Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:15][O:16][CH2:17][C:18](Cl)=O>>[CH3:15][O:16][CH2:17][C:18]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([F:12])([F:13])[F:14])[C:2]=2[N:1]=1
Reactant: Nc1c(C(=O)O)cccc1C(F)(F)F
Reactant: COCC(=O)Cl
Product: COCc1nc2c(C(F)(F)F)cccc2c(=O)o1
Temperature: 140 °C
Reaction time: 0.29 h
Yield: 60.2 %

Procedure:
A mixture of 7.1 g of 2-amino-3-trifluoromethylbenzoic acid [prepared by the process of J. Med. Chem., Vol. 16 (2) (1973), p. 101-106] and 10 g of methoxy acetic acid chloride was progressively heated and at 35° to 40° C., a very important disengagement of gas occurred for 15 to 20 minutes and at 120° C. a brown solution was formed and gas disengagement slackened but continued. The temperature was maintained at 140° C. for one hour during which gas formation practically ceased. The mixture was cooled to room temperature and excess acid chloride was distilled under reduced pressure. The residue was taken up in 70 ml of water and the mixture was vacuum filtered. The product was washed with water and was dissolved in methylene chloride. The organic phase was dried and filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and eluted with methylene chloride to obtain 5.4 g of 2-methoxymethyl-8-trifluoromethyl-4-H-3,1-benzoxazine-4-one melting at 104° to 106° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]2[C:6](=[CH:7][C:8]([CH2:19][OH:20])=[CH:9][CH:10]=2)[N:5]=1.Cl.Cl[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>>[CH3:3][C:4]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]2[C:6](=[CH:7][C:8]([CH2:19][O:20][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1cc(N2CCCC2)c2ccc(CO)cc2n1
Reactant: Clc1ccncc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(N2CCCC2)c2ccc(COc3ccncc3)cc2n1
Temperature: 90 °C
Reaction time: 24 h
Yield: 24.4 %

Procedure:
Sodium hydride (55–65% dispersion in mineral oil, 40 mg, 1.0 mmol) was added to a mixture of (2-methyl-4-pyrrolidin-1-yl-quinolin-7-yl)-methanol (example 2, 100 mg, 0.41 mmol) and 4-chloropyridine hydrochloride (62 mg, 0.41 mmol), and the mixture was heated at 90° C. for 18 h. Then another portion of sodium hydride (40 mg) and 4-chloropyridine hydrochloride (62 mg) was added, and stirring at 90° C. was continued for 24 h. After cooling, the reaction mixture was partitioned between 1 M aq. sodium carbonate solution and ethyl acetate. The organic layer was separated, washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, dichloromethane/methanol 9:1) afforded the title compound (32 mg, 24%). Yellow solid, ISP-MS: m/e=320.4 ([M+H]+).
Reaction SMILES: C1(C=CC=C(O)C=1)O.C(C1C=C(C=CC=1)C(O)(C)C)(C)C.C(C1C=C(C=CC=1)C(O)(C)C)(=O)C.[C:35]([C:38]1[CH:39]=[C:40]([OH:44])[CH:41]=[CH:42][CH:43]=1)([CH3:37])=[CH2:36].C(C1C=C(C(=O)C)C=CC=1)(C)=C.C(C1C=C(C(C)C)C=CC=1)(C)=C>CC(C)=O>[CH:35]([C:38]1[CH:39]=[C:40]([OH:44])[CH:41]=[CH:42][CH:43]=1)([CH3:37])[CH3:36]
Reactant: C=C(C)c1cccc(O)c1
Agent: C=C(C)c1cccc(C(C)=O)c1
Agent: C=C(C)c1cccc(C(C)C)c1
Agent: CC(=O)c1cccc(C(C)(C)O)c1
Solvent: CC(C)=O
Product: CC(C)c1cccc(O)c1

Procedure:
The reaction mixture formed by the acid-decomposition contains not only resorcin, acetone and the inert solvent used but also various by-products, for example, carbinols such as m-isopropyl-α,α-dimethylbenzyl alcohol, m-acetyl-α,α-dimethylbenzyl alcohol and m-hydroxy-α,α-dimethylbenzyl alcohol, olefins such as m-isopropenylphenol, m-isopropenylacetophenone and m-isopropenylcumene, peroxides which are estimated to have been formed by condensation reaction between carbinols or olefins and hydroperoxides, m-isopropylphenol, m-hydroxyacetophenone, and high-boiling-point condensates.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH3:22])=[C:11]([C:18]([F:21])([F:20])[F:19])[C:12]=2[C:13](OCC)=[O:14])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([CH3:22])=[C:11]([C:18]([F:21])([F:19])[F:20])[C:12]=2[CH2:13][OH:14])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)sc(C)c1C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1sc(-c2ccc(Cl)cc2)c(CO)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 100-mL round-bottom flask, was placed ethyl 2-(4-chlorophenyl)-5-methyl-4-(trifluoromethyl)thiophene-3-carboxylate (200 mg, 0.57 mmol, 1.00 equiv), tetrahydrofuran (20 mL). This was followed by the addition of LAH (44 mg, 1.16 mmol, 2.02 equiv) in several batches at 0° C. The resulting solution was stirred for 2 h at 25° C. The reaction was then quenched by the addition of 1 g of Na2SO4.10H2O. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/5). The collected fractions were combined and concentrated under vacuum. This resulted in 80 mg (43%) of (5-methyl-2-phenyl-4-(trifluoromethyl)thiophen-3-yl)methanol as light yellow oil.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[SH:11].[Cl:12][C:13]1[N:20]=[C:19](Cl)[CH:18]=[CH:17][C:14]=1[C:15]#[N:16].Cl>C(O)C.O>[Cl:12][C:13]1[N:20]=[C:19]([S:11][C:5]2[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:4]=2[F:3])[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: Fc1ccc(S)c(F)c1
Reactant: N#Cc1ccc(Cl)nc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(Sc2ccc(F)cc2F)nc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.7 %

Procedure:
A solution of 362 mg (1.05 eq) of potassium hydroxide in 10 mL of ethanol is added, under nitrogen, to a solution of 698 μL (6.16 mmol) of 2,4-difluorobenzenethiol in 30 mL of ethanol. The reaction medium is stirred at room temperature for 15 minutes and then cooled in ice before adding a solution of 1.015 g (0.95 eq) of 2,6-dichloronicotinonitrile in 30 mL of ethanol. The reaction medium is stirred for 2 hours at 0-5° C. 63 mL of a 0.1N HCl solution is added to stop the reaction. Water is added and the producted is extracted with ethyl acetate. The organic phase is dried on anhydrous magnesium sulfate, filtered and evaporated. The residue is purified by silica gel chromatography (eluent: cyclohexane/ethyl acetate 94:6) to yield 1.09 g (66%) of 2-chloro-6-(2,4-difluorophenylthio)-nicotinonitrile in the form of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Mg].C(O[CH2:21][C:22]([F:34])=[CH:23][C:24]1([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:26][CH2:25]1)(=O)C>O1CCCC1>[F:34][C:22]([CH2:21][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]=1)=[CH:23][C:24]1([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[CH2:25][CH2:26]1
Reactant: Fc1ccc(Br)cc1Oc1ccccc1
Reactant: CC(=O)OCC(F)=CC1(c2ccc(F)cc2)CC1
Agent: [Mg]
Solvent: C1CCOC1
Product: FC(=CC1(c2ccc(F)cc2)CC1)Cc1ccc(F)c(Oc2ccccc2)c1
Yield: 34.4 %

Procedure:
The method of Example 25 was repeated using a Grignard reagent, prepared from 4-fluoro-3-phenoxyphenyl bromide (0.3 g), tetrahydrofuran (2 ml) and magnesium (21 mg) and 1-(3-acetoxy-2-fluoroprop-1-enyl)-1-(4-fluorophenyl)-cyclopropane (Example 20) (88 mg). The residue after evaporation was purified by preparative thin layer chromatography (solvent: diethyl ether/hexane; 1:9) and then preparative high performance liquid chromatography (column: C18; solvent: methanol; flow rate: 2 ml/min) to afford 1-(2-fluoro-3-(4-fluoro-3-phenoxy-phenyl)prop-1-enyl)-1-(4-fluorophenyl)cyclopropane (45.6 mg, 37%).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SC)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[N:31]1([C:37](=[O:39])[CH3:38])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[C:37]([N:31]1[CH2:36][CH2:35][N:34]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:25]=[CH:26][C:2]([F:1])=[CH:3][C:4]=3[C:27]([F:30])([F:29])[F:28])[N:8]=[CH:9]4)[C:18](=[O:24])[N:19]=2)[CH2:33][CH2:32]1)(=[O:39])[CH3:38]
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(F)cc3C(F)(F)F)c2)S1
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(F)cc4C(F)(F)F)c3)S2)CC1

Procedure:
2-(4-Acetyl-piperazin-1-yl)-5-[1-(4-fluoro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one was prepared from 5-[1-(4-fluoro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 1-piperazin-1-yl-ethanone following General Procedure C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]=O)[C:5]=2[O:4][CH2:3][CH2:2]1.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16]>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]=[CH:14][C:15]([OH:17])=[O:16])[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cccc2c1OCCO2
Product: O=C(O)C=Cc1cccc2c1OCCO2

Procedure:
Similar procedure as described in example 343a was used, starting from 2,3-Dihydro-benzo[1,4]dioxine-5-carbaldehyde and malonic acid to give 3-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-acrylic acid. LC-MS: m/e 207 (MH+).
Reaction SMILES: Cl.C([SiH2][O:7][C:8](C1C=CC=CC=1)(C1C=CC=CC=1)[C:9]1[N:10]=[CH:11][C:12]2[N:13]([C:15]([C:19]3[C:20](=[O:34])[NH:21][C:22](=[O:33])[C:23]=3[C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[NH:26][CH:25]=3)=[C:16]([CH3:18])[N:17]=2)[CH:14]=1)(C)(C)C>O1CCOCC1>[OH:7][CH2:8][C:9]1[N:10]=[CH:11][C:12]2[N:13]([C:15]([C:19]3[C:20](=[O:34])[NH:21][C:22](=[O:33])[C:23]=3[C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[NH:26][CH:25]=3)=[C:16]([CH3:18])[N:17]=2)[CH:14]=1
Reactant: Cc1nc2cnc(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)cn2c1C1=C(c2c[nH]c3ccccc23)C(=O)NC1=O
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc2cnc(CO)cn2c1C1=C(c2c[nH]c3ccccc23)C(=O)NC1=O
Temperature: 50 °C
Yield: 68.3 %

Procedure:
Hydrochloric acid (1.0 ml of a 4.0 M solution in dioxane) is added to 3-[6-(tert-butyl-diphenyl-silanyloxymethyl)-2-methyl-imidazo[1,2-a]pyrazin-3-yl]-4-(1H-indol-3-yl)-pyrrole-2,5-dione (60 mg, 0.098 mmol). The reaction mixture is heated to 50° C. for 16 hours under an atmosphere of argon. After cooling, volatiles are removed in vacuo, and the residue is purified by flash chromatography (gradient of CH2Cl2/MeOH 100:0 to 90:10) to afford the title compound (25 mg, 68%). MS (ES+): 374 (M+H)+.
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[CH3:10][O:11][C:12](=[O:22])/[C:13](/I)=[CH:14]\[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:42][C:43]1[CH:48]=[C:47](I)[CH:46]=[CH:45][C:44]=1[N:50]1[C:54]([C:55]([F:58])([F:57])[F:56])=[N:53][N:52]=[N:51]1.[Cl-].[NH4+]>O1CCCC1.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:10][O:11][C:12](=[O:22])/[C:13](/[C:47]1[CH:46]=[CH:45][C:44]([N:50]2[C:54]([C:55]([F:56])([F:57])[F:58])=[N:53][N:52]=[N:51]2)=[C:43]([Cl:42])[CH:48]=1)=[CH:14]/[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: FC(F)(F)c1nnnn1-c1ccc(I)cc1Cl
Reactant: COC(=O)/C(I)=C\C1CCCCC1
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COC(=O)/C(=C/C1CCCCC1)c1ccc(-n2nnnc2C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
A mixture of zinc dust (650 mg, 10 mmol, Aldrich, −325 mesh) and dry tetrahydrofuran (2 mL) under argon was treated with 1,2-dibromoethane (187 mg, 1 mmol). The zinc suspension was then heated with a heat gun to ebullition, allowed to cool, and heated again. This process was repeated three times to make sure the zinc dust was activated. The activated zinc dust suspension was then treated with trimethylsilyl chloride (110 mg, 1 mmol), and the suspension was stirred for 15 min at 25° C. The reaction mixture was then treated dropwise with a solution of (E)-3-cyclohexyl-2-iodo-acrylic acid methyl ester (1.32 g, 4.5 mmol) in dry tetrahydrofuran (2 mL) over 5 min. After the addition, the reaction mixture was stirred for 1 h at 40-45° C. and then stirred overnight at 25° C. The reaction mixture was then diluted with dry tetrahydrofuran (4 mL), and the stirring was stopped to allow the excess zinc dust to settle down (˜2 h). In a separate reaction flask, bis(dibenzylideneacetone)palladium(0) (54 mg, 0.1 mmol) and triphenylphosphine (104 mg, 0.4 mmol) in dry tetrahydrofuran (8 mL) was stirred at 25° C. under argon for 10 min and then treated with 1-(2-chloro-4-iodo-phenyl)-5-trifluoromethyl-1H-tetrazole (1.12 g, 3 mmol) and the freshly prepared zinc compound in tetrahydrofuran. The resulting brick red solution was heated at 50° C. for 15 h. The reaction mixture was cooled to 25° C. and then poured into a saturated aqueous ammonium chloride solution (70 mL), and the organic compound was extracted into ethyl acetate (3×50 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 6/1 hexanes/ethyl acetate) afforded the (E)-2-[3-chloro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-acrylic acid methyl ester (908 mg, 73%) as an amorphous white solid: EI-HRMS m/e calcd for C18H18ClF3N4O2 (M+) 414.1070, found 414.1075.
Reaction SMILES: CN(C)C=O.[CH3:6][N:7]([CH3:23])[CH:8]([CH3:22])[CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[C:13]([NH2:21])=[N:12]1.Br.Br[CH2:26][CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[CH3:23][N:7]([CH3:6])[CH:8]([CH3:22])[CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[C:13]([NH:21][CH2:26][CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[N:12]1
Reactant: CC(CCn1nc(N)c2cc(Cl)ccc21)N(C)C
Reactant: CCN(CC)CCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCN(CC)CCCNc1nn(CCC(C)N(C)C)c2ccc(Cl)cc12
Reaction time: 12 h
Yield: 58.3 %

Procedure:
To 60 ml of anhydrous N,N-dimethylformamide were added 8.71 g of the 1-(3-dimethylaminobutyl)-3-amino-5-chloroindazole, 8.98 g of 3-bromopropyldiethylamine hydrobromide and 7.89 g of anhydrous potassium carbonate, and the mixture was atirred for 12 hours at 80° C. After cooling, the mixture was added with 80 ml of water and extracted with diethyl ether. The diethyl ether layer was extracted three times with 2N hydrochloric acid, and the hydrochloric acid layer was washed with diethyl ether. The pH of the layer was adjusted to at least 11 with potassium carbonate, and the alkali layer was extracted three times with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, and chloroform was removed under reduced pressure. The residue thus obtained was subjected to an alumina-column chromatography (alumina: 200 g) using chloroform as the developing solvent to give 7.23 g of 1-(3-dimethylaminobutyl)-3-(3-diethylaminopropylamino)-5-chloroindazole having the following analytical values in a yield of 58 %.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]([O:27][C:28]([NH:30][C@H:31]([C@H:39]1[O:41][CH2:40]1)[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>CO.O>[OH:41][C@H:39]([C@@H:31]([NH:30][C:28]([O:27][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:29])[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:40][N:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:15][CH:16]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: CC(C)(C)OC(=O)NNCc1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CO1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
A solution of 58.7 g (197 mmol) of N1 -(tert-butoxycarbonyl)-N2 -(4-biphenylylmethyl)hydrazine and 51.8 g (197 mmol) of N-(tert-butoxycarbonyl)-2(S)-amino-1-phenyl-3(R)-3,4-epoxybutane (=(2R,3S)-1-[3-Boc-amino-2-phenylethyl]-oxirane) in 700 ml of absolute methanol is heated to reflux temperature during 16 h. The mixture is then cooled to 0° C. and diluted with 1.5 l of water. The solid is filtered and dried at 70° C. for 6 h to give the title compound:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:18][CH2:19][CH3:20])[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].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:30][C:31]([CH3:37])=[C:32]([CH2:34][CH2:35]O)[N:33]=2)=[CH:25][CH:24]=1.ClC1C=CC(C=O)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:18][CH2:19][CH3:20])[CH2:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([O:17][CH2:35][CH2:34][C:32]2[N:33]=[C:29]([C:26]3[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=3)[O:30][C:31]=2[CH3:37])=[CH:9][CH:8]=1)[CH3:2]
Reactant: Cc1oc(-c2ccc(Cl)cc2)nc1CCO
Reactant: CCOC(=O)C(Cc1ccc(O)c2c1CCCC2)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=Cc1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccc(Cl)cc3)oc2C)c2c1CCCC2)OCC

Procedure:
In analogy to the procedure described in example 17 a], [rac]-2-ethoxy-3-(4-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid ethyl ester (example 108 b]) was reacted with 2-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-yl]-ethanol (prepared by conversion of the 4-chloro-benzaldehyde into 2-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-yl]-ethanol in analogy to the sequence described in examples 21 a] to 21 e]) in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-3-(4-{2-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-5,6,7,8-tetrahydro-naphthalen-1-yl)-2-ethoxy-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 91 e] to yield [rac]-3-(4-{2-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-5,6,7,8-tetrahydro-naphthalen-1-yl)-2-ethoxy-propionic acid as colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:15]=CC(OC(C)(C)C(O)=O)=C[CH:4]=1)#N.COC(OC)OC.S(=O)(=O)(O)O.[C:28](=O)([O-])[O-].[K+].[K+].[C:34]([O:37][CH:38]([CH3:40])[CH3:39])(=[O:36])[CH3:35]>CO>[CH:38]([O:37][C:34](=[O:36])[CH3:35])([CH3:40])[CH3:39].[CH:3]([CH2:15][C:38]([CH3:39])([CH3:40])[CH3:28])([CH3:4])[CH3:1]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(Oc1ccc(C#N)cc1)C(=O)O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Solvent: COC(OC)OC
Solvent: CC(=O)OC(C)C
Product: CC(C)CC(C)(C)C
Reaction time: 1.75 h
Yield: 93 %

Procedure:
Suitable reaction conditions are: 2-(4-cyanophenoxy)-2-methylpropionic acid (or compound (viii)) (1 wt) was dissolved in methanol and trimethylorthoformate (TMOF, 1 vol) with stirring under nitrogen1. Sulfuric acid (98%, 0.08 vol, 0.32 eq) was then added, and the mixture was heated to reflux with HPLC monitoring. The reaction was typically complete after approx 1.5-2 hrs at reflux. The batch was cooled, and added to a stirred suspension of potassium carbonate (0.65 eq) in isopropyl acetate and then concentrated in vacuo to a total volume of approx 4 vol. Isopropyl acetate was added, and the slurry concentrated in vacuo to a total volume of approx 4 vol. Isopropyl acetate (4 vol) and water (5 vol) was added, the resultant biphasic solution was separated, and the organics were washed with water. The product was obtained by crystallisation from isopropylacetate/iso-octane with seeding. Expected yield: 93% theory, 99% w/w. Suitable reaction conditions for compound of formula (II) where X is H are: The compound (vii) is suspended in IMS containing AcOH, and treated with 10% Pd/C catalyst (50% wet, 0.1 wt). Hydrogenated at room temp for 60-90 mins until essentially complete by HPLC. The aminoacid precipitates during the reduction to give a fairly thick slurry at the end of the reaction. This is diluted with water and heated to obtain a complete solution. Filtered through celite to remove catalyst and washed through with 1:1 aq IMS. The filtrate and washings are concentrated in vacuo to ca 10 vols, and treated with cHCl (1 vol). Reconcentrated in vacuo to ca 4 vols, by which time a thick slurry results. This is collected by vacuum filtration and washed with water and dried at 50C in vacuo to constant weight. Yield is 70-75% as hydrochloride salt.
Reaction SMILES: Cl.[CH2:2]([N:4]([C:7]([O:9][CH2:10][CH:11]1[CH2:16][NH:15][CH2:14][CH2:13][NH:12]1)=[O:8])[CH2:5][CH3:6])[CH3:3].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[C:22](Cl)=[O:23]>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[C:22]([N:12]1[CH2:13][CH2:14][N:15]([C:22](=[O:23])[C:21]2[CH:20]=[C:19]([O:18][CH3:17])[C:27]([O:28][CH3:29])=[C:26]([O:30][CH3:31])[CH:25]=2)[CH2:16][CH:11]1[CH2:10][O:9][C:7]([N:4]([CH2:5][CH3:6])[CH2:2][CH3:3])=[O:8])=[O:23]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: CCN(CC)C(=O)OCC1CNCCN1
Agent: Cl
Product: CCN(CC)C(=O)OCC1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1C(=O)c1cc(OC)c(OC)c(OC)c1
Yield: 79.5 %

Procedure:
Working again according to a protocol identical to the one used in step 1.3 of Example 1, followed by treating, under the same conditions as those of step 1.4 of Example 1, 0.5 g (1.73 mmol) of 2-(N,N-diethylaminocarbonyloxymethyl)piperazine hydrochloride with 1 g of 3,4,5-trimethoxybenzoyl chloride, 0.83 g of 1,4-bis(3′,4′,5′-trimethoxybenzoyl)-2-(N,N-diethylaminocarbonyloxymethyl)piperazine is obtained. Yield: 80%. Melting point: 128.6° C. Rf=0.35 (3/97 v/v MeOH/CH2Cl2).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N+:4]=1[O-])#N.Cl.O.C(=O)(O)[O-:14].[Na+]>C(Cl)Cl>[CH3:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([CH:1]=[O:14])[CH:8]=1
Reactant: Cc1cc[n+]([O-])c(C#N)c1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccnc(C=O)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 14.8 %

Procedure:
To a solution of 2-cyano-4-methylpyridine-N-oxide (3.29 g, 0.0279 mol) in 164 mL of methylene chloride at -78° C. was added 27.6 mL of DIBAL(H) and the mixture was stirred at -78 ° C. for 2 h. To the above mixture was added 13 mL of HCl (conc.) and 52 mL of water, and the mixture was warmed to room temperature. To the aqueous layer was added sodium bicarbonate solution, the solution was extracted with ether, and the combined organic layer was concentrated in vacuo. The residue was purified by chromatography on silica (ether) to afford 0.5 g (14.8%) of 4-methylpyridine-2-carboxaldehyde, as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:17](=[O:20])[CH2:18][CH2:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:15][CH3:16])[CH:10]=3.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[OH-].[Na+]>C(O)C.O>[CH2:21]([C:18]1[C:17](=[O:20])[C:7]2[CH:8]=[C:9]([O:15][CH3:16])[CH:10]=[C:11]3[C:6]=2[N:5]([CH:19]=1)[C:4]1[CH:3]=[C:2]([Br:1])[CH:14]=[CH:13][C:12]3=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1cc2c3c(c1)c1ccc(Br)cc1n3CCC2=O
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc2c(=O)c(Cc3ccccc3)cn3c4cc(Br)ccc4c(c1)c23
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.6 %

Procedure:
9-bromo-5,6-dihydro-2-methoxy-4H-pyrido[3,2,1-jk]carbazole-4-one (200 mg) obtained in Example 101, step 6 was suspended in ethanol (12 ml), and benzaldehyde (103 mg) and sodium hydroxide (190 mg) dissolved in water (1 ml) were added to the suspension. The mixture was stirred at room temperature for 12 hours, and approximately half of the solvent was evaporated under reduced pressure. The crystals precipitated were recovered by filtration, and washed with water, ethanol and ether in succession to obtain the title compound (217 mg, 87%).