 mmol) and stirred for 2 hours at rt. The reaction mixture was partitioned between DCM and saturated aqueous sodium hydrogen-carbonate solution and the organic phase washed with brine, dried and concentrated in vacuo to give the crude title compound.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:13].O>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][CH3:13])=[CH:4][CH:3]=1
Reactant: OCc1ccc(Br)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In THF (200 ml) was dissolved 4-bromobenzyl alcohol (19.8 g), and to the solution was added under ice-cooling 65% sodium hydride (3.6 g). The mixture was stirred at room temperature for 30 minutes, and to the mixture was added dropwise under ice-cooling iodomethane (8.0 ml). The mixture was stirred at room temperature for 2 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=12/1) to give 1-bromo-4-(methoxymethyl)benzene (14.8 g). In THF (10 ml) was dissolved 1-bromo-4-(methoxymethyl)benzene (12.8 g), and to the mixture was added dropwise at−78° C. 1.6M n-butyllithium/hexane (42.4 ml). The mixture was stirred for 1 hour, and to the mixture was added dropwise a solution of trimethyl borate (19.2 g) in THF (38.4 ml). The mixture was stirred for30 minutes and warmed to room temperature. To the mixture was added 5% sulfuric acid (124 ml), and the mixture was stirred for 15 minutes. The reaction mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was washed with hexane/isopropylether to give 4-(methoxymethyl)phenyl borate (6.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28]([OH:30])=O)[CH:23]=2)=[C:20]2[C:15]([N:16]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:17](=[O:33])[N:18]([CH3:32])[C:19]2=[O:31])=[N:14]1.Cl.[O:39]([NH2:41])[CH3:40].C(P(=O)(OCC)OCC)#N>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28]([NH:41][O:39][CH3:40])=[O:30])[CH:23]=2)=[C:20]2[C:15]([N:16]([CH2:34][CH:35]([CH3:36])[CH3:37])[C:17](=[O:33])[N:18]([CH3:32])[C:19]2=[O:31])=[N:14]1
Reactant: CON
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)O)cn3C)n(Cc3ccnc4ccc(Cl)cc34)nc21
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Product: CONC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC(C)C)c3nn2Cc2ccnc3ccc(Cl)cc23)n(C)c1

Procedure:
This compound was synthesized by the reaction of 5-{2-[(6-chloroquinolin-4-yl)methyl]-7-isobutyl-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carboxylic acid and methoxylamine hydrochloride using diethyl cyanophosphonate as a coupling reagent Mass: 550.13 (M+H).
Reaction SMILES: [CH3:1][S:2]([CH2:4][S:5][CH3:6])=[O:3].C([Li])CCC.CCCCCC.[F:18][C:19]1[CH:26]=[C:25](F)[C:24]([F:28])=[CH:23][C:20]=1[C:21]#[N:22]>C1COCC1>[F:18][C:19]1[CH:26]=[C:25]([CH:4]([S:2]([CH3:1])=[O:3])[S:5][CH3:6])[C:24]([F:28])=[CH:23][C:20]=1[C:21]#[N:22]
Reactant: CSCS(C)=O
Reactant: N#Cc1cc(F)c(F)cc1F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSC(c1cc(F)c(C#N)cc1F)S(C)=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
(Methylsulfinyl)(methylthio)methane (3.16 g, 0.0255 mol) was dissolved in 50 mL of dry THF under argon and then cooled to −78° C. Butyllithium in hexane (16 mL 1.6M, 0.0256 mol) was added dropwise with stirring. The mixture was stirred for 15 min. Meanwhile a solution of 2,4,5-trifluorobenzonitrile (2.0 g; 0.013 mol) in 50 mL of dry THF was cooled to −78° C. under argon and the former solution was added through a cannula to the latter solution over a period of 3-5 min. After 30 min, the cooling bath was removed and when the reaction had reached room temperature it was poured into 200 mL of water. The THF was evaporated and the remaining aqueous layer was extracted three times with diethyl ether. The combined ether phase was washed with water, dried (Na2SO4) and evaporated. The crude product started to crystallise and could be used as such in the next step. Yield: 2.8 g (84%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[Cl:27]C1C=C(C2CCC3C(=CC=C(O)C=3)O2)C=CC=1>>[Cl:27][C:25]1[CH:26]=[C:21]([CH:16]2[CH2:15][CH2:14][C:13]3[C:18](=[CH:19][CH:20]=[C:11]([O:10][C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=4)[CH:12]=3)[O:17]2)[CH:22]=[CH:23][CH:24]=1
Reactant: Oc1ccc2c(c1)CCC(c1cccc(Cl)c1)O2
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2cccc(Cl)c2)O3)nc1

Procedure:
2-[2-(3-Chlorophenyl)chroman-6-yloxy]-5-nitropyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 590 mg of 2-(3-chlorophenyl)chroman-6-ol. The product was recrystallised from a 3:1 mixture of 2-propanol and ethyl acetate. 1H NMR (400 MHz, CDCl3) δ: 9.04 (d, 1H, J 2.9 Hz), 8.60 (dd, 1H, J 9.0, 2.9 Hz), 7.53 (s, 1H), 7.467-7.42 (m, 3H), 7.20 (d, 1H, J 9.0 Hz), 7.00 (dd, 1H, J 8.7, 2.7 Hz), 6.97 (d, 1H, J 2.7 Hz), 6.94 (d, 1H, J 8.7 Hz), 5.18 (dd, 1H, J 10.2, 2.2 Hz), 2.97 (ddd, 1H, J −17.0, 11.5, 5.9 Hz), 2.83 (ddd, 1H, J −17.0, 8.1, 4.5 Hz), 2.21 (m, 1H), 2.00 (m, 1H).
Reaction SMILES: [Na].[NH2:2][C:3]1[C:8]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:17][C:18]([OH:20])=[O:19].[CH3:21]N(C)C=O.CI>O>[NH2:2][C:3]1[C:8]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: CN(C)C=O
Reactant: Nc1c(CC(=O)O)cccc1C(=O)c1ccccc1
Agent: [Na]
Solvent: CI
Solvent: O
Product: COC(=O)Cc1cccc(C(=O)c2ccccc2)c1N
Reaction time: 2 h

Procedure:
A solution of 4.0 g. (0.014 mole) of the sodium salt of 2-amino-3-benzoylphenylacetic acid in 100 ml. of dry dimethylformamide was treated with 8.0 g. (0.057 mole) of methyl iodide. After stirring for two hours the solution was poured into water and the aqueous solution extracted several times with ethyl ether. The combined extracts were washed with water, dried over sodium sulfate and concentrated under vacuum to a yellow oil. The oil was crystallized from a chilled methanol-water solution to give 3.5 gms. (90%) of a yellow solid which melted at 52°-54° C.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.[ClH:15].[O:16]([NH2:18])[CH3:17].C(=O)(O)[O-].[Na+]>C1COCC1.O>[ClH:15].[CH3:17][O:16][N:18]=[C:2]1[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CON
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CON=C1CCNCC1
Reaction time: 0.17 h
Yield: 128.3 %

Procedure:
A solution of tert-butyl 4-oxo-1-piperidinecarboxylate (2.0 g) and methoxylamine hydrochloride (2.93 g) in THF (66 mL) was treated with sodium bicarbonate (2.95 g) dissolved in water (20 mL). The biphasic mixture was stirred vigorously for 10 minutes, diluted with water, and extracted with ethyl acetate (×3). The combined extracts were dried over magnesium sulfate, filtered and concentrated to afford 2.12 g of the title compound, which was used without further purification. 1H NMR (CDCl3, 300 MHz) δ ppm 1.49 (s, 9H), 2.34 (t, 2H, J=6.07 Hz), 2.57 (t, 2H, J=6.07 Hz), 3.51 (t, 2H, J=6.07 Hz), 3.56 (t, 2H, J=6.07 Hz), 3.85 (s, 3H).
Reaction SMILES: [S:1]1[C:5]([CH:6]=O)=[CH:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[C:12](Br)(Br)([Br:14])[Br:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:13][C:12]([Br:14])=[CH:6][C:5]1[S:1][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=Cc1cc2ccccc2s1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrC(Br)=Cc1cc2ccccc2s1
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
A solution of benzo[b]thiophene-2-carbaldehyde (1.0 g, 6.17 mmol) and carbon tetrabromide (3.1 g, 9.25 mmol) in methylene chloride (50 mL) was cooled to 0° C. A solution of triphenylphosphine (4.86 g, 18.3 mmol) in methylene chloride (20 mL) was added dropwise. After ½ hour the solution was placed on a plug of silica gel and eluted with 20% ethyl acetate:hexane. Concentration of the eluent resulted in the isolation of 1.3 g (67%) of 2-(2,2-Dibromo-vinyl)-benzo[b]thiophene as a yellow oil, which was used as such in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=1)[CH2:6][C:5]2([CH3:20])[CH3:19].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([NH:18][S:22]([CH3:21])(=[O:24])=[O:23])[CH:15]=[CH:16][CH:17]=1)[CH2:6][C:5]2([CH3:20])[CH3:19]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(Cl)cc21
Solvent: c1ccncc1
Product: CC1(C)CC(c2cccc(NS(C)(=O)=O)c2)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
3-(6-Chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (150 mg, 0.53 mmol) and methanesulfonyl chloride (60 mg, 0.63 mmol) were dissolved in pyridine (5 ml). The mixture was stirred at room temperature overnight. The solvent was removed and the residue was purified on column chromatography using petroleum ether/ethyl acetate=5:1 as eluent to afford N-[3-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-methanesulfonamide (149 mg, yield: 55%) as yellow solid. MS (ESI+APCI) M+1=445.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]4[CH2:21][O:20]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]([OH:20])[CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]c(-c3ccc(OCC4CO4)cc3)nc2c1
Reactant: C1CCNCC1
Product: OC(COc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1)CN1CCCCC1

Procedure:
The title compound was prepared from 6-bromo-2-[4-(oxiran-2-ylmethoxy)phenyl]-3H-imidazo[4,5-b]pyridine and piperidine.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([O:24][CH2:25][CH:26]([F:28])[F:27])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.C[O-].[Na+].CO.[C:34](OCC)(=[O:36])C>CO.CCCCCC>[F:28][CH:26]([F:27])[CH2:25][O:24][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([O:36][CH3:34])[CH:3]=1)[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:22])([F:21])[F:23])=[CH:15][CH:14]=1)[CH2:7]2
Reactant: O=C1c2c(Cl)cc(OCC(F)F)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Product: COc1cc(OCC(F)F)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 100 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
A mixture of 7-chloro-5-(2,2-Difluoro-ethoxy)-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.057 g, 0.14 mmol), and 30% sodium methoxide-methanol (0.12 mL) in methanol (4 mL) was stirred at 100° C. for 1 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-(2,2-Difluoro-ethoxy)-7-methoxy-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.030 g, 51%). 1H NMR (300 MHz, CDCl3): δ (ppm) 3.96 (s, 3H), 4.22 (m, 4H), 4.73 (s, 2H), 5.94-6.32 (m, 1H), 6.45 (d, 2H), 7.17 (d, 2H), 7.35 (d, 2H). GC-MS: m/z 417 (M)+, 399 (M−18)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([OH:17])=[CH:9][CH:8]=1)[CH3:2].[CH3:19][C:20]1[C:25]([CH2:26][CH2:27]O)=[CH:24][CH:23]=[C:22]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[N:21]=1>>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([O:17][CH2:27][CH2:26][C:25]2[C:20]([CH3:19])=[N:21][C:22]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:31][CH:30]=3)=[CH:23][CH:24]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CCc1ccc(O)c2c1CCCC2
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCO
Product: CCOC(=O)CCc1ccc(OCCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c2c1CCCC2

Procedure:
In analogy to the procedures described in example 4D] and 4E], 3-(4-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid ethyl ester (example 5B]) was reacted with 2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethanol (example 4K]) to give 3-(4-{2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:11])[C:9]=1[OH:10])[CH:5]=O.[NH2:12][C@@H:13]([C:18]([OH:20])=[O:19])[C:14]([SH:17])([CH3:16])[CH3:15]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[NH:12][C@@H:13]([C:18]([OH:20])=[O:19])[C:14]([CH3:16])([CH3:15])[S:17]2)[CH:7]=[C:8]([Br:11])[C:9]=1[OH:10]
Reactant: O=Cc1cc(Br)c(O)c(Br)c1
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Solvent: CO
Product: CC1(C)SC(c2cc(Br)c(O)c(Br)c2)N[C@H]1C(=O)O
Reaction time: 16 h
Yield: 82.3 %

Procedure:
A solution containing 5.6 g (20 mmoles) of 3,5-dibromo-4-hydroxybenzaldehyde and 3 g (20 mmoles) of D-penicillamine in 100 ml of 30% methanol is stirred for 16 hours. The precipitated product is filtered and washed with aqueous methanol to give 6.77 g (82.3%) of the title acid which can be recrystallized from a mixture containing ethanol, dimethylformamide and water, m.p.: 154°-155° C., [α]D25 =+87° (c=1.362, dimethylsulphoxide).
Reaction SMILES: O1CCCCC1[O:7][C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:11]=[CH:12][C:13]=1[O:14]C1CCCCO1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(N(CC)CC)C>[OH:7][C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:11]=[CH:12][C:13]=1[OH:14]
Reactant: CCCCC=Cc1ccc(OC2CCCCO2)c(OC2CCCCO2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCCC=Cc1ccc(O)c(O)c1
Reaction time: 2 h
Yield: 57.8 %

Procedure:
In 10 ml of absolute methanol was dissolved 198 mg of 1-(3',4'-bistetrahydropyranyloxy-phenyl)-1-hexene obtained in Example 17-(1), and a catalytic amount of p-toluenesulfonic acid was added to the solution at 0° C. The mixture was stirred for 2 hours at the same temperature. After reaction, one drop of triethylamine was added to the reaction mixture and the mixture was concentrated to give crude product. By purification of the crude product by means of column chromatography [silica gel/ether:hexane (1:2)], 61 mg of pure product was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[N+:9]([O-:11])=[O:10].[H-].[Na+].[CH3:14][O:15][CH:16]1[CH2:21][CH2:20][CH:19]([CH2:22]Br)[CH2:18][CH2:17]1>CN(C=O)C.O>[N+:9]([C:3]1[C:4](=[O:8])[N:5]([CH2:22][C@H:19]2[CH2:20][CH2:21][C@@H:16]([O:15][CH3:14])[CH2:17][CH2:18]2)[CH:6]=[CH:7][C:2]=1[CH3:1])([O-:11])=[O:10]
Reactant: Cc1cc[nH]c(=O)c1[N+](=O)[O-]
Reactant: COC1CCC(CBr)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CO[C@H]1CC[C@@H](Cn2ccc(C)c([N+](=O)[O-])c2=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-methyl-3-nitro-2-pyridone (0.93 g, 6.0 mmol) and sodium hydride (60% in oil, 0.25 g, 6.3 mmol) in DMF (20 mL) was stirred at rt for 1 hour. 4-Methoxycyclohexylmethylbromide (1.5 g, 7.2 mmol) in DMF (5 mL) was added. After 60 hours, the mixture was diluted with water, and extracted with ethyl acetate. The organic phase was washed, dried (MgSO4), and evaporated. Chromatography of the residue over silica gel (ethyl acetate/hexane 1/1 to 3/1) gave cis-3-nitro-1-(4-methoxycyclohexylmethyl)-4-methyl-2-pyridone which crystallized from ethyl acetate/hexane (0.16 g, 10%) and trans-3-nitro-1-(4-methoxycyclohexylmethyl)-4-methyl-2-pyridone which crystallized from ethyl acetate/hexane (0.18 g, 11%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].CC(N(C)C)=O.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH:26]=O.OS([O-])=O.[Na+]>O>[CH3:14][O:13][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][C:9]=1[O:11][CH3:12])[N:1]=[C:26]([C:25]1[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:23]([O:22][CH3:21])[CH:24]=1)[N:6]=[C:4]2[OH:5]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: COc1cc(N)c(C(N)=O)cc1OC
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc2nc(-c3cc(OC)c(OC)c(OC)c3)nc(O)c2cc1OC
Temperature: 139 °C
Reaction time: 8 h

Procedure:
Into a 500-mL 3-necked round-bottom flask, was placed 2-amino-4,5-dimethoxybenzamide (12 g, 61.16 mmol, 1.00 equiv), dimethylacetamide (200 mL), 3,4,5-trimethoxybenzaldehyde (12 g, 61.16 mmol, 1.00 equiv) and NaHSO3 (9.55 g, 91.83 mmol, 1.50 equiv). The resulting solution was stirred overnight at 139° C. The mixture was cooled to room temperature. The resulting solution was diluted with 800 mL of water. The solids were collected by filtration. The filter cake was washed with 1×100 ml of water, 100 ml of diethyl ether and 100 mL of methanol. This resulted in 12 g (53%) of 6,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)quinazolin-4-ol as a brown solid. MS (ESI) m/z 373 [M+h]+