Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([OH:14])[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[CH3:15]I>CN(C=O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([O:14][CH3:15])[CH2:13][CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: CI
Reactant: OC1(c2ccc(Br)cc2)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(c2ccc(Br)cc2)CCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
To a suspension of NaH (24 mg, ˜55% dispersion in oil, 0.53 mmol) in DMF (2 ml) at 0° C. was added a solution of 1-(4-bromophenyl)-cyclobutanol (100 mg, 0.44 mmol, described in example S2-A) in DMF (2 ml). The mixture was stirred at 0° C. for 30 min and then methyl iodide (41 μl, 0.66 mmol) was added. The reaction mixture was then warmed up to RT and stirring was continued overnight. The mixture was quenched with water and extracted with ether. The organic phase was washed with water and brine, dried (MgSO4), filtered, and concentrated in vacuo to give a residue which was purified by flash column chromatography (1:9 ether/pentane) to give 1-bromo-4-(1-methoxycyclobutyl)-benzene (79 mg, 75%) as a colourless oil. 1HNMR (CDCl3, 300 MHz): δ 7.50 (d, J=8.5 Hz, 2H), 7.30 (d, J=8.5 Hz, 2H), 2.92 (s, 3H), 2.38-2.33 (m, 4H), 1.94 (m, 1H), 1.67 (m, 1H).
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].[Br:12][C:13]1[CH:14]=[C:15]([S:20](Cl)(=[O:22])=[O:21])[CH:16]=[N:17][C:18]=1[Cl:19].Cl[CH2:25]C(O)=O.[OH-].[Na+]>O>[Br:12][C:13]1[C:18]([Cl:19])=[N:17][CH:16]=[C:15]([S:20]([CH3:25])(=[O:22])=[O:21])[CH:14]=1
Reactant: O=S(=O)(Cl)c1cnc(Cl)c(Br)c1
Reactant: O=C(O)CCl
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1cnc(Cl)c(Br)c1
Temperature: 15 °C
Reaction time: 3 h
Yield: 19.3 %

Procedure:
A stirred solution of sodium sulfite (4.80 g, 38.1 mmol) and sodium bicarbonate (6.10 g, 72.6 mmol) in water (100 mL) was cooled to 15° C., and 5-bromo-6-chloropyridine-3-sulfonyl chloride (10.00 g, 34.4 mmol) was added. After being stirred at 15° C. for 3 hours and then at room temperature overnight under a nitrogen atmosphere, the mixture was heated to 40° C., and a solution of 2-chloroacetic acid (3.80 g, 40.2 mmol) and sodium hydroxide (1.90 g. 47.5 mmol) in water (20 mL) was added. The resulting mixture was stirred at reflux for 48 hours and then cooled to room temperature. The precipitated product was collected by filtration, washed with water (50 mL) and purified by column chromatography (gradient elution with 15-20% ethyl acetate in petroleum ether) to afford 3-bromo-2-chloro-5-methanesulfonyl-pyridine (1.80 g, 6.65 mmol) as a white solid. A solution of 2-chloroacetic acid (1.90 g, 20.1 mmol) and sodium hydroxide (0.80 g, 20.0 mmol) in water (10 mL) was added to the filtrate. The mixture was heated at reflux overnight, and then evaporated to remove most of the water (about 100 mL). The residue was cooled to room temperature, and then extracted with dichloromethane (80 mL×3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (gradient elution with 15-20% ethyl acetate in petroleum ether) to afford another batch of 3-bromo-2-chloro-5-methanesulfonyl-pyridine (1.30 g, 4.8 mmol, yield of two batches 35.5%) as a white solid (reference: U.S. Pat. No. 5,424,481).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[CH2:18][CH:17]([C:22](Cl)=[O:23])[CH2:16]2)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.S(Cl)(Cl)=O.O>O1CCOCC1>[OH:2][CH2:1][CH2:3][NH:4][C:22]([CH:17]1[CH2:16][C:15]2[C:19](=[CH:20][CH:21]=[C:13]([C:5](=[O:12])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:14]=2)[CH2:18]1)=[O:23]
Reactant: O=C(c1ccccc1)c1ccc2c(c1)CC(C(=O)Cl)C2
Reactant: NCCO
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1ccccc1)c1ccc2c(c1)CC(C(=O)NCCO)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.2 g (0.084 mole+20%) of monoethanolamine dissolved in 30 cm3 of dioxane is placed in a 250 cm3 reaction vessel equipped with a stirrer, a cooler, a dropping funnel and a thermometer. At a temperature of between 15° and 20° C., a solution of 12.2 g (0.042 mole) of 5-benzoyl-indan-2-carboxylic acid chloride (prepared in conventional manner by reacting thionyl chloride with the corresponding acid) in 30 cm3 of dioxane is slowly added. The reaction mixture is stirred for one hour at ambient temperature and then poured into iced, acidified water. A whitish oil separates and finally crystallizes. Upon recrystallization from acetone, a solid which melts at 106°-107° C. (capillary tube) is obtained.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][C:52]([CH3:60])=[C:53]([O:58][CH3:59])[CH:54]=4)[O:49][C:48]=3[C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C>>[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][C:52]([CH3:60])=[C:53]([O:58][CH3:59])[CH:54]=4)[O:49][C:48]=3[C:61]3[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=3)=[CH:45][CH:46]=2)[CH2:38][CH2:39][CH2:40]1
Reactant: COc1cc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc2cc1C
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: COc1cc2c(=O)c(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)oc2cc1C
Yield: 87.2 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(6-methoxy-7-methyl-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (40 mg, 0.078 mmol) was reacted to give the title compound (28 mg, 88%). LCMS (Method E): RT=3.99 min, [M+H]+=412. 1H NMR (400 MHz, DMSO-d6): δ 7.55 (s, 1H), 7.37-7.24 (m, 8H), 7.06 (d, J=7.8 Hz, 2H), 3.86 (s, 3H), 2.35-2.16 (m, 7H), 2.07-1.87 (m, 3H), 1.64-1.53 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[C:5]([NH:7][C@@H:8]([CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]([OH:11])=O)=[O:6].C1C=CC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C.[CH3:43][O:44][C:45]1[CH:50]=[CH:49][C:48]([NH:51][CH2:52][CH2:53][NH2:54])=[CH:47][CH:46]=1>C(Cl)Cl>[CH3:43][O:44][C:45]1[CH:50]=[CH:49][C:48]([NH:51][CH2:52][CH2:53][NH:54][C:9]([C@@H:8]([NH:7][C:5](=[O:6])[C:4]2[CH:21]=[CH:22][CH:23]=[C:2]([CH3:1])[CH:3]=2)[CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])=[CH:47][CH:46]=1
Reactant: Cc1cccc(C(=O)N[C@@H](CCCc2ccccc2)C(=O)O)c1
Reactant: COc1ccc(NCCN)cc1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1ccc(NCCNC(=O)[C@H](CCCc2ccccc2)NC(=O)c2cccc(C)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.1 %

Procedure:
L-Styryl alanine 1 (50 mg, 0.26 mmol) was dissolved in MeOH (5 mL) and the reaction vessel was flushed with nitrogen. Catalytic amount of palladium (10% on carbon) was added and the reaction vessel was placed under a hydrogen atmosphere. The mixture was stirred for 2 h at room temperature, then filtered over celite. The organic solvent was removed in vacuo to yield (S)-2-amino-5-phenyl-pentanoic acid 2 (51 mg, quant.) as a white powder: 1H-NMR (400 MHz, CD3OD) δ=7.42–7.25 (m, 5H), 3.71 (t, J=6.0, 1H), 2.69 (t, J=6.4, 2H), 1.85 (m, 2H), 1.70 (m, 2H). MS calcd. for C11H16NO2 (M+H+) 194.12. found 194.4. Step B: (S)-2-Amino-5-phenyl-pentanoic acid 2 (23 mg, 0.12 mmol) was dissolved in H2O (1 mL) containing equimolar amounts of NaOH (5 mg, 0.12 mmol). The solution was cooled to 0° C., then m-Toluic acid chloride (16 μL, 0.12 mmol) was added dropwise under vigorous stirring. The mixture was allowed to warm to room temperature and stirred for approx. 12 h. After acidification with 1 M HCl (1 mL), the product was extracted from the reaction mixture with DCM (4 mL). The organic layer was separated and the solvent was removed in vacuo to yield (S)-2-(3-methyl-benzoylamino)-5-phenyl-pentanoic acid 3 (21 mg, 56%) as a white solid: 1H-NMR (400 MHz, CD3OD) δ=7.83–7.09 (m, 9H), 4.62 (dd, J=5.0, J=9.1, 1H), 2.65 (m, 2H), 2.37 (s, 3H), 2.01–1.67 (m, 4H). MS calcd. for C19H22NO3 (M+H+) 312.16. found 312.4. Step C: (S)-2-(3-Methyl-benzoylamino)-5-phenyl-pentanoic acid 3 (21 mg, 0.07 mmol) was dissolved in DCM (2 mL), HOBt (20 mg, 0.14 mmol) and DIC (23 μL, 0.14 mmol) were added and the solution was stirred for 10 min at room temperature. N-(4-Methoxyphenyl)-ethane-1,2-diamine (24 mg, 0.14 mmol) was added and the solution was stirred for 3 h at room temperature. The solvent was removed in vacuo, and the remainder was purified by reverse HPLC to afford the title compound (S)-N-{1-[2-(4-Methoxy-phenylamino)-ethylcarbamoyl]-4-phenyl-butyl}-3-methyl-benzamide 4 (18 mg, 0.04 mmol, 56%) as a white solid: 1H-NMR (400 MHz, CD3OD) δ=7.56–7.48 (m, 2H), 7.36–7.16 (m, 7H), 6.96–6.87 (m, 4H), 4.48 (dd, J=6.2, J=13.7, 1H), 3.82 (s, 3H), 3.78–3.64 (m, 2H), 3.58–3.50 (m, 2H), 2.71–2.64 (m, 2H), 2.35 (s, 3H), 2.06–1.70 (m, 4H). MS calcd. for C28H34N3O3 (M+H+) 460.26. found 460.5.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:46]=[CH:47][CH:48]=4)[C:28]([NH:30][CH2:31][CH2:32][C:33]4[CH:45]=[CH:44][C:36]([O:37][CH2:38][C:39]([O:41]CC)=[O:40])=[CH:35][CH:34]=4)=[O:29])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:50]>CO.O1CCOCC1>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:46]=[CH:47][CH:48]=4)[C:28]([NH:30][CH2:31][CH2:32][C:33]4[CH:45]=[CH:44][C:36]([O:37][CH2:38][C:39]([O-:41])=[O:40])=[CH:35][CH:34]=4)=[O:29])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+:50]
Reactant: CCOC(=O)COc1ccc(CCNC(=O)c2cccc(CC3CCCC=C3c3nc(-c4ccccc4)c(-c4ccccc4)o3)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: O=C([O-])COc1ccc(CCNC(=O)c2cccc(CC3CCCC=C3c3nc(-c4ccccc4)c(-c4ccccc4)o3)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
To a solution of ethyl (±)-4-{2-{3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}-benzoylamino}ethyl}phenoxyacetate (115 mg, 0.18 mmol) in MeOH-1,4-dioxane (1:1, 4 ml) was added 1N sodium hydroxide solution (0.18 ml, 0.18 mmol) at 5° C. and the mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated and Et2O was added thereto. The resulting solid was collected by filtration to give sodium (±)-4-{2-{3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}-benzoylamino}ethyl}phenoxyacetate (105.0 mg, 92%).
Reaction SMILES: [CH:1]1([CH:6]=[C:7]([C:17]2[CH:22]=[CH:21][C:20]([C:23](=O)C)=[CH:19][CH:18]=2)[C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][OH:27]>[Pd]>[CH:1]1([CH2:6][CH:7]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:26]=[O:27])=[CH:19][CH:18]=2)[C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Reactant: CO
Agent: [Pd]
Product: O=CCc1ccc(C(CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Temperature: 25 °C
Yield: 35 %

Procedure:
A mixture 1-{4-[2-cyclopentyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-vinyl]-phenyl}-ethanone (prepared as in Example 64, 280 mg, 0.84 mmol) and 10% palladium on activated carbon (56 mg) in methanol (200 mL) was heated at 50° C. under hydrogen (50 psi) for 5 h. The mixture was cooled to 25° C., the solids filtered off, washed with ethyl acetate and concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-{4-[2-cyclopentyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-ethyl]-phenyl}-ethanone (100 mg, 35%): LC/MS m/e calcd for C22H24N2O [M+H]+ 333.45, observed 333.1; 1H NMR (400 MHz, CD3OD) δ ppm 8.06 (d, J=4.5 Hz, 1H), 7.85-7.95 (m, 3H), 7.45 (d, J=7.6 Hz, 2H), 6.99-7.05 (m, 1H), 6.35 (s, 1H), 4.25 (t, J=7.8 Hz, 1H), 2.56 (s, 3H), 2.24 (dt, J=13.6, 7.0 Hz, 1H), 2.09 (dt, J=13.6, 7.0 Hz, 1H), 1.57-1.85 (m, 5H), 1.41-1.54 (m, 2H), 1.13-1.27 (m, 2H).
Reaction SMILES: [CH:1]1([C:7]2(C#N)[C:17]3[CH:16]=[C:15]4[C:11]([CH2:12][CH2:13][NH:14]4)=[CH:10][C:9]=3[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N.[Na].[Cl-].[NH4+]>O1CCCC1.C(O)C>[CH:1]1([CH:7]2[C:17]3[CH:16]=[C:15]4[C:11]([CH2:12][CH2:13][NH:14]4)=[CH:10][C:9]=3[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#CC1(C2CCCCC2)Cc2cc3c(cc21)NCC3
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: c1c2c(cc3c1CC3C1CCCCC1)NCC2
Reaction time: 0.5 h

Procedure:
A solution of 0.5 g of the product obtained in Step 1 of Example 10 in 10 ml of anhydrous tetrahydrofuran and 0.11 ml of absolute ethanol are poured into 20 ml of liquid ammonia at a temperature of −78° C., and then 0.15 g of sodium are introduced in portions. After contact for 30 minutes at that temperature, the reaction mixture is treated with 0.83 g of ammonium chloride. After removal of the ammonia by evaporation, the residue is taken up in a saturated solution of ammonium chloride and extracted with ether and the ethereal phases are washed, dried and concentrated to yield the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[CH:12]=[C:13]([CH2:17][NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:14]=[N:15][CH:16]=3)[NH:8]2)=[CH:4][CH:3]=1.[C:23](=O)(OC)OC.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[CH:12]=[C:13]([CH2:17][N:18]([CH3:23])[S:19]([CH3:22])(=[O:20])=[O:21])[CH:14]=[N:15][CH:16]=3)[NH:8]2)=[CH:4][CH:3]=1
Reactant: COC(=O)OC
Reactant: CS(=O)(=O)NCc1cncc(-c2cc3ccc(Cl)cc3[nH]2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(Cc1cncc(-c2cc3ccc(Cl)cc3[nH]2)c1)S(C)(=O)=O
Temperature: 150 °C
Reaction time: 5 h

Procedure:
A flask is charged with N-[5-(6-chloro-1H-indol-2-yl)-pyridin-3-ylmethyl]-methanesulfonamide (670 mg, 1.49 mmol), DMF (10 mL), dimethyl carbonate (403 mg, 4.47 mmol) and potassium carbonate (319 mg, 2.31 mmol), and the mixture is stirred at 150° C. for 5 h. The mixture is cooled to room temperature and purified using Xbridge C18 eluting with a 1:9 to 9:1 acetonitrile-water gradient to give N-[5-(6-chloro-1H-indol-2-yl)-pyridin-3-ylmethyl]-N-methyl-methanesulfonamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.74 (s, 3H), 3.02 (s, 3H), 4.35 (s, 2H), 7.04 (dd, J=8.5, 1.9 Hz, 1H), 7.09 (d, J=1.5 Hz, 1H), 7.43 (d, J=1.8 Hz, 1H), 7.59 (d, J=8.6 Hz, 1H), 8.14 (t, J=2.1 Hz, 1H), 8.47 (d, J=2.0 Hz, 1H), 9.05 (d, J=2.3 Hz, 1H), 11.92 (s, 1H). HRMS (ESI) m/z 350.0738 [(M+H)+ Calcd for C16H17ClN3O2S: 350.0730].
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16].C(O)C.Cl>O.CCOCC>[F:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]([C:5]1[S:6][CH:7]=[CH:8][C:4]=1[CH:3]=[O:2])=[O:17]
Reactant: COC(OC)c1ccsc1C(=O)c1ccccc1F
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: O=Cc1ccsc1C(=O)c1ccccc1F
Temperature: 25 °C
Yield: 27 %

Procedure:
To 2-(2-fluorobenzoyl)-3-thiophenecarboxaldehyde dimethylacetal was added a solution of absolute ethanol (575 ml) and hydrogen chloride (39 g). The reaction mixture was heated at reflux for 10 mins, with stirring under nitrogen. The solution was cooled to room temperature, diluted with water and ether, and the layers were separated. The aqueous layer was extracted with ether, and the combined organic layers washed with dilute aqueous sodium bicarbonate solution, brine, dried over anhydrous potassium carbonate, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0-20% ethyl acetate/hexanes) to afford 20.3 g (27%) of product.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:19][O:20][CH2:21][C:22](=O)[C:23]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[C:25]([F:31])[CH:24]=1)[C@H:9]([O:11]CC1C=CC=CC=1)[CH3:10])(C)(C)C.Cl.C(OCC)(=O)C>C(OCC)(=O)C>[F:31][C:25]1[CH:24]=[C:23]([C@H:22]2[NH:7][C@@H:8]([C@H:9]([OH:11])[CH3:10])[CH2:19][O:20][CH2:21]2)[CH:28]=[C:27]([F:29])[C:26]=1[F:30]
Reactant: C[C@@H](OCc1ccccc1)[C@@H](COCC(=O)c1cc(F)c(F)c(F)c1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1COC[C@@H](c2cc(F)c(F)c(F)c2)N1
Reaction time: 10 h
Yield: 51.1 %

Procedure:
To a solution of {(1R,2R)-2-benzyloxy-1-[2-oxo-2-(3,4,5trifluorophenyl)ethoxymethyl]-propyl}carbamic acid t-butyl ester (13.9 g, purity: about 84.9%) in ethyl acetate (20 mL) was added a 4 N hydrochloric acid/ethyl acetate solution (63 mL), and the resultant solution was stirred at room temperature for 5 hours. Solvent was removed by distillation under reduced pressure, and to the resultant product in methanol (100 ml) was added 10% palladium-carbon (1 g, 50% water content). Under a hydrogen atmosphere, the reaction mixture was stirred for 10 hours. The catalyst was filtered off over Celite. To the resultant product was added methanol (100 ml) and 20% palladium hydroxide-carbon (1 g), and under a hydrogen atmosphere, the reaction mixture was stirred for 8 hours. The catalyst was filtered off over Celite, and solvent was removed by distillation under reduced pressure. The residue was passed through a silica pad (carrier: silica gel, 500 cc; elution solvent: 5% triethylamine/ethyl acetate, 6 L), and the filtrate was then concentrated by distillation under reduced pressure. The residue was diluted with ethyl acetate. The resultant solution was washed with brine, and then dried over anhydrous magnesium sulfate. Solvent was removed by distillation under reduced pressure, to thereby obtain the titled compound (3.97 g). The physical properties of the compound were as follows. ESI-MS; m/z 262 [M++H]. 1H-NMR (CDCl3) δ (ppm): 1.22 (d, J=6.8 Hz, 3H), 1.93 (brs, 1H), 2.88 (ddd, J=10.0, 6.8, 3.6 Hz, 1H), 3.14 (dd, J=11.2, 10.0 Hz, 1H), 3.31 (dd, J=10.4, 10.4 Hz, 1H), 3.64 (ddd, J=12.4, 6.0, 6.0 Hz, 1H), 3.76 (dd, J=11.2, 3.2 Hz, 1H), 3.83 (dd, J=11.2, 3.2 Hz, 1H), 3.91 (dd, J=10.0, 3.2 Hz, 1H), 7.05 (dd, J=8.0, 6.4 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](N(C2C=CC=C(O)C=2)CC2NCCN=2)=[CH:6][CH:7]=1.CC([N:32]([CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[CH2:33][CH2:34][Cl:35])COC1C=CC=CC=1.COC1C=C2C(N)=NC(N3CCN(C(C4OC=CC=4)=O)CC3)=NC2=CC=1OC.C1C=CC(CC2NCCN=2)=CC=1>>[CH:40]1[CH:39]=[CH:38][C:37]([CH2:36][N:32]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:33][CH2:34][Cl:35])=[CH:42][CH:41]=1
Reactant: Cc1ccc(N(CC2=NCCN2)c2cccc(O)c2)cc1
Reactant: CC(COc1ccccc1)N(CCCl)Cc1ccccc1
Agent: COc1cc2nc(N3CCN(C(=O)c4ccco4)CC3)nc(N)c2cc1OC
Agent: c1ccc(CC2=NCCN2)cc1
Product: ClCCN(Cc1ccccc1)Cc1ccccc1

Procedure:
phentolamine; phenoxybenzamine; prazosin; tolazoline;
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([S:9][C:10]1[CH:15]=[C:14]([NH2:16])[C:13]([F:17])=[CH:12][C:11]=1[Cl:18])[CH2:6][CH2:7]Cl)[CH3:2].C(=O)([O-])[O-].[K+].[K+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1([S:9][C:10]2[CH:15]=[C:14]([NH2:16])[C:13]([F:17])=[CH:12][C:11]=2[Cl:18])[CH2:7][CH2:6]1)=[O:19])[CH3:2]
Reactant: CCOC(=O)C(CCCl)Sc1cc(N)c(F)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(Sc2cc(N)c(F)cc2Cl)CC1

Procedure:
A mixture of 12.5 g of 2-(5-amino-2-chloro-4-fluorophenylthio)-4-chlorobutyric acid ethyl ester, 10.6 g of potassium carbonate and 0.7 g of tetrabutylammonium hydrogen sulfate in 14 ml of toluene is maintained at +80° C. for 40 hours. The solid portions of the reaction mixture are then filtered off and washed with acetone. Evaporation of the solvent and recrystallisation from n-hexane and a small amount of ethyl acetate yield 7.9 g of 1-(5-amino-2-chloro-4-fluoro-phenylthio)-cyclopropanecarboxylic acid ethyl ester having a melting point of from +96° to +97° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=2)[CH:9]=[CH:8]1)[CH3:6])[CH3:2].[F:18][C:19]([F:40])([F:39])[CH2:20][N:21]1[C:25]([CH2:26]O)=[CH:24][C:23]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)=[N:22]1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:26][C:25]3[N:21]([CH2:20][C:19]([F:39])([F:18])[F:40])[N:22]=[C:23]([C:28]4[CH:33]=[CH:32][C:31]([O:34][C:35]([F:37])([F:38])[F:36])=[CH:30][CH:29]=4)[CH:24]=3)[CH:14]=2)[CH:9]=[CH:8]1)[CH3:6])[CH3:2]
Reactant: OCc1cc(-c2ccc(OC(F)(F)F)cc2)nn1CC(F)(F)F
Reactant: CCOC(=O)C(C)n1ccc2ccc(O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)C(C)n1ccc2ccc(OCc3cc(-c4ccc(OC(F)(F)F)cc4)nn3CC(F)(F)F)cc21

Procedure:
In analogy to the procedure described for example 3 c], [rac]-2-(6-hydroxy-indol-1-yl)-propionic acid ethyl ester (J. E. D. Barton, D. Cartwright, C. J. Mathews, Brit. UK Pat. Appl. (1992), GB 2253848 A1) was reacted with [2-(2,2,2-trifluoro-ethyl)-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-methanol (example 15 b]) in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give [rac]-2-{6-[2-(2,2,2-trifluoro-ethyl)-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-propionic acid ethyl ester as colorless oil.
Reaction SMILES: Cl[C@@H](C(C)CC)C(O)=[O:4].[CH:10]1([N:16]=[C:17]=[N:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>CN(C)C1C=CN=CC=1.CCOCC>[CH:19]1([NH:18][C:17]([NH:16][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)=[O:4])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CCC(C)[C@H](Cl)C(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 60 h
Yield: 40 %

Procedure:
While stirring, 1.5 g (0.01 moles) of (S)-2-chloro-3-methylpentanoic acid, 2.06 g (0.01 moles) of DCC, 0.12 g (0.001 moles) of 4-dimethylaminopyridine (DMAP) and an amount of 1-(4-n-alkoxy-benzoyloxy)-4-hydroxy-benzene corresponding to 0.01 moles are added to 50 mL of ether. The mixture is allowed to stand 2-3 days at room temperature. The N,N'-dicyclohexylurea formed is then filtered off with suction. The mother liquor is washed several times with water and dried over sodium sulfate. The solvent is then distilled off in a rotary evaporator and the residue is recrystallized several times from methanol.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)#[N:2].[CH3:14][Si]([N-][Si](C)(C)C)(C)C.[Na+].IC.O>C1COCC1.C(OCC)(=O)C>[C:10]([O:9][C:7]([N:5]1[CH2:6][C:3]([C:1]#[N:2])([CH3:14])[CH2:4]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC(C#N)C1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CCOC(C)=O
Product: CC1(C#N)CN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
tert-Butyl 3-cyanoazetidine-1-carboxylate (0.5 g, 2.74 mmol) was dissolved in 11 mL of THF and the reaction was cooled to −78° C. Sodium bis(trimethylsilyl)amide (3.02 mL of a 1M THF solution, 3.02 mmol) was added slowly. After 30 min, iodomethane (0.26 mL, 4.12 mmol) was added. The reaction mixture was stirred at −78° C. for 30 min then warmed to room temperature over 16 h. Water and ethyl acetate were added to the reaction, the layers were separated and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with sodium chloride solution, dried over magnesium sulfate, and evaporated. The residue was purified by silica gel chromatography (ethyl acetate/hexanes) to give 0.23 g (42%) 3-cyano-3-methyl-azetidine-1-carboxylic acid tert-butyl ester.