Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].Br[CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][C:12]=1[O:21][CH3:22]>>[CH3:22][O:21][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][C:11]=1[CH2:10][O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[C:15]([OH:17])=[O:16]
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Product: COc1cc(C(=O)O)ccc1COCC(F)(F)F
Reaction time: 0.17 h

Procedure:
To a solution of 2,2,2-trifluoroethanol (874 μL, 12.0 mmol) at 0° C. was added NaH (60%, 520 mg, 13.0 mmol) and the mixture was stirred at this temp for 10 min, then at room temperature for 10 min. The mixture was cooled to 0° C. before methyl 4-(bromomethyl)-3-methoxybenzoate (2.59 g, 10.0 mmol) was added. The cooling bath was removed and the mixture was stirred at room temperature for 3 hours. The mixture was poured into water and extracted with EtOAc (3×). The organics were combined, washed with water, brine, dried (MgSO4) and evaporated to dryness. Crushed NaOH was added to the residue, followed by water (4 mL) and MeOH (20 mL). The mixture was stirred at room temperature for 1 hour. The MeOH was evaporated and the residue was taken up in 1N NaOH (30 ml) and the pH was adjusted to pH 2 with conc HCl. The precipitate was filtered, washed with water (2×) then hexanes (2×) and desiccated to give 3-methoxy-4-((2,2,2-trifluoroethoxy)methyl)benzoic acid. 1H NMR (400 MHz, CDCl3) δ 7.79 (dd, J=7.8, 1.4 Hz, 1H), 7.61 (d, J=1.4 Hz, 1H), 7.53 (d, J=7.8 Hz, 1H), 4.80 (s, 2H), 4.00-3.91 (m, 5H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][N:6]=[C:5]2[C:12]([OH:14])=[O:13].CC1(C)COB([C:22]2[CH:27]=[CH:26][C:25]([C:28]([OH:34])([CH3:33])[C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=2)OC1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CCO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([C:12]([OH:14])=[O:13])=[N:6][NH:7]2)=[CH:3][C:2]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28]([OH:34])([CH3:33])[C:29]([F:31])([F:32])[F:30])=[CH:24][CH:23]=1
Reactant: O=C(O)c1n[nH]c2cc(Cl)c(Br)cc12
Reactant: CC1(C)COB(c2ccc(C(C)(O)C(F)(F)F)cc2)OC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(O)(c1ccc(-c2cc3c(C(=O)O)n[nH]c3cc2Cl)cc1)C(F)(F)F
Temperature: 110 °C
Yield: 15.4 %

Procedure:
A mixture of 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (30.0 mg, 0.11 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7.3 mg, 0.010 mmol) was purged with N2. To this mixture was added 2-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-phenyl]-1,1,1-trifluoropropan-2-ol (35.0 mg, 0.12 mmol) in toluene (1.0 mL) and EtOH (0.5 mL), followed by 2N aqueous potassium carbonate solution (0.22 mL, 0.44 mmol). The reaction mixture was heated to 110° C. for 18 hours, cooled to room temperature and concentrated in vacuo. The resulting solid was partitioned between water and EtOAc, and acidified to pH 5 with aqueous 1N citric acid. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by reverse phase HPLC (Column: Waters Sunfire C18 19×100 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); HOLD at 100.0% H2O/0.0% MeCN for 1.0 min. 100.0% H2O/0.0% MeCN linear to 5.0% H2O/95.0% MeCN in 6.75 min, linear to 0% H2O/100% MeCN to 7.0 min. HOLD at 0% H2O/100% MeCN from 7.0 to 8.0 min. Flow: 30 mL/min) to give the title compound (6.5 mg, 15% yield).
Reaction SMILES: [C:1]([CH2:3][CH:4]([N:19]1[CH:23]=[C:22]([C:24]2[C:25]3[CH:32]=[CH:31][N:30]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:26]=3[N:27]=[CH:28][N:29]=2)[CH:21]=[N:20]1)[CH2:5][N:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)#[N:2].[ClH:41].O1CCOCC1>>[ClH:41].[N:6]1([CH2:5][CH:4]([N:19]2[CH:23]=[C:22]([C:24]3[C:25]4[CH:32]=[CH:31][N:30]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:38])([CH3:40])[CH3:39])[C:26]=4[N:27]=[CH:28][N:29]=3)[CH:21]=[N:20]2)[CH2:3][C:1]#[N:2])[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(CC#N)n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCNCC4)c3)ncnc21

Procedure:
tert-Butyl 4-{3-cyano-2-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}piperazine-1-carboxylate (second peak from chiral purification, 0.70 g, 0.0012 mol) was stirred with 4.0 M of hydrogen chloride in p-dioxane (5.0 mL, 0.020 mol) at RT for 30 min. After evaporating to dryness, the resulting HCl salt was used directly in next step. LCMS calculated for C23H34N9OSi(M+H)+: m/z=467.3; Found: 467.0.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11]3[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=3)[C:6]=2[N:7]=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][S:19]([CH3:18])(=[O:21])=[O:20])[CH:14]=[CH:15][CH:16]=3)[C:6]=2[N:7]=1
Reactant: Nc1cccc(-c2csc3cnc(Cl)nc23)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1cccc(-c2csc3cnc(Cl)nc23)c1
Reaction time: 2 h
Yield: 91.4 %

Procedure:
3-(2-Chlorothieno[3,2-d]pyrimidin-7-yl)benzenamine (800 mg, 3.06 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL) and methanesulfonyl chloride (0.27 mL, 3.37 mmol) and triethylamine (0.85 mL, 6.13 mmol) were added. The mixture solution was stirred for 2 hours, diluted with ethyl acetate, and then washed with brine. The organic layer was concentrated by drying with magnesium sulfate. Purification by chromatography (10% ethyl acetate/hexane) yielded the target compound (950 mg, 91% yield).
Reaction SMILES: [CH:1]([C:4]([CH3:6])=[O:5])([CH3:3])[CH3:2].Cl[CH:8]([Cl:16])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>O1CCCC1>[Cl:16][C:8]1([O:5][C:4]1([CH:1]([CH3:3])[CH3:2])[CH3:6])[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10]
Reactant: CC(=O)C(C)C
Reactant: CC(C)(C)OC(=O)C(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)C1(C)OC1(Cl)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
A solution of 122 g of potassium tert.-butylate in 720 ml of tetrahydrofuran was added at -20°C with stirring under an inert atmosphere to a mixture of 95 g of methyl isopropyl ketone and 185 g of tert.butyl dichloroacetate and after returning the temperature to room temperature, the mixture was stirred for 2 hours. The mixture was poured into ice water and the mixture was stirred and the organic phase was separated. The organic phase was washed with aqueous sodium chloride solution, dried over magnesium sulfate, passed through vegetable charcoal and concentrated to dryness to obtain 230.4 g of tert.butyl 2-chloro-2,3-epoxy-3-isopropyl-butanoate.
Reaction SMILES: [H-].[Na+].[CH3:3]CCCC.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:20]([OH:23])[C:21]#[CH:22])[CH:13]=[C:14]([O:18][CH3:19])[C:15]=1[O:16][CH3:17].COS(OC)(=O)=O>C1COCC1.O>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([CH:20]([O:23][CH3:3])[C:21]#[CH:22])[CH:11]=[C:10]([O:9][CH3:8])[C:15]=1[O:16][CH3:17]
Reactant: CCCCC
Reactant: C#CC(O)c1cc(OC)c(OC)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: COS(=O)(=O)OC
Product: C#CC(OC)c1cc(OC)c(OC)c(OC)c1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 90 %

Procedure:
To a flame-dried 100 mL round-bottom flask was added NaH (0.240 mg, 6.0 mmol) that had been prewashed with pentane (3×15 mL) and dried. THF (48 mL) was added and the suspension cooled to 0° C. 1-(3,4,5-Trimethoxyphenyl)prop-2-yn-1-ol (1.11 g, 5.0 mmol) in THF (2.0 mL) was added dropwise and the reaction stirred at 0° C. for 25 min. Me2SO4 (0.571 mL, 6.0 mmol) was added and the reaction stirred at 0° C. for 20 min. Water (10 mL) was added, and the layers were separated. The aqueous layer was extracted with Et2O (20 mL). The combined organics were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography (SiO2, 20 g) using 10% EtOAc in hexanes as the eluent to afford 1,2,3-Trimethoxy-5-(1-methoxyprop-2-ynyl)benzene as a colorless oil (1.06 g, 90%): Rf=0.18 (4:1, Hex:EtOAc); 1H NMR (CDCl3) δ 6.75 (s, 2H), 5.01 (d, J) 2.2 Hz, 1H), 3.88 (s, 6H), 3.84 (s, 3H), 3.45 (s, 3H), 2.68 (d, J) 2.2 Hz, 1H); 13C NMR (CDCl3) δ 153.4, 138.2, 133.7, 104.4, 81.3, 76.0, 73.1, 61.0, 56.3, 56.2; HRFAB [M+Li] 243.1208 (calculated C13H16O4Li: 243.1209).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH:9]([C:20](O)=[O:21])[NH:8][CH:7]=1)=[O:5])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>C(Cl)Cl>[N:35]1([C:20]([CH:9]2[NH:8][CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:12]3[NH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:11]=3[CH2:10]2)=[O:21])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: C1CCNCC1
Reactant: CCOC(=O)C1=CNC(C(=O)O)Cc2c1[nH]c1ccccc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CCOC(=O)C1=CNC(C(=O)N2CCCCC2)Cc2c1[nH]c1ccccc21
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a suspension of 1,2,3,6-tetrahydroazepino[4,5-b]indole-2,5-dicarboxylic acid 5-ethyl ester (45 mg, 0.15 mmol) in DCM (3 mL) was added CDI (27 mg, 1.1 equiv.). After stirring for 1 hour at 20° C., piperidine (23 μL, 1.5 equiv.) was added. The mixture was stirred overnight at 20° C. and a clear solution was obtained. Evaporation of solvent gave a crude product, which was purified by trituration with MeOH to afford the title compound (22 mg); 1H-NMR (CDCl3): δ 10.44 (1H, br s), 7.95 (1H, d), 7.38 (2H, d), 7.05-7.13 (2H, m), 6.69 (1H, d), 4.29 (2H, q), 3.98 (1H, dd), 3.65-3.73 (2H, m), 3.46 (1H, m), 3.31 (1H, m), 2.71 (1H, dd), 1.58-1.76 (6H, m), 1.36 (3H, t); MS (ES): 368 (MH+).
Reaction SMILES: [Mg+2].[Cl-].[Cl-].[Cl:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1.I[C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>C1COCC1.[NH4+].[Cl-].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]>[Cl:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=2)[CH:8]=[CH:7][N:6]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-c2ccnc(Cl)c2[N+](=O)[O-])cc1
Reaction time: 0.02 h
Yield: 57.7 %

Procedure:
A dry, argon-filled Schlenk tube with a magnetic stirrer bar and septum is initially charged with (TMP)2Zn.MgCl2 (3.16 ml, 1.2 mmol). After adding 2-chloro-3-nitropyridine (159 mg, 1 mmol) in anhydrous THF (2 ml) at 25° C., the mixture is stirred for 1 min, then a solution of ethyl 4-iodobenzoate (387 mg, 1.4 mmol), bis(dibenzylideneacetone)palladium(0) (17 mg, 3 mol %) and tri-2-furylphosphine (14 mg, 6 mol %) in anhydrous THF (2 ml) is added dropwise and the mixture is stirred at 25° C. for 1 h. For workup, the mixture is diluted with aqueous sat. NH4Cl solution (30 ml) and extracted with ethyl acetate (3×30 ml). After the combined organic phases have been dried over Na2SO4, the solvent has been distilled off and purification has been effected by column chromatography on silica gel (heptane:ethyl acetate), the desired compound (177 mg, 58% of theory) was obtained as a yellowish oil.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[Br-].[O:15]1CCO[CH:16]1[CH2:20][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOCCN(CCOCCOC)CCOCCOC>ClCCl.C([O-])([O-])=O.[K+].[K+]>[N:1]1([C:6]2[CH:13]=[CH:12][C:9](/[CH:10]=[CH:20]/[CH:16]=[O:15])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: c1ccc([P+](CC2OCCO2)(c2ccccc2)c2ccccc2)cc1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: ClCCl
Product: O=C/C=C/c1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
A mixture of 4-(1H-pyrazol-1-yl)-benzaldehyde (prepared as described in J. Med Chem. 1998, 41, 2390) (1.65 g, 9.58 mmol), (1,3-dioxolan-2-ylmethyl)triphenylphosphonium bromide (6.45 g, 15.02 mmol), and TDA-1 (3.20 mL, 10.00 mmol) in dichloromethane (50 mL) and sat. aq. K2CO3 (50 mL) was heated to reflux for 20 h. The layers were separated and the aqueous layer was extracted with dichloromethane (2×25 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (MgSO4), and concentrated. THF (25 mL) and 10% HCl (25 mL) were added and the mixture was stirred for 1 h at rt. The reaction mixture was cooled to 0° C., made basic with 10% NaOH, and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (MgSO4), and concentrated. Purification by chromatography (SiO2, 3:1 hexane/ethyl acetate) provided 1.69 g (89%) of the title compound as a yellow solid. MS 199 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[C:10]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:9]=[CH:8][C:5]=1[CH:6]=O)[CH3:2].[CH:17]1([N:22]2[C:26]([NH2:27])=[C:25]([C:28]([NH2:30])=[O:29])[C:24]([CH2:31][CH3:32])=[N:23]2)[CH2:21][CH2:20][CH2:19][CH2:18]1.C1C=CC=CC=1.O>[Pd].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCCCCC>[CH:17]1([N:22]2[C:26]3=[N:27][C:6]([C:5]4[CH:8]=[CH:9][C:10]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:11][C:4]=4[O:3][CH2:1][CH3:2])=[N:30][C:28](=[O:29])[C:25]3=[C:24]([CH2:31][CH3:32])[NH:23]2)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCOc1cc(N(CC)CC)ccc1C=O
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCC
Solvent: O
Solvent: c1ccccc1
Product: CCOc1cc(N(CC)CC)ccc1-c1nc2n(C3CCCC3)[nH]c(CC)c-2c(=O)n1
Yield: 15.8 %

Procedure:
A mixture of 2-ethoxy-4-(diethylamino)benzaldehyde (7.87 g, 35.56 mmol), 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (3.95 g, 17.78 mmol), p-toluenesulfonic acid monohydrate (0.05 g), 10% palladium on carbon (0.11 g) and benzene (150 ml) was refluxed overnight with the azeotropic removal of water. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo. The residue was combined with that from a similar experimental run, and dissolved in CH2Cl2, and loaded onto a silica gel column. Elution of the column with ether/hexane (60/40) afforded a green foam which was titurated with refluxing hexane, and cooled and the product, as pale yellow needles, was collected by filtration to afford 1.19 g (8%) of 1-cyclopentyl-3-ethyl-6-[2-ethoxy-4-(diethylamino)phenyl]pyrazolo[3,4-d]pyrimidin-4-one, m.p. 138-139° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=O)[C:5]([O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:18][N:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)[C:5]([O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)COc1c(C=O)cc(Cl)cc1C(=O)OC
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)COc1c(CN2CCN(C)CC2)cc(Cl)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.5 %

Procedure:
A solution of methyl 5-chloro-3-formyl-2-(2-methoxy-2-oxoethoxy)benzoate (0.99 g, 3.5 mmol) in methylene chloride (30 mL) was added with N-methylpiperazine (0.38 g, 3.8 mmol), and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was cooled to 0° C., and then added portionwise with sodium triacetoxyborohydride (0.12 g, 5.5 mmol). After completion of the addition, the reaction mixture was warmed to room temperature, and stirred for 12 hours. The reaction mixture was added with water, the mixture was extracted with ethyl acetate, and the organic layer was successively washed with saturated aqueous sodium hydrogencarbonate, and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluted with chloroform/methanol (99:1→95:5)) to obtain methyl 5-chloro-2-(2-methoxy-2-oxoethoxy)-3-[(4-methylpiperazin-1-yl)methyl]benzoate (1.2 g, 75%).
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:40][C:41]([N:43]([CH2:45][CH2:46][O:47][CH3:48])[CH3:44])=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:40][CH2:41][N:43]([CH2:45][CH2:46][O:47][CH3:48])[CH3:44])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: COCCN(C)C(=O)CCl
Product: CCN(Cc1ccc(OCCN(C)CCOC)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 23.7 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-N-(2-methoxyethyl)-N-methylacetamide (13 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (4.9 mg) was obtained.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]2[S:14][C:15]3[CH:21]=[C:20]([S:22]C#N)[CH:19]=[CH:18][C:16]=3[N:17]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.SCC(C(CS)O)O>P([O-])(O)(O)=O.[K+]>[N:1]1([CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]2[S:14][C:15]3[CH:21]=[C:20]([SH:22])[CH:19]=[CH:18][C:16]=3[N:17]=2)=[O:11])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: N#CSc1ccc2nc(NC(=O)NCCN3CCOCC3)sc2c1
Agent: O=P([O-])(O)O
Agent: OC(CS)C(O)CS
Agent: [K+]
Product: O=C(NCCN1CCOCC1)Nc1nc2ccc(S)cc2s1
Yield: 75.5 %

Procedure:
The 1-(2-morpholin-4-ylethyl)-3-(6-sulphanyl-1,3-benzothiazol-2-yl)urea was prepared according to the method described in Example 1b, but using 900 mg of 2-{[(2-morpholin-4-ylethyl)carbamoyl]amino}-1,3-benzothiazol-6-yl thiocyanate, 11 mg of potassium dihydrogen phosphate and 1.1 g of DL-dithiothreitol. 633 mg of 1-(2-morpholin-4-ylethyl)-3-(6-sulphanyl-1,3-benzothiazol-2-yl)urea are thus obtained in the form of a white solid, the characteristics of which are as follows:
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][N:9]2[C:17]([C:18](OC)=[O:19])=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][C:14]=3[NH2:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH:1]1([CH2:7][CH2:8][N:9]2[C:17]([CH2:18][OH:19])=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][C:14]=3[NH2:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1nc2c(N)ncnc2n1CCC1CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1ncnc2c1nc(CO)n2CCC1CCCCC1

Procedure:
A solution of N9-cyclohexylethyl-8-methoxycarbonyladenine (1 mmol) in tetrahydrofuran was treated with lithium aluminum hydride (1 mmol) at 0° C. for 1 h. Extraction and chromatography give N9-cyclohexylethyl-8-hydroxymethyladenine as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[O:6][C@@H:7]([C@:11]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][NH:12]1)[C:8]([OH:10])=[O:9].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41](Cl)=[O:42])=[CH:36][CH:35]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[O:6][C@@H:7]([C@:11]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][N:12]1[C:41](=[O:42])[CH2:40][C:37]1[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=1)[C:8]([OH:10])=[O:9]
Reactant: COc1cc(OC)cc(O[C@H](C(=O)O)[C@@]2(c3ccccc3)NCCc3ccccc32)c1
Reactant: COc1ccc(CC(=O)Cl)cc1
Product: COc1ccc(CC(=O)N2CCc3ccccc3[C@@]2(c2ccccc2)[C@H](Oc2cc(OC)cc(OC)c2)C(=O)O)cc1
Yield: 60.9 %

Procedure:
(±)-(S*)-(3,5-dimethoxy-phenoxy)-{(1S*)-2-[2-(4-methoxy-phenyl)-acetyl]-1-phenyl-1,2,3,4-tetrahydro-isoquinolin-1-yl}-acetic acid (74 mg) is prepared in analogy to Example 5 starting from (±)-(S*)-(3,5-dimethoxy-phenoxy)-((1S*)-1-phenyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetic acid (90 mg, 0.214 mmol, Example 1) and 4-methoxyphenylacetyl chloride (49 μl, 0.321 mmol). LC-MS2: tR=5.25 min, [M+1]+=568.43, [M−1]−=566.51.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:69]=[CH:68][C:13]([O:14][CH2:15][C@@H:16]([CH2:42][O:43][C:44](=[O:67])[C@H:45]([CH3:66])[NH:46][C:47](=[O:65])[CH2:48][C@H:49]([NH:57]C(OC(C)(C)C)=O)[C:50]([O:52]C(C)(C)C)=[O:51])[O:17][C:18](=[O:41])[C@H:19]([CH3:40])[NH:20][C:21](=[O:39])[CH2:22][C@H:23]([NH:31]C(OC(C)(C)C)=O)[C:24]([O:26]C(C)(C)C)=[O:25])=[CH:12][CH:11]=2)[C:5]([C:70]#[N:71])=[C:4]([S:72][CH2:73][C:74]2[N:75]=[C:76]([C:79]3[CH:84]=[CH:83][C:82]([Cl:85])=[CH:81][CH:80]=3)[O:77][CH:78]=2)[N:3]=1.[F:86][C:87]([F:92])([F:91])[C:88]([OH:90])=[O:89]>ClCCl>[F:86][C:87]([F:92])([F:91])[C:88]([OH:90])=[O:89].[F:86][C:87]([F:92])([F:91])[C:88]([OH:90])=[O:89].[NH2:31][C@@H:23]([CH2:22][C:21](=[O:39])[NH:20][C@@H:19]([CH3:40])[C:18](=[O:41])[O:17][C@@H:16]([CH2:15][O:14][C:13]1[CH:12]=[CH:11][C:10]([C:6]2[C:5]([C:70]#[N:71])=[C:4]([S:72][CH2:73][C:74]3[N:75]=[C:76]([C:79]4[CH:80]=[CH:81][C:82]([Cl:85])=[CH:83][CH:84]=4)[O:77][CH:78]=3)[N:3]=[C:2]([NH2:1])[C:7]=2[C:8]#[N:9])=[CH:69][CH:68]=1)[CH2:42][O:43][C:44](=[O:67])[C@H:45]([CH3:66])[NH:46][C:47](=[O:65])[CH2:48][C@H:49]([NH2:57])[C:50]([OH:52])=[O:51])[C:24]([OH:26])=[O:25]
Reactant: C[C@H](NC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC[C@H](COc1ccc(-c2c(C#N)c(N)nc(SCc3coc(-c4ccc(Cl)cc4)n3)c2C#N)cc1)OC(=O)[C@H](C)NC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](NC(=O)C[C@H](N)C(=O)O)C(=O)OC[C@H](COc1ccc(-c2c(C#N)c(N)nc(SCc3coc(-c4ccc(Cl)cc4)n3)c2C#N)cc1)OC(=O)[C@H](C)NC(=O)C[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An amount of 190 mg (0.156 mmol) of the compound from example 22A was introduced in 1 ml of dichloromethane, admixed with 0.120 ml (1.559 mmol) of trifluoroacetic acid and stirred at RT overnight. The reaction mixture was then concentrated and the residue was purified by means of preparative HPLC (eluent gradient: acetonitrile/water 10:90→95:5 with addition of 0.1% TFA). This gave 76 mg (43% of theory) of the target compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[CH:16]=[CH:17][CH:18]=1.[N-:30]=[N+:31]=[N-:32].[Na+].[Cl-].[NH4+].[OH-].[Na+]>CN(C)C=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][C:22]2[CH:29]=[CH:28][C:25]([C:26]3[NH:32][N:31]=[N:30][N:27]=3)=[CH:24][CH:23]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(CCCc2cccc(OCc3ccc4ccccc4n3)c2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cc(CCCc2ccc(-c3nnn[nH]3)cc2)cc(OCc2ccc3ccccc3n2)c1

Procedure:
4-(3-(3-(2-Quinolinylmethyloxy)phenyl)propyl)benzonitrile (0.006 mol) with sodium azide (0.018 mol) and ammonium chloride (0.018 mol) in dimethylformamide (15 ml) is heated at 100° C. for 18 hours. The reaction mixture is poured into 10% aqueous sodium hydroxide solution and washed with ethyl acetate. The aqueous layer is acidified to pH 6 with 1 Naqueous HCl and the solid which precipitates is collected to obtain 5-(4-(3-(3-(2-quinolinylmethyloxy)phenyl)propyl)phenyl)tetrazole.