Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([C:9](=O)[CH3:10])[CH:5]=[C:6](O)[CH:7]=1.BrCC(OCC)=O.C([O-])([O-])=O.[K+].[K+].[CH2:25]([O:27][C:28](=[O:41])[CH2:29][O:30][C:31]1[CH:36]=[C:35]([OH:37])[CH:34]=[C:33]([C:38](=[O:40])[CH3:39])[CH:32]=1)[CH3:26].C(OC(=O)COC1C=C(OCC(OCC)=O)C=C(C(=O)C)C=1)C.C(OC(=O)COC1C=C(OCC(OC)=O)C=C(C(=O)C)C=1)C.BrC(C1C=CC=CC=1)C>CC(C)=O>[C:38]([C:33]1[CH:34]=[C:35]([O:37][CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=2)[CH3:10])[CH:36]=[C:31]([CH:32]=1)[O:30][CH2:29][C:28]([O:27][CH2:25][CH3:26])=[O:41])(=[O:40])[CH3:39]
Reactant: CC(=O)c1cc(O)cc(O)c1
Reactant: CCOC(=O)COc1cc(O)cc(C(C)=O)c1
Agent: CC(Br)c1ccccc1
Agent: CCOC(=O)CBr
Agent: CCOC(=O)COc1cc(OCC(=O)OC)cc(C(C)=O)c1
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(OC(C)c2ccccc2)cc(C(C)=O)c1

Procedure:
To a solution of 3′,5′-dihydroxyacetophenone (10.0 g, 66 mmol) and ethyl bromoacetate (11.0 g, 66 mmol) in acetone (300 mL) is added K2CO3 (9.0 g, 66 mmol), and the resulting mixture is refluxed for 3 hours. After cooling, the mixture is filtered, and the filtrate is concentrated in vacuo. The residue is chromatographed (silica, 3:2 hexane/EtOAc) to give a mixture of (3-acetyl-5-hydroxyphenoxy)-acetic acid ethyl ester, 3′,5′-dihydroxyacetophenone and [3-acetyl-5-(ethoxycarbonylmethoxy)-phenoxy]-acetic acid ethyl ester (the dialkylation product), which is carried on to the next step without further purification. To a solution of ethyl (3-acetyl-5-hydroxyphenoxy)-acetate (2.4 g, 10.1 mmol), contaminated with 3′,5′-dihydroxyacetophenone and (3-acetyl-5-methoxycarbonylmethoxyphenoxy) acetic acid ethyl ester, and (1-bromoethyl)benzene (2.24 g, 12.1 mmol) in acetone (100 mL) is added K2CO3 (2.09 g, 15.1 mmol), and the resulting mixture is refluxed for 3 hours. After cooling, the mixture is filtered, and the filtrate is concentrated in vacuo. The residue is chromatographed (silica, 3:1 hexane/EtOAc) to give ethyl [5-acetyl-3-(1-phenylethoxy)-phenoxy]-acetate.
Reaction SMILES: Cl.C([O:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]2[N:11]([C:13]([CH2:16][C:17]3[C:18]([F:28])=[C:19]4[C:24](=[CH:25][C:26]=3[F:27])[N:23]=[CH:22][CH:21]=[CH:20]4)=[N:14][N:15]=2)[N:12]=1)=[CH2:6])C>CC(O)=O>[F:28][C:18]1[C:17]([CH2:16][C:13]2[N:11]3[N:12]=[C:7]([C:5](=[O:4])[CH3:6])[CH:8]=[CH:9][C:10]3=[N:15][N:14]=2)=[C:26]([F:27])[CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][CH:22]=[N:23]2
Reactant: C=C(OCC)c1ccc2nnc(Cc3c(F)cc4ncccc4c3F)n2n1
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)c1ccc2nnc(Cc3c(F)cc4ncccc4c3F)n2n1
Temperature: 40 °C
Reaction time: 6 h
Yield: 49.7 %

Procedure:
Aqueous 3N HCl (0.2 mL, 0.6 mmol) was added to a solution of 6-[6-(1-ethoxy-vinyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl]-5,7-difluoro-quinoline (87 mg, 0.237 mmol) in HOAc (2 mL). The reaction mixture was stirred at 40° C. for 6 h. LC/MS showed reaction was complete. The solvent was removed in vacuo, and the residue dissolved in EtOAc was neutralized, and extracted with EtOAc. The organic layer was dried, concentrated and purified by flash chromatography to afford 40 mg of the title compound as a pale yellow solid. 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.95 (dd, 1H), 8.56 (d, 1H), 8.29 (d, 1H), 7.85 (d, 1H), 7.60-7.67 (m, 2H), 4.94 (s, 2H), 2.67 (s, 3H). LCMS (method A): [MH]+=339, tR=4.88 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH:10]2[CH:5]([CH:6]([OH:11])[CH2:7][CH2:8][CH2:9]2)[C:4]([CH3:13])([CH3:12])[CH:3]1[CH3:14].[CH3:16][O:17][CH2:18]OC>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:15])[CH:10]2[CH:5]([CH:6]([O:11][CH2:16][O:17][CH3:18])[CH2:7][CH2:8][CH2:9]2)[C:4]([CH3:13])([CH3:12])[CH:3]1[CH3:14]
Reactant: CC1C(C)(C)C2CCCC(O)C2C1(C)C
Reactant: COCOC
Solvent: Cc1ccccc1
Product: COCOC1CCCC2C1C(C)(C)C(C)C2(C)C
Temperature: 100 °C
Yield: 55 %

Procedure:
A reaction flask was charged with 300 g (1.4 mole) 1,1,2,3,3-pentamethyl-hexahydro-4-indanol, 306 g (4 mole) dimethoxymethane, 0.25 liter toluene, and 3 g boron trifluoride etherate complex. The reaction mass was heated to 100° C. and methanol and lite organics were collected in a Dean Stark trap (337 g recovered). After aging the reaction for 3 hrs the reaction was cooled to 25° C. and acid catalyst was quenched with 100 g of 10% aqueous sodium carbonate. The mass was transferred to a separatory funnel and water washed. The organic layer was separated and purified by fractional distillation. The procedure affords a 55% yield (196 g) of 1,1,2,3,3-pentamethyl-octahydro-4-(methoxymethoxy)-1H-indene.
Reaction SMILES: [I-].[K+].II.[CH3:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([N:16]2[C:20]([SH:21])=[N:19][N:18]=[N:17]2)[CH:13]=[CH:14][CH:15]=1)=[S:8]>O.C(O)C>[CH3:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([N:16]2[C:20]([S:21][S:21][C:20]3[N:16]([C:12]4[CH:13]=[CH:14][CH:15]=[C:10]([NH:9][C:7](=[S:8])[CH2:6][CH3:5])[CH:11]=4)[N:17]=[N:18][N:19]=3)=[N:19][N:18]=[N:17]2)[CH:13]=[CH:14][CH:15]=1)=[S:8]
Reactant: CCC(=S)Nc1cccc(-n2nnnc2S)c1
Agent: II
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCC(=S)Nc1cccc(-n2nnnc2SSc2nnnn2-c2cccc(NC(=S)CC)c2)c1

Procedure:
A solution of 3.0 g of potassium iodide and 3.2 g of iodine in 50 ml of water and 25 ml of ethanol was added dropwise with stirring and at room temperature to 7 g of 1-[m-(methylthioacetylamino)-phenyl]-5-mercaptotetrazole. The precipitate was purified by recrystallization from methanol.
Reaction SMILES: [O-2].[Zn+2:2].[CH3:3][O:4][C:5](=[O:13])[C@H:6]([CH2:8][CH2:9][C:10]([O-:12])=[O:11])[NH2:7].[CH3:14][O:15][C:16](=[O:24])[CH2:17][CH2:18][C@@H:19]([C:21]([OH:23])=[O:22])[NH2:20].O>C1(C)C=CC=CC=1>[CH3:14][NH:7][C@H:6]([C:5]([O-:4])=[O:13])[CH2:8][CH2:9][C:10]([O-:12])=[O:11].[CH3:3][NH:20][C@H:19]([C:21]([O-:23])=[O:22])[CH2:18][CH2:17][C:16]([O-:15])=[O:24].[Zn+2:2].[Zn+2:2]
Reactant: COC(=O)[C@@H](N)CCC(=O)[O-]
Reactant: COC(=O)CC[C@H](N)C(=O)O
Agent: [O-2]
Agent: [Zn+2]
Solvent: O
Solvent: Cc1ccccc1
Product: CN[C@@H](CCC(=O)[O-])C(=O)[O-]

Procedure:
Zinc bis(methyl-glutamate) was prepared by reacting 12.2 grams of zinc oxide and 48.3 grams of monomethyl-glutamate also known in the art as glutamic acid 5-methyl ester as named in C.A.S. Reg. No. 1499-55-4, pg. 458 Aldrich Catalog Handbook 1979-80 in 500 ml of toluene in a one-liter, one-neck round-bottom flask equipped with a magnetic stirrer, reflux condenser and Dean-Stark Trap. The mixture was refluxed to obtain a theoretical amount of water in the Dean-Stark Trap. A white powdery product was recovered by filtration.
Reaction SMILES: F[C:2]1[C:14]2[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[NH2:21])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>CN(C=O)C>[CH:2]1[C:14]2[N:13]3[C:12]4[C:7]([C:6]=2[CH:5]=[CH:4][CH:3]=1)=[CH:8][CH:9]=[CH:10][C:11]=4[NH:21][C:16]1[C:15]3=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccccc1-n1c2ccccc2c2cccc(F)c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc2c(c1)Nc1cccc3c4ccccc4n-2c13
Temperature: 25 °C

Procedure:
30 g (109 mmol) of 1-fluoro-9-(2-aminophenyl)-9H-carbazole are dissolved in 200 ml of DMF under a protective gas, 4.4 g (109 mmol) of NaH (60% in oil) are added at room temperature, and the mixture is boiled under reflux for 6 h. The mixture is subsequently warmed to room temperature over the course of 1 h, the solvent is removed, and the residue is purified by chromatography.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[Cl-].[Cl-].[Cl-].[Al+3].[P:14]([Cl:18])(Cl)(Cl)=[O:15]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][P:14]([Cl:18])(=[O:15])[O:9][C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cccc(C)c1O
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cccc(C)c1OP(=O)(Cl)Oc1c(C)cccc1C

Procedure:
2,6-dimethylphenol (1 g, 8.18 mmol) and aluminum trichloride (109 mg, 0.818 mmol, 0.1 eq) were added to a microwave vial. Phosphorus oxychloride (0.375 mL, 4.09 mmol, 0.5 eq) was added, the vial was sealed and subsequently heated in the microwave for 1 h. Reaction progress was monitored by TLC, and the reaction was quenched before going to completion. The reaction mixture was diluted with dicholoromethane, washed with water and brine, dried over MgSO4, and filtered through celite. The filtrate was concentrated under reduced pressure providing an oily residue that was taken directly to the next step without further purification.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:10][C:11]1[CH:37]=[CH:36][CH:35]=[CH:34][C:12]=1[C:13]([C:15]1[C:22](=[O:23])[N:18]2[CH2:19][CH2:20][CH2:21][N:17]2[C:16]=1[C:24]1[CH:29]=[CH:28][N:27]=[C:26](S(C)(=O)=O)[N:25]=1)=[O:14]>C1COCC1.C([O-])(O)=O.[Na+]>[Cl:10][C:11]1[CH:37]=[CH:36][CH:35]=[CH:34][C:12]=1[C:13]([C:15]1[C:22](=[O:23])[N:18]2[CH2:19][CH2:20][CH2:21][N:17]2[C:16]=1[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:25]=1)=[O:14]
Reactant: Oc1ccccc1
Reactant: CS(=O)(=O)c1nccc(-c2c(C(=O)c3ccccc3Cl)c(=O)n3n2CCC3)n1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(c1ccccc1Cl)c1c(-c2ccnc(Oc3ccccc3)n2)n2n(c1=O)CCC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of phenol (0.04 g, 0.43 mmol) in THF (1 mL) is added sodium hydride (0.02 g of a 60% dispersion in mineral oil, 0.32 mmol). After stirring 5 min at room temperature a solution of 2-(2-chloro-benzoyl)-3-(2-methanesulfonyl-pyrimidin-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazol-1-one, 24, (0.09 g, 0.21 mmol) in THF (2 mL) is added to the reaction mixture. After stirring 1.5 hours at room temperature, the mixture is diluted with aqueous saturated NaHCO3. The aqueous phase is extracted three times with CHCl3 and the combined organic phases are washed with aqueous saturated NaHCO3, dried (MgSO4), filtered and concentrated in vacuo. The crude residue is purified over silica (10% MeOH/CHCl3) to afford 30 mg of the desired product. 1H NMR (300 MHz, CDCl3) δ 8.77 (d, J=5.1 Hz, 1H), 8.04 (d, J=5.1 Hz, 1H), 7.49 (t, J=7.8 Hz, 1H), 7.41-7.20 (m, 9H), 4.00 (t, J=7.2 Hz, 2H), 3.95 (t, J=7.2 Hz, 2H), 2.54 (dddd, J=7.5, 7.5, 7.5, 7.5 Hz, 2H); ESI− MS: m/z (rel intensity) 431.1 (100, M+−H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([C:12](=[O:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:6][C:5]=1[O:19][CH3:20])[CH3:2].[BH4-].[Na+]>O>[CH2:1]([NH:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([CH:12]([OH:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:6][C:5]=1[O:19][CH3:20])[CH3:2]
Reactant: CCNc1c(OC)cc(C(=O)CS(C)(=O)=O)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CCNc1c(OC)cc(C(O)CS(C)(=O)=O)cc1OC

Procedure:
A suspension of 48 g. of 4'-(ethylamino)-3',5'-dimethoxy-2-(methylsulfonyl)acetophenone and 23.8 g. of sodium borohydride in 1 liter of alcohol was stirred at room temperature for 20 hours, resulting in a solution. After the addition of 1 liter of water, the alcohol was evaporated under vacuum. The crystals formed were removed by filtration with suction, washed with water and dried, whereby there was obtained 4-(ethylamino)-3,5-dimethoxy-α-[(methylsulfonyl)-methyl]-benzyl alcohol having a melting point of 121°-122° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:29][C:30]1[N:31]=[C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:33][C:34]=1[CH3:35]>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][N:22]([CH2:29][C:30]5[N:31]=[C:32]([C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=6)[O:33][C:34]=5[CH3:35])[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: [H-]
Agent: [Na+]
Product: Cc1oc(-c2ccccc2)nc1CN1C[C@@H](C)n2c(cc3cc(OC4CCN(C(C)C)CC4)ccc32)C1=O
Yield: 71 %

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8), sodium hydride and 4-chloromethyl-5-methyl-2-phenyloxazole, to give the desired product as a brown solid (71%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:38]=[CH:37][CH:36]=[CH:35][C:7]=1[O:8][C:9]1[C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:22][C:12]2[NH:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[N:15][C:11]=2[CH:10]=1)=O)C.[CH3:39][N:40](C)[C:41](=O)C1C=CC=CC=1O>>[CH3:39][N:40]([CH3:41])[C:4]([C:6]1[CH:38]=[CH:37][CH:36]=[CH:35][C:7]=1[O:8][C:9]1[C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:22][C:12]2[NH:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[N:15][C:11]=2[CH:10]=1)=[O:3]
Reactant: CN(C)C(=O)c1ccccc1O
Reactant: CCOC(=O)c1ccccc1Oc1cc2nc(-c3ccccn3)[nH]c2cc1Oc1ccc(S(C)(=O)=O)cc1
Product: CN(C)C(=O)c1ccccc1Oc1cc2nc(-c3ccccn3)[nH]c2cc1Oc1ccc(S(C)(=O)=O)cc1

Procedure:
The entitled compound was obtained in the same method as in Example 14 or in accordance with the method or by combining it with an ordinary method but using 4-fluoro-5-(4-methanesulfonyl-phenoxy)-2-nitro-phenylamine obtained in Example 14 and 2-hydroxybenzoic acid dimethylamide in order.
Reaction SMILES: C(Cl)(=O)C1C=CC=C(C(Cl)=O)C=1.[CH3:13][O:14][C:15](=[O:26])[C:16]1[CH:25]=[CH:24][CH:23]=[C:18]([C:19]([O:21]C)=[O:20])[CH:17]=1.O[Li].O>ClCCl.CO>[CH3:13][O:14][C:15](=[O:26])[C:16]1[CH:25]=[CH:24][CH:23]=[C:18]([C:19]([OH:21])=[O:20])[CH:17]=1
Reactant: COC(=O)c1cccc(C(=O)OC)c1
Agent: O=C(Cl)c1cccc(C(=O)Cl)c1
Agent: [Li]O
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COC(=O)c1cccc(C(=O)O)c1
Reaction time: 8 h

Procedure:
A solution of 12.18 g (60 mmol) isophthaloyl chloride in 60 ml dichloromethane was added to 60 ml anhydrous methanol at 0° C. The reaction was left overnight at rt. The reaction mixture was evaporated and the residue was dissolved in dichloromethane. The organic phase was washed twice with saturated NaHCO3 aq. The dichloromethane phase was dried and evaporated. Yield 11.05 g (56.9 mmol, 95%). A solution of 11.05 g (56.9 mmol) of isophthalic acid dimethyl ester and 2.39 g (56.9 mmol) LiOH.H2O in 150 ml anhydrous methanol was stirred for 4 d at rt The solvent was evaporated and the product was dissolved in water. The aqueous phase was washed with dichloromethane. The aqueous phase was made acidic with 2 M HCl aq. The product precipitated from the aqueous phase. The product was filtered off and dried in vacuo. The product was dissolved in 200 ml dry ethanol, and thereafter 600 ml water was added slowly while stirring. The product precipitated slowly overnight at +4° C. The product was filtered and dried in vacuo. Yield 8.32 g (46.2 mmol, 81%)
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([OH:17])=O)[N:13]=2)=[O:7])=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]2=[O:33])=[CH:23][C:22]=1[F:34]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15](=[O:17])[NH:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]4=[O:33])=[CH:23][C:22]=3[F:34])[N:13]=2)=[O:7])=[CH:18][CH:19]=1
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Reactant: O=C(O)Cc1csc(NC(=O)c2ccc(Cl)cc2)n1
Product: O=C(Cc1csc(NC(=O)c2ccc(Cl)cc2)n1)Nc1ccc(-n2ccccc2=O)cc1F

Procedure:
In analogy to example 1.3, [2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) was coupled with 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (CAS 536747-52-1, prepared according to C. F. Bigge et al., patent application WO 2003045912) to give 4-chloro-N-(4-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-methyl}-thiazol-2-yl)-benzamide, using general procedure B. Off-white solid. MS 483.3 ([M+H]+)
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[C:8]([OH:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[H][H].C>CO.C(O)(=O)C.[Pd]>[OH:11][C:8]1[CH:7]=[CH:6][C:3]([CH3:4])=[C:2]([OH:1])[C:9]=1[CH3:10]
Reactant: Cc1c(O)ccc(C=O)c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(O)c(C)c1O
Yield: 30.5 %

Procedure:
1 g (6.5 mmol) of 2,4-dihydroxy-3-methylbenzaldehyde is hydrogenated, at 3 bar hydrogen pressure for 24 h, with 100 mg of Pd on active charcoal (10%) in 100 ml of methanol and 1 ml of glacial acetic acid. A further 100 mg of Pd on active charcoal (20%) are added and the mixture is hydrogenated at 3 bar hydrogen pressure for 12 h. The catalyst is filtered off, the solvent is removed in vacuo and the residue is purified by chromatography (dichloromethane/acetone). 274 mg (30%) of 1,3-dihydroxy-2,4-dimethylbenzene are obtained.
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:26]=[CH:25][C:17]([O:18][CH:19]([CH2:23][CH3:24])[C:20](O)=[O:21])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CC1(C)C2C(=CC(O)=CC=2)C(C)(C)C1.C[O-].[Na+].COC(=O)C(Br)CC.[Na].[OH-].[Na+].[ClH:55]>CO.C(O)(C)C.C1(C)C=CC=CC=1>[CH2:1]([O:13][C:14]1[CH:26]=[CH:25][C:17]([O:18][CH:19]([CH2:23][CH3:24])[C:20]([Cl:55])=[O:21])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: Cl
Reactant: CCCCCCCCCCCCOc1ccc(OC(CC)C(=O)O)cc1
Agent: CC1(C)CC(C)(C)c2cc(O)ccc21
Agent: CCC(Br)C(=O)OC
Agent: C[O-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CCCCCCCCCCCCOc1ccc(OC(CC)C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In the same way as in the case of 2-(4-n-dodecyloxyphenoxy)-butyric acid all of the methanol was distilled off from a mixture of 89 g (0.468 mole) of 1,1,3,3-tetramethyl-5-indanol, 750 ml of anhydrous toluene, and 86.7 ml (0.468 mole) of a 30% solution of sodium methanolate in methanol. 93.2 g (0.515 mole) of α-bromobutyric acid methyl ester were added to the suspension of the resulting sodium salt of 1,1,3,3-tetramethyl-5-indanol. The mixture was refluxed for 7 hours. 180 ml of isopropanol and 140 ml of 5 N sodium hydroxide were added to the hot (80° C.) mixture and refluxing was then continued for 1 hour. The mixture was cooled down to room temperature and admixed with 164 ml of 5 N hydrochloric acid. The toluene layer was decanted. The residue was dried and the solvent was evaporated.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]1.[H-].[Na+].CS(O[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)(=O)=O.O>CN(C)C=O>[CH:6]([C:4]1[N:3]=[CH:2][N:1]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH:5]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: O=Cc1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cnc(C=O)c2)CC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 23.1 %

Procedure:
To 137 mg of imidazole-4-carboxaldehyde diluted in 2 ml of anhydrous dimethylformamide under argon are added portionwise at 0° C. 63 mg of sodium hydride (60% in mineral oil). The reaction mixture is stirred for 45 min at 0° C. then 400 mg of tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate are added portionwise, and the solution is brought to 100° C. for 15 h. Water is added and the product is extracted several times with ethyl acetate. The organic phases are combined, washed with sodium chloride saturated aqueous solution, dried over magnesium sulfate, and concentrated. The residue is purified by chromatography on silica (cyclohexane/ethyl acetate eluent: 2:8 to 100% ethyl acetate) to yield 92 mg of tert-butyl 4-(4-formyl-1H-imidazol-1-yl)piperidine-1-carboxylate in the form of a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([C:16]2[C:20]3[N:21]=[C:22](Cl)[N:23]=[CH:24][C:19]=3[S:18][CH:17]=2)=[O:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C@@H:26]1([NH2:33])[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]1[NH2:32].O.ClCCl>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([C:16]2[C:20]3[N:21]=[C:22]([NH:32][C@@H:27]4[CH2:28][CH2:29][CH2:30][CH2:31][C@@H:26]4[NH2:33])[N:23]=[CH:24][C:19]=3[S:18][CH:17]=2)=[O:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: N[C@@H]1CCCC[C@@H]1N
Reactant: COc1cc(NC(=O)c2csc3cnc(Cl)nc23)cc(OC)c1OC
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(NC(=O)c2csc3cnc(N[C@@H]4CCCC[C@@H]4N)nc23)cc(OC)c1OC
Yield: 60 %

Procedure:
To a solution of 0.0885 g (0.233 mmole) 2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid (3,4,5-trimethoxy-phenyl)-amide in 2.33 mL of dioxane was added 0.168 mL (1.4 mmole) of cis-cyclohexane-1,2-diamine. The mixture was heated at 100 degrees for over night. Water and dichloromethane were added, separated. The aqueous layer was washed with dichloromethane twice. The organic layer was washed with aqueous sodium carbonate, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-0.7 N ammonia solution in methanol (gradient 100:0-90:10) gave 0.064 g of 2-(cis-2-amino-cyclohexylamino)-thieno[3,2-d]pyrimidine-7-carboxylic acid (3,4,5-trimethoxy-phenyl)-amide as a light yellow solid. MH+/Z=458.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:25])[CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)=[C:4]([O:26][CH3:27])[CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:25])[CH2:10][CH2:11][CH:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)=[C:4]([O:26][CH3:27])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(N)c(Cl)cc1C(=O)CCC1CCNCC1
Yield: 100 %

Procedure:
1-(4-Amino-5-chloro-2-methoxyphenyl)-3-[1-(tert-butoxycarbonyl)-piperidin-4-yl]propan-1-one (1.5 g, 3.8 mmol) was dissolved in methylene chloride (20 mL) and trifluoroacetic acid (5 mL) was added to the solution. After 30 minutes the solution was washed with aqueous ammonium hydroxide, and dried over sodium sulfate. Evaporation of the solvents gave 1-(4-amino-5-chloro-2-methoxyphenyl)-3-(piperidin-4-yl)-propan-1-one (1.1 g, 3.8 mmol), m.p. 138°-140° C.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([O:11][CH:12]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])(=[O:10])[CH3:9]>C1C=CC=CC=1.C1(C)C=CC=CC=1>[C:8]([O:11][CH:12]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:13][C:14]([OH:16])=[O:15])(=[O:10])[CH3:9]
Reactant: CCCCCCCCCCCC(CC(=O)OC(C)(C)C)OC(C)=O
Solvent: c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCC(CC(=O)O)OC(C)=O
Reaction time: 2 h
Yield: 85.4 %

Procedure:
Trifluoroacetic acid (32 ml) was added to t-butyl (3RS)-3-acetoxytetradecanoate (14 g) under ice-cooling. The mixture was stirred at the same temperature for 2 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in a mixture of benzene and toluene, and concentrated under reduced pressure to give (3RS)-3-acetoxytetradecanoic acid (10.0 g).