Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:6][C@H:5]([CH2:7][C:8]2([S:11]([O-])(=[O:13])=[O:12])[CH2:10][CH2:9]2)[CH2:4][O:3]1.[Na+].P(Cl)(Cl)([Cl:19])=O>>[CH3:1][C:2]1([CH3:15])[O:6][C@H:5]([CH2:7][C:8]2([S:11]([Cl:19])(=[O:13])=[O:12])[CH2:10][CH2:9]2)[CH2:4][O:3]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC1(C)OC[C@@H](CC2(S(=O)(=O)[O-])CC2)O1
Agent: [Na+]
Product: CC1(C)OC[C@@H](CC2(S(=O)(=O)Cl)CC2)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of sodium (R)-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)cyclopropane-1-sulfonate (1 eq) and phosphoryl trichloride (POCl3, 0.7 mL/mmol) is heated at 80° C. for 1 hour. The reaction mixture is cooled to room temperature, poured onto ice, stirred for 30 minutes and extracted with chloroform (2×). The combined organic extracts are dried (Mg504) and concentrated under reduced pressure.
Reaction SMILES: [CH2:1]([CH:3]([CH2:29][CH2:30][CH2:31][CH3:32])[C:4]([NH:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][N:13]2[CH2:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][C:18]=2[O:27][CH3:28])=[CH:9][CH:8]=1)=[O:5])[CH3:2].O.[OH-].[Li+].O1CCCC1.Cl>O.CO>[CH2:1]([CH:3]([CH2:29][CH2:30][CH2:31][CH3:32])[C:4]([NH:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][N:13]2[CH2:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=2[O:27][CH3:28])=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: CCCCC(CC)C(=O)Nc1ccc2ccn(Cc3ccc(C(=O)OC)cc3OC)c2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCCC(CC)C(=O)Nc1ccc2ccn(Cc3ccc(C(=O)O)cc3OC)c2c1
Reaction time: 8 h
Yield: 19.2 %

Procedure:
A mixture of ester (C) (0.7 g), lithium hydroxide hydrate (0.41 g), tetrahydrofuran (4 ml), methanol (4 ml), and water (1.6 ml) was stirred overnight. The mixture was then evaporated. The white solid obtained was dissolved in water (50 ml). Acidification of this homogeneous alkaline solution by dropwise addition of 10% v/v hydrochloric acid gave a fine white precipitate which was recrystallized from ethyl acetate (40 ml) to give 4-[6-(2-ethylhexanamido)indol-1-ylmethyl]-3-methoxybenzoic acid (D) (0.13 g; 30%) as a solid; mp 234°-235° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:11]([C:13]1[CH:18]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:15][C:14]=1[O:23][C@@H:24]([CH3:29])[C:25]([F:28])([F:27])[F:26])=[O:12].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1>[CH3:22][S:19]([C:17]1[CH:16]=[CH:15][C:14]([O:23][C@@H:24]([CH3:29])[C:25]([F:27])([F:28])[F:26])=[C:13]([C:11]([N:6]2[C:7]3[C:3](=[C:2]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH:10]=[CH:9][CH:8]=3)[CH2:4][CH2:5]2)=[O:12])[CH:18]=1)(=[O:20])=[O:21]
Reactant: C1COCCN1
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2c(Br)cccc21)C(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2c(N3CCOCC3)cccc21)C(F)(F)F
Yield: 57 %

Procedure:
A mixture of 0.2 mmol (4-Bromo-2,3-dihydro-indol-1-yl)-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone (example 211), 0.4 mmol morpholine, 0.3 mmol sodium tert-butylate, 2.5 mg rac.BINAP and 2.0 mg tris-(dibenzylidenaceton)-dipalladium chloroform complex in 5 ml toluene is heated at 80° C. for 3 hours. Fresh morpholine (0.4 mmol) is added and the mixture hold at 80° overnight. The reaction mixture is concentrated. Chromatography of the residue (silica gel; ethyl acetate/heptane) yields the title compound as a slightly yellow solid. Yield=57%. MS (m/e): 499.3 [M+H]+, 100%).
Reaction SMILES: [OH-].[K+].F[C:4]1[C:7]([F:9])([F:8])[C:6]([F:11])([F:10])[C:5]=1[F:12].[CH:13]([OH:16])([CH3:15])[CH3:14]>C(OCC)C>[CH:13]([O:16][C:4]1[C:7]([F:8])([F:9])[C:6]([F:10])([F:11])[C:5]=1[F:12])([CH3:15])[CH3:14]
Reactant: CC(C)O
Reactant: FC1=C(F)C(F)(F)C1(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(C)OC1=C(F)C(F)(F)C1(F)F

Procedure:
70 g (1.23 mol) of powdered potassium hydroxide are metered into a solution of 200 g (1.23 mol) of 1,2,3,3,4,4-hexafluorocyclobutene and 90 g (1:5 mol) of isopropanol in 800 ml of diethyl ether at room temperature. The mixture is stirred for a further hour and worked up as described in Example 1. The product is then distilled.
Reaction SMILES: C([C@H]([C@@H](C(OCC)=O)O)O)(OCC)=[O:2].O.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=1.C(OO)(C)(C)C.C1(C)C=CC=CC=1>ClCCl.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[CH3:25][S@@:24]([C:21]1[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)=[O:2]
Reactant: COc1ccc(SC)cc1
Reactant: CCOC(=O)[C@@H](O)[C@H](O)C(=O)OCC
Agent: [Ti+4]
Agent: CC(C)(C)OO
Agent: CC(C)[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: COc1ccc([S@](C)=O)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To titanium tetraisopropoxide (1.49 ml) in dichloromethane (50 ml) were added diethyl (S,S)-tartrate (1.71 ml) and water (90 μl), and the mixture was stirred at room temperature for 20 minutes. After 1-methoxy-4-(methylthio)benzene (0.69 ml) was dropwise added, the reaction mixture was cooled to -20° C., dropwise added with 3.07M t-butylhydroperoxide-toluene solution (1.8 ml), and stirred at -20° C. for 15 hours. Water (0.9 ml) was added, and the mixture was stirred at -20° C. for 1 hour, and then at room temperature for 1 hour. A small amount of alumina was added, and the reaction mixture was suction-filtered with celite and washed well with dichloromethane. The filtrate and the washing were combined, added with 5% sodium hydroxide-saturated brine and stirred at room temperature for 1 hour. The organic layer was separated, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluate; ethyl acetate), and the residue (730 mg) was recrystallized from ether-pentane to give 586 mg of the title compound, [α]D -103° C. (c=1.98, acetone).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[C:10]([CH3:14])=[N:11][N:12]([CH3:13])[C:5]=12)([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:23])C=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-:23])=[C:6]2[C:10]([CH3:14])=[N:11][N:12]([CH3:13])[C:5]=12)([CH3:3])[CH3:2]
Reactant: Cc1nn(C)c2c(C(C)C)ccnc12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1nn(C)c2c(C(C)C)cc[n+]([O-])c12
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To 7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine (prepared in the previous step, 2.50 g, 13.22 mmol) in 100 mL of chloroform was added 77% MCPBA (5.91 g, 26.44 mmol) at 0° C. The resulting solution was stirred at 90° C. for 3 hours. After cooling, it was neutralized with aq NaHCO3 and extracted with DCM thoroughly. The combined organic phases were then washed with water, brine and concentrated. Column chromatography using 5% 7N NH3 in MeOH/DCM as eluant afforded the title compound as a white solid. Spectroscopic data: 1H-NMR (300 MHz, CDCl3): δ ppm 1.37 (d, J=6.73 Hz, 6 H), 2.83 (s, 3 H), 3.60 (hept, J=6.73 Hz, 1 H), 4.21 (s, 3 H), 6.78 (d, J=6.30 Hz, 1 H), 8.01 (d, J=6.30 Hz 1 H).
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[O:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][N:37]=2)[CH2:32][CH2:31]1>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:39]3[CH:38]=[N:37][C:36]([N:33]4[CH2:32][CH2:31][O:30][CH2:35][CH2:34]4)=[CH:41][CH:40]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: OB(O)c1ccc(N2CCOCC2)nc1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2ccc(N3CCOCC3)nc2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 2-morpholino-5-pyridine boronic acid. The title compound was obtained in 7% yield as yellow solid. MS (m/e): 568.4 (MH+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Cl:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[Li][CH2:17][CH2:18]CC.C(I)C>C1COCC1>[Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Cl:15])=[CH:9][CH:10]=3)[CH:5]([CH2:17][CH3:18])[C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)Cc1cc(Cl)ccc1-2
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCI
Product: CCC1c2cc(Cl)ccc2-c2ccc(Cl)cc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 119.3 %

Procedure:
To a solution of 2,7-dichlorofluorene (1.0 g, 4.3 mmol) in 3 mL of THF was added n-BuLi (2 mL, 5.0 mmol) at -78° C. under argon and the solution was stirred at -78° C. for 0.5 hours. A solution of C2H5I (0.78 g, 5.0 mmol) in 1 mL of THF was poured into the solution and stirred at -78° for 15 min, quenched with NH4Cl solution, concentrated and extracted the residue with ethyl acetate, dried with MgSO4 and evaporated to get the crude product which was purified by silica gel column chromatography using hexane as the eluent to obtain 1.35 g (74%) of 2,7-dichloro-9-ethylfluorene was a white solid, mp 80°-83° C.: IR: 3435, 1453, 1422, 1296, 1160, 1072, 885, 807 cm-1.H1NMR (CDCl3, 300 MHz) δ 7.2-7.8 (m, 6H), 3.9-4.1 (t, 1H), 2.0-2.2 (m, 2H), 0.6-0.8 (t, 3H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].C(Cl)Cl.[C:10]1(C)[CH:15]=[CH:14]C=[CH:12][CH:11]=1.C(C1C=CC=CC=1)C>O.C1(C)C(C)=CC=CC=1>[CH2:5]1[C:6]2[C:12](=[CH:11][CH:10]=[CH:15][CH:14]=2)[CH2:2][C:1](=[O:3])[O:4]1
Reactant: CCOC(C)=O
Reactant: Cc1ccccc1
Solvent: Cc1ccccc1C
Solvent: ClCCl
Solvent: CCc1ccccc1
Product: O=C1Cc2ccccc2CO1

Procedure:
Recovery of isochromanones after the reaction is possible by concentration of reaction mixture or extraction with organic solvents such as ethyl acetate, methylene chloride, toluene, xylene, and ethylbenzene. Depending on the target isochromanones, when there are two layers, i.e., water layer and product layer, it is possible to separate the water layer and remove it. In particular, when the product is 3-isochromanone, the product layer is liquid at 85° C. or higher, and the solubility in water is low so that the target compound can be recovered by the operation of separation. Further, it is possible to obtain high purity 3-isochromanone by distillation purification under reduced pressure.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([Cl:15])[NH:10][C:9]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][CH2:26][Cl:27]>CN(C)C=O>[CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([Cl:15])[N:10]([CH2:24][CH2:25][CH2:26][Cl:27])[C:9]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(Cl)[nH]c(=O)n1Cc1ccccc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1cc(Cl)n(CCCCl)c(=O)n1Cc1ccccc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a suspension of 18.93 g (80 mmol) of 3-benzyl-6-chloropyrimidine-2,4(1H,3H)-dione and 17.69 g (128 mmol) of potassium carbonate in 120 ml of N,N-dimethylformamide, 15.8 ml (160 mmol) of 1-bromo-3-chloropropane was added at room temperature. This mixture was stirred at 90° C. for 3 hours. After cooling, the reaction mixture was concentrated to dryness; the resulting residue was dissolved in chloroform-water. After the organic layer was washed with water and dried, the solvent was distilled off to yield an oily substance, which was then purified by column chromatography (eluent, n-hexane/ethyl acetate=5/1→3/1) to yield 13.46 g (53.7%, light yellow powder) of the desired product.
Reaction SMILES: [OH-].[Na+].N1(C([O:10][CH2:11][CH2:12][CH2:13][N:14]2[C:26]3[C:25]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[N:19]=[C:18]([Cl:27])[C:17]=3[N:16]=[C:15]2[OH:28])=O)C=CN=C1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[Cl:27][C:18]1[C:17]2[N:16]=[C:15]([OH:28])[N:14]([CH2:13][CH2:12][CH2:11][OH:10])[C:26]=2[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:19]=1
Reactant: O=C(OCCCn1c(O)nc2c(Cl)nc3ccccc3c21)n1ccnc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OCCCn1c(O)nc2c(Cl)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 864.2 %

Procedure:
Aqueous sodium hydroxide (700 mL of 2 N) was added to a stirred suspension of 3-(4-chloro-2-hydroxy-1H-imidazo[4,5-c]quinolin-1-yl)propyl 1H-imidazole-1-carboxylate (38 g, 0.010 mol) in methanol (100 mL), and the resulting solution was stirred for two hours at room temperature and then adjusted to pH 7 with the addition of 10% w/w aqueous citric acid. A precipitate formed, and the mixture was stirred overnight. The precipitate was isolated by filtration and washed with acetonitrile to provide 24 g of 4-chloro-1-(3-hydroxypropyl)-1H-imidazo[4,5-c]quinolin-2-ol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:24][C:25](=O)[C@@H:26]([NH:28][C:29]2[N:37]=[CH:36][N:35]=[C:34]3[C:30]=2[N:31]=[CH:32][N:33]3C2CCCCO2)[CH3:27])=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][O:17]C(=O)C(C)(C)C)[CH2:10]2)[CH:7]=1>Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:24]=[C:25]([C@@H:26]([NH:28][C:29]3[N:37]=[CH:36][N:35]=[C:34]4[C:30]=3[N:31]=[CH:32][NH:33]4)[CH3:27])[N:8]([C@H:9]3[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][OH:17])[CH2:10]3)[C:6]=2[CH:7]=1
Reactant: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)C(=O)Nc1ccc(F)cc1N[C@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Agent: Cl
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1[C@H]1CCCN(CCO)C1
Temperature: 25 °C
Yield: 21.3 %

Procedure:
A solution of 2,2-dimethylpropionic acid 2-[(S)-3-(5-fluoro-2-{(S)-2-[9-(tetrahydropyran-2-yl)-9H-purin-6-ylamino]propionylamino}phenylamino)piperidin-1-yl]ethyl ester (583 mg, 0.95 mmol), in aqueous 6M HCl (20 mL) was refluxed for 30 min. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue loaded in dioxane/water (1:1) onto an Isolute® SCX-2 cartridge. The cartridge was washed with dioxane/water (1:1), then dioxane and the product eluted with 10% 880 NH3 in dioxane. The fractions containing product were purified by column chromatography (C18, gradient 2-40% MeOH in 0.5% TFA/H2O) then loaded in dioxane onto an Isolute® SCX-2 cartridge. The cartridge was washed with dioxane then the product eluted with 10% 880 NH3 in dioxane. Further purification by column chromatography (Si—PCC, gradient 3-21% 2M NH3/MeOH in DCM) afforded 278 as a colourless solid (85.8 mg, 21%). LCMS (Method K): RT 2.05 min [M+H]+ 425.1. 1H NMR (CD3OD, 400 MHz): δ 8.29 (1H, s), 8.09 (1H, s), 7.58 (1H, dd, J=9.0, 5.0 Hz), 7.50 (1H, dd, J=9.6, 2.3 Hz), 7.00 (1H, dt, J=9.3, 2.3 Hz), 5.97 (1H, bs), 4.80-4.71 (1H, m), 3.41-3.39 (2H, m), 3.15-3.10 (1H, m), 2.92 (1H, bd, J=11.3 Hz), 2.81 (1H, t, J=11.0 Hz), 2.53-2.21 (4H, m), 2.01-1.97 (1H, m), 1.92-1.86 (1H, m), 1.80 (3H, d, J=6.9 Hz), 1.78-1.70 (1H, m)
Reaction SMILES: [O:1]=[C:2]1[O:6][C@H:5]([C:7]([OH:9])=O)[CH2:4][CH2:3]1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[C:25]([O:29][C:30](=[O:37])[C@H:31]([CH2:33][CH:34]([CH3:36])[CH3:35])[NH2:32])([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl.C1COCC1>[C:25]([O:29][C:30](=[O:37])[C@H:31]([CH2:33][CH:34]([CH3:35])[CH3:36])[NH:32][C:7]([C@@H:5]1[CH2:4][CH2:3][C:2](=[O:1])[O:6]1)=[O:9])([CH3:28])([CH3:27])[CH3:26]
Reactant: O=C1CC[C@@H](C(=O)O)O1
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)[C@@H]1CCC(=O)O1)C(=O)OC(C)(C)C

Procedure:
To a solution of (S)-(+)-5-oxo-tetrahydrofuran-2-carboxylic acid (1.0 g, 7.68 mmols) and N-methylmorpholine (0.84 ml, 7.68 mmols) in anhydrous/THF anhydrous dioxan 2/1 (15 ml), cooled at −15° C. was added dropwise, under stirring, the equivalent quantity of isobutylchloroformate (1.04 ml, 7.68 mmols). After 30 minutes a solution of L-leucine tertbutylester (1.44 g, 7.68 mmols) and anhydrous THF (5 ml) was slowly added, maintaining the mixture under stirring at −15° C. for two hours. The reaction mixtures was diluted with CH2Cl2 (70 ml) and washed with NaCl saturated solution (20 ml) KHSO4 1M (20+10 ml), NaHCO3 saturated solution (20+10 ml) and NaCl saturated solution (20 ml). The organic phase was dried on Na2SO4 and concentrated at reduced pressure. The raw product was purified through chromatography on silica gel (CH2Cl2/i-PrOH 98/2). By grinding in n-hexane the solid raw residue, the N-{[(S)-(5-Oxo-tetrahydrofuran-2-yl)carbonyl]}-L-leucine tertbutyl-ester was obtained as white crystals: 920 mg (40%); m.p. 79-81° C.; [a]D22=−25° (1, methanol); IR (CHCl3): 3415, 2934, 1788, 1727, 1677, 1517, 1369, 1149 cm−1; 1H-NMR (CDCl3): d 0.87 and 0.97 [two s, 6, CH2CH(CH3)2], 1.18-1.62 [m, 3, CH2CH(CH3)2 and 1.40 (s, 9, C(CH3)3], 2.15-2.80 (m, 4, ring CH2CH2), 4.25-4.55 (m, 1, ring CH), 4.62-4.88 (m, 1, aCH), 6.56 (d, 1, NH, J=8 Hz). Calculated for C15H25NO5: C, 60.18; H, 8.42; N, 4.68. Found C, 60.12; H, 8.61; N, 4.65%.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([C:7]#[N:8])[CH2:3][CH2:2]1.[CH3:9][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>O1CCCC1>[CH3:9][C:4]1([C:7]#[N:8])[CH2:5][CH2:6][S:1][CH2:2][CH2:3]1
Reactant: N#CC1CCSCC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1(C#N)CCSCC1
Reaction time: 0.5 h
Yield: 53.4 %

Procedure:
A solution of tetrahydro-thiopyran-4-carbonitrile (3.05 g, 24 mmol) in anhydrous tetrahydrofuran (60 ml) was cooled to −78° C. and treated with lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran, 26.4 ml, 26.4 mmol) dropwise. After 30 minutes of stirring, iodomethane (1.8 ml, 29 mmol) was added dropwise. The cooling bath was removed, and the reaction mixture was allowed to slowly rise to room temperature and stir overnight. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic layers were collected, dried over MgSO4, filtered, and concentrated giving an orange oil. The oil was purified by silica gel chromatography using 5-50% EtOAc in hexanes as eluant to provide 1.81 g (53%) of 4-methyl-tetrahydro-thiopyran-4-carbonitrile as a colorless oil.
Reaction SMILES: [ClH:1].[N:2]1([CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:12]([OH:21])[CH2:13][N:14]2[CH2:19][CH2:18]N(C)[CH2:16][CH2:15]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.Cl.Cl.N1(C(C2C=CC=CC=2)C([OH:49])CN2CCN(C)CC2)C2C(=CC=CC=2)C=C1.N1CCOCC1>>[ClH:1].[N:2]1([CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:12]([OH:21])[CH2:13][N:14]2[CH2:19][CH2:18][O:49][CH2:16][CH2:15]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1
Reactant: CN1CCN(CC(O)C(c2ccccc2)n2ccc3ccccc32)CC1
Agent: Cl
Solvent: C1COCCN1
Product: OC(CN1CCOCC1)C(c1ccccc1)n1ccc2ccccc21

Procedure:
In an analogous manner to EXAMPLE 1, step 3 (1RS,2SR)-1-(1H-indol-1-yl)-3-(4-methylpiperazin-1-yl)-1-phenylpropan-2-ol hydrochloride was prepared from (2RS,3RS)-toluene-4-sulfonic acid 2-hydroxy-3-indol-1-yl-3-phenyl-propyl ester (EXAMPLE 1, step 3) and morpholine. MS (ESI) m/z 337 ([M+H]+); HRMS: calcd for C21H24N2O2+H+, 337.19105; found (ESI, [M+H]+), 337.1909.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[F:22][C:23]1[CH:31]=[C:30]2[C:26]([C:27]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[N:28][NH:29]2)=[CH:25][CH:24]=1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:35]4[CH2:36][CH2:37][N:32]([C:27]5[C:26]6[C:30](=[CH:31][C:23]([F:22])=[CH:24][CH:25]=6)[NH:29][N:28]=5)[CH2:33][CH2:34]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: Fc1ccc2c(N3CCNCC3)n[nH]c2c1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCN(c2n[nH]c3cc(F)ccc23)CC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 6-fluoro-3-piperazin-1-yl-1H-indazole (Table No.1, SM 4) in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=506.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.[CH:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.[Pd](Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: Brc1ccccc1I
Reactant: C#CCCCCCCCCCCC
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC#Cc1ccccc1Br

Procedure:
A mixture of 1-bromo-2-iodobenzene (5 g, 17.7 mmol), 1-tridecyne (4.9 ml, 21.2 mmol), triphenylphosphine (5 mg), palladium (II) chloride (5 mg) in triethylamine (45 ml) was refluxed under argon for 15 h. After cooling, the mixture was poured into ice-cold dilute hydrochloric acid and extracted thoroughly with ethyl ether. Evaporation of the dried (magnesium sulfate) extracts gave an oil, which was purified by a silica column using hexane. Fractions with Rf of about 0.36 on evaporation gave the title alkyne as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:15])=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].CCN(CC)CC.[Cl:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>C(Cl)Cl>[Cl:23][CH2:24][CH2:25][CH2:26][C:27]([NH:1][C:2]1[C:3]([F:15])=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[O:28]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(N)c1F
Reactant: O=C(Cl)CCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc([N+](=O)[O-])cc(NC(=O)CCCCl)c1F
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a solution of methyl 3-amino-2-fluoro-5-nitrobenzoate (D138) (12 g, 56 mmol, 1 equiv) in CH2Cl2 (150 ml) at room temperature were added NEt3 (11.7 ml, 84 mmol, 1.5 equiv) and 4-chlorobutanoyl chloride (6.9 ml, 61.6 mmol, 1.1 equiv) and the resulting mixture was stirred for 2 h then washed with a 2N aqueous HCl solution and a saturated aqueous NaHCO3 solution, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (iso-hexane/AcOEt: 4/1) gave methyl 3-[(4-chlorobutanoyl)amino]-2-fluoro-5-nitrobenzoate (D139) (16.2 g, 91%) as a yellow solid. [M+H]+=319.1, RT=3.12 min.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:10]=1)[C:8]#[N:9])#[CH:2].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1I.C(N(CC)CC)C>C(OCC)(=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]#[C:1][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:10]=1)[C:8]#[N:9]
Reactant: C#Cc1cncc(C#N)c1
Reactant: Clc1ccccc1I
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: N#Cc1cncc(C#Cc2ccccc2Cl)c1
Temperature: 70 °C

Procedure:
Add bis(triphenylphosphine)palladium (II) dichloride (63.2 mg, 0.090 mmol), copper (I) iodide (34.3 mg, 0.180 mmol), and 5-ethynylnicotinonitrile (242 mg, 1.89 mmol), (prepared essentially as described in PREPARATION 4), to a solution of 1-chloro-2-iodobenzene (0.22 mL, 1.77 mmol) in triethylamine (3.60 mL, 25.8 mmol) and heat to 70° C. in a sealed tube for 1.5 h. Cool to room temperature and dilute with ethyl acetate. Wash with a saturated aqueous solution of sodium chloride, dry (sodium sulfate), filter and concentrate. Purify the residue by silica gel chromatography, eluting with a gradient from 95:5 to 80:20 (90:10 hexanes:ethyl acetate):dichloromethane, to give the title compound as a yellow solid. Further purify the title compound by recrystallizing from cyclohexane (20 mL) to give a white solid (95 mg, 22%).