Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][C:20]=1[CH3:27]>>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][C:20]=3[CH3:27])=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Reactant: Cc1cc(CO)ccc1N
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(CO)cc2C)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-[(cyclopropylmethyl)(propyl)amino]pyrimidine-4-carboxylic acid (Intermediate 21) and (4-amino-3-methylphenyl)methanol (Intermediate 28), the title compound was obtained as a white solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](OC)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([OH:17])([CH3:16])([CH3:15])[CH3:14].C(OC(C)C)(C)C>[Zn]>[C:1]1([CH2:7][CH2:8][C:9]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCc1ccccc1
Reactant: CC(C)(C)O
Agent: [Zn]
Solvent: CC(C)OC(C)C
Product: CC(C)(C)OC(=O)CCc1ccccc1

Procedure:
Under a nitrogen atmosphere, a mixture of methyl 3-phenylpropionate (3.0 mmol), t-butanol (3.6 mmol), the zinc cluster obtained in the above-described Example 5 (0.0375 mmol), and diisopropyl ether (5.0 ml) was refluxed for 18 hours. As a result, t-butyl 3-phenylpropionate was obtained quantitatively.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=2[O:18][CH3:19])[CH:6]=[CH:7][CH:8]=1.[BH4-].[Na+].[CH3:22][C:23]([CH3:25])=O>C(Cl)Cl>[CH:23]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=2[O:18][CH3:19])[CH:6]=[CH:7][CH:8]=1)([CH3:25])[CH3:22]
Reactant: CC(C)=O
Reactant: COc1ccc([N+](=O)[O-])cc1-c1cccc(CN)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc([N+](=O)[O-])cc1-c1cccc(CNC(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
2-(3-Aminomethylphenyl)-4-nitroanisole (0.10 g, 0.39 mmol) was dissolved in anhydrous acetone (25 mL). The solution was distilled at atmospheric pressure until the volume was reduced to approximately 5 mL. The solution was then distilled under reduced pressure at room temperature to remove the last traces of acetone. The resultant oil was re-dissolved in CH2Cl2/MeOH (2 mL: 1 mL). Sodium borohydride (44 mg, 3 equiv) was added, and the reaction mixture stirred at room temperature for 2 h. The solution was then diluted with CH2Cl2 (10 mL), extracted with 1M NaOH (4×5 mL), dried (Na2SO4), and evaporated to afford 2-(3-(N-isopropylamino)methylphenyl)-4-nitroanisole (120 mg, 0.39 mmol, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:18]([OH:20])=O)[C:5]2[CH:6]=[N:7][N:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:9]=2[CH:10]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:61][CH2:62][C:63]1[CH:68]=[CH:67][C:66]([S:69]([NH:72][CH3:73])(=[O:71])=[O:70])=[CH:65][CH:64]=1>CN(C=O)C>[CH3:73][NH:72][S:69]([C:66]1[CH:67]=[CH:68][C:63]([CH2:62][NH:61][C:18]([C:4]2[C:5]3[CH:6]=[N:7][N:8]([C:11]4[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=4)[C:9]=3[CH:10]=[C:2]([Br:1])[CH:3]=2)=[O:20])=[CH:64][CH:65]=1)(=[O:70])=[O:71]
Reactant: CNS(=O)(=O)c1ccc(CN)cc1
Reactant: O=C(O)c1cc(Br)cc2c1cnn2-c1ccc(F)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNS(=O)(=O)c1ccc(CNC(=O)c2cc(Br)cc3c2cnn3-c2ccc(F)cc2)cc1
Reaction time: 0.25 h

Procedure:
To a stirred room temperature solution of 6-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid (0.25 g, 0.70 mmol) in DMF (15 mL) was added PyBOP (0.45 g, 0.90 mmol) and triethylamine (0.20 g, 1.6 mmol). After 15 minutes, 4-aminomethyl-N-methyl-benzenesulfonamide (0.15 g, 0.7 mmol) was added. After 5 hours, the reaction was quenched with water (30 mL), and extracted with ethyl acetate (30 mL). The combined organic layers were washed with brine (30 mL) and dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 30-50% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][CH:7]=1.[O:17]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([O:13][CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:25]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cccc(Oc2ccccc2)c1
Reactant: CC(C)C(C=Cc1cccc(F)c1)C(=O)O
Product: CC(C)C(C=Cc1cccc(F)c1)C(=O)OCc1cccc(Oc2ccccc2)c1

Procedure:
The acid chloride of 4-(3-fluorophenyl)-2-isopropyl-3-butenoic acid is reacted with m-phenoxybenzyl alcohol to yield m-phenoxybenzyl 4-(3-fluorophenyl)-2-isopropyl-3-butenoate, MS m/e 404 (M+).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4]Cl.[K].[Cl:8][C:9]1[CH:10]=[N:11][C:12](=[O:15])[NH:13][CH:14]=1>CN(C)C=O>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][N:11]1[CH:10]=[C:9]([Cl:8])[CH:14]=[N:13][C:12]1=[O:15]
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: CN(C)CCCl
Agent: [K]
Solvent: CN(C)C=O
Product: CN(C)CCn1cc(Cl)cnc1=O
Temperature: 80 °C
Reaction time: 7 h
Yield: 47 %

Procedure:
2-Dimethylaminoethyl chloride (0.016 mol) was added to the potassium salt of 5-chloropyrimid-2-one (0.012 mol) in dimethylformamide (50 ml) and the reaction mixture stirred at 80° C. for 7 h. The solvent was then evaporated at reduced pressure (1 mm Hg) and the residue was extracted with chloroform (150 ml). The chloroform solution was washed with 1 N NaOH (2×4 ml), with water (5 ml) and dried (MgSO4) before evaporation. The product was recrystallized from benzene containing a little pet. ether; yield 47%, m.p. 157° C. (Found: C, 47.87; H, 6.05 Calc. for C8H12ClN3O: C, 47.64; H, 5.99).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:37](=[O:38])[CH2:36][O:35][CH3:34])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: COCC(=O)Cl
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 66.2 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.62 g, 4.07 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.600 g, 1.85 mmol) in CH3CN (50 ml). After stirring for 20 min, methoxyacetyl chloride (0.22 g, 2.03 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 ml). The CH2Cl2 solution was washed with 1N HCl (30 ml), H2O (30 ml), brine (30 ml) and dried (MgSO4). The solvent was removed in vacuo'and the residue was purified by chromatography (SiO2, CH2Cl2:CH3OH 100:2.5) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}-2-methoxyacetamide (0.44 g, 66%) as a white solid: mp 196-198° C.; 1H NMR (DMSO-d6) δ d 11.14 (s, 1H), 8.49 (t, J=6.1 Hz, 1H), 7.86-7.79 (m, 2H), 7.68-7.65 (m, 1H), 5.19-5.12 (dd, J=5.3 and 12.5 Hz, 1H), 4.77 (d, J=6.1 Hz, 2H), 3.92 (s, 2H), 3.36 (s, 3H), 2.96-2.83 (m, 1H), 2.64-2.49 (m, 2H), 2.09-2.04 (m, 1H); 13C NMR (DMSO-d6) δ d 172.71, 169.78, 169.58, 167.52, 166.94, 139.09, 134.70, 133.00, 131.51, 127.08, 121.82, 71.46, 58.70, 48.86, 37.47, 30.91, 21.95; Anal. Calcd. For C17H17N3O6: C, 56.82; H, 4.77; N, 11.69. Found: C, 57.02; H, 4.87; N, 11.36.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:29])([CH3:28])[O:6][CH2:7][CH:8]([NH:19][C:20](=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:9]([NH:11]CC1C=CC=CC=1)[CH3:10])([CH3:4])[CH3:3]>CO.[OH-].[OH-].[Pd+2]>[NH2:11][CH:9]([CH3:10])[CH:8]([NH:19][C:20](=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:7][O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:28])[CH3:29]
Reactant: CCCCCCC(=O)NC(CO[Si](C)(C)C(C)(C)C)C(C)NCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCCCCC(=O)NC(CO[Si](C)(C)C(C)(C)C)C(C)N
Reaction time: 18 h
Yield: 102.2 %

Procedure:
A mixture of 28c (208.6 g, 0.50 mmol) and 104 mg of Pd(OH)2 in 15 mL of methyl alcohol is shaken in a Parr apparatus under hydrogen pressure for 18 h. The reaction mixture is filtered through diatomaceous earth and the filtrate concentrated to give 169 mg of the desired product 25c as an oil. NMR δ0.84 (s, 9H), 1.05 (d, 3H), 1.60 (m, 2H), 2.10 (t, 2H), 3.31 (m, 1H), 6.47 (br d, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH:11]1([O:16][C:17](=[O:30])[C@@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:20]O)[CH2:15][CH2:14][CH2:13][CH2:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[CH:11]1([O:16][C:17](=[O:30])[C@@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:20][O:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)OC1CCCC1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCOc1cccc([N+](=O)[O-])c1)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a slurry of 3-nitrophenol (1.2 g, 8.4 mmol) in anhydrous DCM (60 ml) at 0° C. was added (S)-2-tert-butoxycarbonylamino-4-hydroxy-butyric acid cyclopentyl ester (2 g, 7 mmol) (see Scheme 9) in DCM (10 ml), triphenyl phosphine (7.5 g, 28.7 mmol) followed by slow addition of DIAD (5.8 g, 28.7 mmol). The reaction was allowed to warm to room temperature and stirred for 16 h. The solvent was removed and the crude material purified by column chromatography. (EtOAc:heptane, 1:9), (1.6 g, 56%). LCMS purity 95%, m/z 309 [M++H-boc]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.[CH:15]([Si:18]([C:25]#[CH:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16].ClCCl>C(N(CC)CC)C.[Cu](I)I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:14][C:5]1[CH:4]=[CH:3][C:2]([C:26]#[C:25][Si:18]([CH:15]([CH3:17])[CH3:16])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])=[CH:7][C:6]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: Fc1ccc(Br)cc1N1CCOCC1
Reactant: C#C[Si](C(C)C)(C(C)C)C(C)C
Agent: I[Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[Si](C#Cc1ccc(F)c(N2CCOCC2)c1)(C(C)C)C(C)C
Yield: 99.6 %

Procedure:
To a CEM snap top microwave vial (10 ml) equipped with a magnetic stir bar (3×10 mm) was added 4-(5-bromo-2-fluorophenyl)morpholine (390 mg, 1.50 mmol) in triethylamine (1.5 mL). Copper iodide (12 mg, 0.060 mmol), Tetrakis(triphenylphosphine) palladium (35 mg, 0.030 mmol) and triisopropylsilyl-acetylene (0.390 mg, 2.14 mmol) were added at room temperature. The reaction was capped and irradiated in a CEM Explorer microwave at 80° C. for 30 minutes then forced air-cooled. The crude material was loaded onto silica gel and chased with dichloromethane. Purification by chromatography (hexanes) afforded 540 mg of an oil (quant); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.06-1.10 (m, 21H) 3.00 (t, J=4.6 Hz, 4H) 3.71 (t, J=4.6 Hz, 4H) 7.01 (dd, J=8.5, 2.0 Hz, 1H) 7.08 (ddd, J=4.9, 2.9, 2.6 Hz, 1H) 7.11-7.18 (m, 1H); MS (ES) m/z 362.2 [M+H]+
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:23]3[CH:24]=[C:25]4[O:30][CH2:29][O:28][C:26]4=[CH:27][C:22]=3[CH2:21][C:20]([CH3:31])=[N:19][N:18]=2)=[CH:13][CH:12]=1>CN(C)C=O.C(OCC)C>[C:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:23]4[CH:24]=[C:25]5[O:30][CH2:29][O:28][C:26]5=[CH:27][C:22]=4[CH2:21][C:20]([CH3:31])=[N:19][N:18]=3)=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC1=NN=C(c2ccc(N)cc2)c2cc3c(cc2C1)OCO3
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC1=NN=C(c2ccc(NC(=O)Nc3ccccc3)cc2)c2cc3c(cc2C1)OCO3
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
0.22 ml (2.04 mmol) of phenyl isocyanate was added to a solution of 0.50 g (1.7 mmol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine in 4 ml of dimethylformamide and the reaction mixture was stirred at 25° C. for one hour. Then it was diluted with 20 ml of diethyl ether and filtered at 5° C. The crystals were washed with 2×5 ml of diethyl ether and dried at 60°-100° C. The resulting 0.70 g of raw product, m.p. 239°-240° C. (sintering at 180° C.) was refluxed in 15 ml of ethanol, filtered after cooling, washed wtih 3×1 ml of ethanol and dried at 100° C. to yield 0.55 g (78.6%) of the aimed product, m.p. 240°-241° C. (decomp.).
Reaction SMILES: C([O:8][C:9](=[O:20])[C:10]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH2:11])C1C=CC=CC=1.N[C@H](C(O)=O)C[OH:24].[OH-].[Na+].CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>O1CCOCC1.O>[C:13]([NH:12][CH:10]([C:9]([OH:8])=[O:20])[CH2:11][OH:24])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: C=C(NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reactant: N[C@@H](CO)C(=O)O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC(CO)C(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
2-tert-butoxycarbonylamino-acrylic acid benzyl ester: Rac-serine (50 g, 0.475 mol) in dioxane (500 mL) was combined with sodium hydroxide (38 g, 0.98 mol) in water (200 mL) and cooled to 0° C. Boc anhydride (105 g, 0.48 mol) was added dropwise and the reaction was stirred at rt overnight. The reaction mixture was concentrated to remove dioxane and the aqueous layer was washed with petroleum ether. The aqueous layer was acidified to pH 4 with citric acid solution and extracted with ethyl acetate. The combined organic layers were washed with water and brine and concentrated to give N-boc-dl-serine (79 g, 81%). To this intermediate (14 g, 0.068 mol) in DMF (140 mL) was added cesium carbonate (13.2 g, 0.041 mol) and the reaction mixture was stirred at rt for 30 min under a nitrogen atmosphere. Benzyl bromide (11.7 g, 0.07 mol) was added dropwise at 0° C. and the reaction was stirred at rt overnight. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine and concentrated. The crude product obtained was purified by flash chromatography on silica gel using chloroform as eluent to give the benzyl ester intermediate (17 g, 85%). To the benzyl ester (10 g, 0.0339 mol) in DCM (150 mL) at 0° C. under a nitrogen atmosphere was added mesyl chloride (5 g, 0.0435 mol). Triethyl amine (10 g, 0.0990 mol) was then added dropwise and the reaction was stirred at rt for 1 h. The reaction mixture was washed with 1% sodium bisulphate solution, dried over anhydrous Na2SO4, and concentrated to give 84A (10 g).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.Cl[CH2:11][C:12](=[O:15])[CH2:13][PH4:14]>[Na].CO>[Cl:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH2:11][C:12](=[O:15])[CH2:13][PH4:14]
Reactant: Oc1cccc(Cl)c1
Reactant: O=C(C[PH4])CCl
Agent: [Na]
Solvent: CO
Product: O=C(C[PH4])COc1cccc(Cl)c1
Yield: 177.5 %

Procedure:
From 5.75 g (0.25 mole) of metallic sodium and 200 ml of methanol sodium methylate is prepared. 32 g (0.25 mole) of m-chloro-phenol are added, the mixture is refluxed for an hour and evaporated to dryness. The solid residue is suspended in 200 ml of benzene and 88 g (0.25 mole) of chloro acetonyl phosphorane are added. The reaction mixture is refluxed for 3 hours. The sodium chloride is removed by filtration of the hot mixture and the benzene filtrate is evaporated in vacuo. The residual solid crude product is rubbed with 50 ml of ether and the crystals formed are filtered and dried. Thus 97 g of the crystalline title compound are obtained, yield 87.2%.
Reaction SMILES: Cl.[F:2][CH:3]([F:32])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25].[CH3:33][N:34]([CH3:39])[S:35](Cl)(=[O:37])=[O:36]>>[CH3:33][N:34]([CH3:39])[S:35]([N:29]1[CH2:28][CH2:27][N:26]([C:24]([C:6]2[N:5]([CH2:4][CH:3]([F:2])[F:32])[C:13]3[C:8]([CH:7]=2)=[CH:9][C:10]([O:14][CH:15]2[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]2)=[CH:11][CH:12]=3)=[O:25])[CH2:31][CH2:30]1)(=[O:37])=[O:36]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCNCC2)n3CC(F)F)CC1
Agent: Cl
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCN(S(=O)(=O)N(C)C)CC2)n3CC(F)F)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [1-(2,2-difluoro-ethyl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone hydrochloride and dimethylsulfamoyl chloride. Light-yellow solid. MS (m/z): 542.3 (M+H)+.
Reaction SMILES: [ClH:1].Cl.[C@H:3]1([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[C:39]([F:44])=[CH:40][C:41]([F:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CC[CH2:4]1.Cl.Cl.Cl.NC1CCN(C[C@@H]([N:58]2[CH2:63][CH2:62][CH:61]([OH:64])[CH2:60][CH2:59]2)C)CC1>>[ClH:1].[ClH:1].[OH:64][CH:61]1[CH2:62][CH2:63][N:58]([C@@H:3]([CH3:4])[CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[C:39]([F:44])=[CH:40][C:41]([F:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[CH2:59][CH2:60]1
Reactant: C[C@@H](CN1CCC(N)CC1)N1CCC(O)CC1
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4cc(F)cc(F)c34)cccc2[nH]1
Agent: Cl
Product: C[C@@H](CN1CCC(NC(=O)c2cc3c(OCc4coc5cc(F)cc(F)c45)cccc3[nH]2)CC1)N1CCC(O)CC1

Procedure:
This compound is synthesized from 4-(4,6-difluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (115, see example 66) and amine 50 analogously to the method described in example 1.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[NH3:11]>[Cu]Cl>[O:10]1[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:11])[C:7]=2[CH:8]=[CH:9]1
Reactant: N
Reactant: Clc1nccc2occc12
Agent: Cl[Cu]
Product: Nc1nccc2occc12
Temperature: 150 °C
Reaction time: 20 h
Yield: 95 %

Procedure:
65.3 g (425 mmol) 4-chlorofuro[3,2-c]pyridine [CAS Reg.-No. 31270-80-1] were suspended in 600 ml aqueous ammonia solution (35%) in an autoclave. After addition of 2 g copper(I)-chloride, the reaction mixture was stirred for 20 h at 150° C. After cooling to rt, the mixture was extracted with dichloromethane (3×400 ml). The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield 46.6 g (82% of th.) of crude title compound (content >95% by GC) which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C@H:2]([CH2:11][OH:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH3:13][C:14]1[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=1[CH2:16][O:17][C:18](Cl)=[O:19].C(=O)([O-])[O-].[Na+].[Na+]>O.C(OCC)(=O)C>[CH3:13][C:14]1[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=1[CH2:16][O:17][C:18]([NH:1][C@H:2]([CH2:11][OH:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)=[O:19]
Reactant: N[C@H](CO)Cc1ccc(O)cc1
Reactant: Cc1ccccc1COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccccc1COC(=O)N[C@H](CO)Cc1ccc(O)cc1
Yield: 72.9 %

Procedure:
In a mixture of 10 ml of water and 20 ml of ethyl acetate, 1.6 g of tyrosinol was dissolved. To the solution were added dropwise 2 g of 2-methylbenzyloxycarbonyl choride and 10 ml of an aqueous solution containing 1.3 g of sodium carbonate alternately with stirring while cooling with ice. After stirring for two hours at room temperature, the ethyl acetate layer was collected and washed with 5% hydrochloric acid and then with water. The layer was dried and concentrated to dryness. The residue was crystallized from ethyl acetate-petroleum ether to give 2.2 g of N-(2-methylbenzyloxycarbonyl)-tyrosinol with a mp. 78°-81° C in a yield of 70%. Analysis, calculated for C18H21O4N C 68.55, H 6.72. N 4.44, found C 68.88, H 6.84, N 4.42. According to the same procedure as used in Example 38, the following tyrosinol derivatives were prepared from the corresponding chlorides.
Reaction SMILES: [F:1][CH:2]([F:37])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[N:8]=[C:7]2[C:14]1[N:15]=[C:16]2[C:22]([C:23]([NH:25][CH:26]([CH3:28])[CH3:27])=[O:24])=[CH:21][N:20](COCC[Si](C)(C)C)[C:17]2=[N:18][CH:19]=1.C(O)(C(F)(F)F)=O>ClCCl>[F:37][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[N:8]=[C:7]2[C:14]1[N:15]=[C:16]2[C:22]([C:23]([NH:25][CH:26]([CH3:27])[CH3:28])=[O:24])=[CH:21][NH:20][C:17]2=[N:18][CH:19]=1
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4ccc(OC(F)F)cc34)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4ccc(OC(F)F)cc34)nc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.8 %

Procedure:
To a pale yellow solution of 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (32.5 mg, 61.2 μmol) in dichloromethane (1.44 mL) was added TFA (426 mg, 288 μL, 3.73 mmol) and stirred at 25° C. for 15 h. The mixture was concentrated then re-dissolved in 5 mL of a solution of dichloromethane/MeOH/ammonium hydroxide (60:10:1) and stirred at 25° C. for 3 h, then evaporated to an off-white solid which was purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco, 0 to 5% MeOH containing 10% ammonium hydroxide in dichloromethane). The pure product was dissolved in dichloromethane/MeOH and dichloromethane evaporated to allow solid formation, then the solid was collected by filtration and dried to give 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-N-isopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (23 mg, 57.4 μmol, 94%) as a light yellow solid. MS (M+H)+=401; 1H NMR (DMSO-d6) δ: 12.83 (br. s., 1H), 9.10 (s, 1H), 8.41 (s, 1H), 8.20 (d, J=2.3 Hz, 1H), 7.96 (d, J=7.9 Hz, 1H), 7.86 (d, J=9.4 Hz, 1H), 7.42 (dd, J=9.1, 1.9 Hz, 1H), 7.21 (t, J=74.4 Hz, 1H), 4.12-4.33 (m, 4H), 2.49 (s, 9H), 1.30 (d, J=6.4 Hz, 6H).
Reaction SMILES: [CH2:1](Br)[CH:2]([CH3:4])[CH3:3].Cl[SiH:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:28])[F:27])=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH2:9][CH2:8]1>>[CH2:1]([Si@H:7]1[CH2:8][CH2:9][C@H:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:27])[F:28])=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)[CH2:11][CH2:12]1)[CH:2]([CH3:4])[CH3:3]
Reactant: FC(F)Oc1ccc(-c2ccc(C3CC[SiH](Cl)CC3)cc2)cc1
Reactant: CC(C)CBr
Product: CC(C)C[Si@H]1CC[C@H](c2ccc(-c3ccc(OC(F)F)cc3)cc2)CC1

Procedure:
Preparation was conducted in the same manner as in Example 1 except for the fact that isobutyl bromide was used instead of n-propylbromide and that 4'-(4-chloro-4-silacyclohexyl)-4-difluoromethoxybiphenyl was used instead of 4'-(4-chloro-4-silacyclohexyl)-4-fluorobiphenyl.