Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CN2C3C=CC=CC=3CC=12.COC1CCC(OC)O1.C[O:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH:36]=[CH:35][CH:34]=[CH:33]1)=[O:25].[K].[OH-].[Na+]>>[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH:36]=[CH:35][CH:34]=[CH:33]1)([OH:25])=[O:23]
Reactant: COC(=O)c1ccccc1-n1cccc1
Agent: COC1CCC(OC)O1
Agent: [K]
Agent: [Na+]
Product: O=C(O)c1ccccc1-n1cccc1

Procedure:
Synthesis substrates 9H-pyrrolo[1,2-a]indole and 9H-pyrrolol[1,2-a]indol-9-one and their derivatives are prepared in accordance with the general methods of Josey and Jenner, J. Org. Chem., 27 (1962) 2466 and Mazzola et al., J. Org. Chem., 32 (1967) 486. The process involves condensation of a substituted or unsubstituted methyl anthranilate (Aldrich Chemical, Inc.) with 2,5-dimethoxytetrahydrofuran (Aldrich Chemical, Inc.) in glacial acetic acid. Ester hydrolysis of the resulting 1-(2-methoxycarbonylphenyl)pyrrole with 10-15% potassium or sodium hydroxide in aqueous alcohol (e.g., 50% methanol) yields after acidification and subsequent work-up yields the corresponding 1-(2-carboxyphenyl)pyrrole. This acid is then converted into the corresponding acyl chloride to facilitate a Friedel-Crafts cyclization to the ketone. The preferred method of preparing the acyl chloride is with phosphorus pentachloride followed with stannic chloride as the Friedel-Crafts catalyst to cyclize the acyl chloride to the desired ketone. ##STR62## Wolf-Kishner reduction, see also Method VIII, via the semicarbazones of the ketone yields the corresponding 9H-pyrrolol[1,2-a]indole heterocycle.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[C:11]([NH2:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:13])[CH3:12].C(N(CC)CC)C.O>ClCCl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:20][C:11]([CH3:13])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:12])=[O:6]
Reactant: CC(C)(N)c1ccccc1
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(NC(=O)c1cccc(Cl)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
3-Chlorobenzoylchloride (110.0 g, 57.1 mmol) was dissolved in dichloromethane (200 mL), and the solution was added with cumylamine (9.04 mL, 62.9 mmol), triethylamine (12.0 mL, 85.7 mmol) and DMAP (698 mg, 5.71 mmol), followed by stirring at room temperature for 3 hours. The reaction mixture was added with water, extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by slurry using diisopropyl ether to obtain 3-chloro-N-(1-methyl-1-phenylethyl)benzamide (15.0 g, yield 96%).
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2([C:13]([OH:15])=[O:14])[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][O:17]C1C=CC(N)=CC=1>>[CH3:16][O:17][C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=1[NH:7][C:8]([C:10]1([C:13]([OH:15])=[O:14])[CH2:11][CH2:12]1)=[O:9]
Reactant: O=C(O)C1(C(=O)Nc2ccccc2)CC1
Reactant: COc1ccc(N)cc1
Product: COc1ccccc1NC(=O)C1(C(=O)O)CC1
Yield: 68 %

Procedure:
Following the procedure described above for compound 161 (scheme 45), but replacing aniline for 4-methoxyaniline, title compound 175 was obtained in 68% yield. M/S (m/z): 236.0 (M+H).
Reaction SMILES: CO.[OH-].[Na+].[F:5][C:6]1[C:11]2[N:12]=[C:13]([CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])[S:14][C:10]=2[C:9]([F:22])=[CH:8][C:7]=1[F:23]>O>[F:5][C:6]1[C:11]2[N:12]=[C:13]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[S:14][C:10]=2[C:9]([F:22])=[CH:8][C:7]=1[F:23]
Reactant: CCOC(=O)CCc1nc2c(F)c(F)cc(F)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCc1nc2c(F)c(F)cc(F)c2s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.6 %

Procedure:
To a mixture of methanol (8 ml), water (6 ml) and 2N sodium hydroxide (2 ml, 4 mmol) was added ethyl 3-(4,5,7-trifluorobenzothiazol-2-yl)propionate (1.1 g, 3.8 mmol) and the mixture was stirred for 15 min. at ambient temperature. The reaction solution was diluted with water and then extracted with ethyl acetate. The organic layer was washed with water, then dried and evaporated to yield a residue, which was recrystallized from hexane-isopropyl ether to give 3-(4,5,7-trifluorobenzothiazol-2-yl)propionic acid (840 mg, 85%) as colorless needles.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](O)=[O:13])=[CH:7][CH:6]=1)(O)=[O:2].CSC.B>C1COCC1>[OH:2][CH2:1][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][OH:13])=[CH:7][CH:6]=1
Reactant: O=C(O)Cc1ccc(CC(=O)O)cc1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: OCCc1ccc(CCO)cc1
Reaction time: 18 h
Yield: 87.6 %

Procedure:
To a stirred solution of (4-carboxymethylphenyl)acetic acid (1.0 g, 5.15 mmol) in THF (100 mL) was slowly added borane dimethyl sulfide (2.3 mL, 30.9 mmol) and the resulting mixture was stirred overnight (˜18 hours). The reaction was then quenched by slowly adding 1N HCl (100 mL). The resulting mixture was then extracted with EtOAc (3×100 mL). The combined organic layers were washed with saturated NaCl (1×100 mL), dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to provide 750 mg of the title intermediate (87% yield), which was used without further purification.
Reaction SMILES: [CH2:1]([Cl:4])[CH:2]=[CH2:3].[CH3:5][Si:6](C)([O:10][CH2:11]C)[O:7][CH2:8]C.C([Si](C=C)(C)O[Si](C)(C)C)=C>C1(C)C=CC=CC=1>[Cl:4][CH2:1][CH2:2][CH2:3][Si:6]([CH3:5])([O:10][CH3:11])[O:7][CH3:8]
Reactant: C=CCCl
Reactant: CCO[Si](C)(C)OCC
Agent: C=C[Si](C)(C=C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CO[Si](C)(CCCCl)OC
Temperature: 50 °C
Yield: 19.7 %

Procedure:
306 mg of allyl chloride, 530 mol of dimethyldiethoxysilane, and 77 mg of toluene were placed in a glass reaction tube. Then, 0.005 mol of a toluene solution of a 0-valent platinum complex of divinyltetramethyldisiloxane (platinum content: 0.4 wt %) was added to this mixture. The reaction tube was sealed and heated for 2 hours in an oil bath at 50° C. When the contents were analyzed by GC-MS following cooling, the conversion rate of allyl chloride was 100% and γ-chloropropylmethyldimethoxysilane was produced at a yield of 19.7%.
Reaction SMILES: [N:1]1[C:5]2=[C:6]3[CH:14]=[CH:13][CH:12]=[N:11][C:7]3=[N:8][CH2:9][CH2:10][C:4]2=[CH:3][N:2]=1.[F:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:34])=[C:20]([CH:33]=1)[C:21]([NH:23][C:24]1[N:29]=[CH:28][C:27]([C:30](Cl)=[O:31])=[CH:26][CH:25]=1)=[O:22]>>[NH:1]1[C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[N:11][C:7]=3[N:8]([C:30]([C:27]3[CH:26]=[CH:25][C:24]([NH:23][C:21](=[O:22])[C:20]4[CH:33]=[C:16]([F:15])[CH:17]=[CH:18][C:19]=4[CH3:34])=[N:29][CH:28]=3)=[O:31])[CH2:9][CH2:10][C:4]=2[CH:3]=[N:2]1
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)cn1
Reactant: C1=C2CCN=c3ncccc3=C2N=N1
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2CCc3cn[nH]c3-c3cccnc32)cn1

Procedure:
As described for Example 13, 4,5-dihydropyrazolo[3,4-d]pyrido[2,3-b]azepine is reacted with 6-[(5-fluoro-2-methylbenzoyl)amino]pyridine-3-carbonyl chloride to give the product as a solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.[CH2:14]([O:16][C:17]([C:19]1[N:24]=[CH:23][C:22]2[CH:25]=[C:26](Br)[S:27][C:21]=2[C:20]=1[OH:29])=[O:18])[CH3:15]>>[CH2:14]([O:16][C:17]([C:19]1[N:24]=[CH:23][C:22]2[CH:25]=[C:26]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=3)[S:27][C:21]=2[C:20]=1[OH:29])=[O:18])[CH3:15]
Reactant: CCOC(=O)c1ncc2cc(Br)sc2c1O
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: CCOC(=O)c1ncc2cc(-c3cccc(C(F)(F)F)c3)sc2c1O

Procedure:
The title compound was prepared from 3-(trifluoromethyl)phenyl boronic acid and 2-bromo-7-hydroxy-thieno[3,2-c]pyridine-6-carboxylic acid ethyl ester, example 21.d, under conditions analogous to experimental example 21.e; MS: (+) m/z 368.0 (M+1)
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:20])=[CH:4][C:5]2[CH:11]([CH3:12])[CH2:10][N:9](C(=O)C(F)(F)F)[CH2:8][CH2:7][C:6]=2[N:19]=1.C([O-])([O-])=O.[K+].[K+]>CO>[Cl:1][C:2]1[C:3]([I:20])=[CH:4][C:5]2[CH:11]([CH3:12])[CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[N:19]=1
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2nc(Cl)c(I)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC1CNCCc2nc(Cl)c(I)cc21
Temperature: 60 °C
Yield: 84.1 %

Procedure:
A mixture of 3-iodo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol (137 mg, 342 μmol), DMF (100 μl) and POCl3 (5 ml) was heated at 100° C. for 16 h. The reaction mixture was concentrated in vacuo and purified by column chromatography to furnish 57.0 mg (40%) of 2-chloro-3-iodo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. MS (ESI) m/z 419.1/421.1. A mixture of 2-chloro-3-iodo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (58.0 mg, 139 μmol), K2CO3 (50 mg) and MeOH (10 ml) was heated for 1 h at 60° C. The reaction mixture was concentrated in vacuo and purified by column chromatography furnishing 37.7 mg (84%) of 2-chloro-3-iodo-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (CDCl3) δ 7.86 (s, 1H), 3.13 (m, 2H), 3.07-2.92 (m, 4H), 2.75 (dd, 1H), 1.33 (d, 3H) ppm.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[N:26]([CH2:27][CH2:28][O:29][CH2:30][CH3:31])[C:25]4[CH:32]=[CH:33][CH:34]=[CH:35][C:24]=4[N:23]=3)[CH2:18][CH2:17]2)=[CH:10][CH:9]=1)([CH3:7])[CH3:6])C.[OH-].[Na+].C(O)C.O>C(O)CCC.C(OC(=O)C)C.C(O)(=O)C>[CH2:30]([O:29][CH2:28][CH2:27][N:26]1[C:25]2[CH:32]=[CH:33][CH:34]=[CH:35][C:24]=2[N:23]=[C:22]1[CH:19]1[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][C:11]2[CH:10]=[CH:9][C:8]([C:5]([CH3:6])([CH3:7])[C:4]([OH:36])=[O:3])=[CH:13][CH:12]=2)[CH2:17][CH2:18]1)[CH3:31]
Reactant: CCOCCn1c(C2CCN(CCc3ccc(C(C)(C)C(=O)OCC)cc3)CC2)nc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOCCn1c(C2CCN(CCc3ccc(C(C)(C)C(=O)O)cc3)CC2)nc2ccccc21
Yield: 84.8 %

Procedure:
In a reaction vessel, 2-[4-(2-{4-[1-(2-ethoxy-ethyl)-1H-benzoimidazol-2-yl]-piperidin-1-yl}-ethyl)-phenyl]-2-methyl-propionic acid ethylester (2.3 g) prepared in the Example 15, sodium hydroxide (0.6 g) and ethyl alcohol (13 mL) were introduced, and the mixture was reacted at 50-55□ for 3 hours. Distilled water (20 mL) was added thereto, and acetic acid was added to control the pH to 7. Ethylacetate (50 mL) was added thereto, and the mixture was stirred to separate layers. The separated organic layer was condensed under reduced pressure. And, butanol (9 mL) was added and dissolved by heating. And then, it was cooled to precipitate crystals, and the crystals were filtered under reduced pressure to obtain 2-[4-(2-{4-[1-(2-ethoxy-ethyl)-1H-benzoimidazol-2-yl]-piperidin-1-yl}-ethyl)-phenyl]-2-methyl-propionic acid (1.84 g, yield 85%, HPLC purity 99% or more).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:14])([CH3:13])[C:9](OC)=[O:10])=[CH:4][CH:3]=1.[Li+].[BH4-]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:14])([CH3:13])[CH2:9][OH:10])=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CO)c1ccc(F)cc1
Reaction time: 15 h

Procedure:
The ester from step 1 was reduced by dissolving in THF (0.15 M) and treating with LiBH4 (5 eq.) and stirring for 15 hours. The reaction mixture was quenched with water and extracted with DCM, the organic layer dried (Na2SO4) and concentrated to provide oily 2-(4-fluorophenyl)-2-methylpropan-1-ol: 1H NMR (600 MHz, CDCl3) δ 7.31-7.34 (m, 2H), 6.99-7.02 (m, 2H), 3.58 (d, J=5.8 Hz, 2H), 1.30 (s, 6H).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:30]=[CH:29][C:9]([C:10]([NH:12][C:13]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:16]3[N:25]=[C:26]([CH3:28])[CH:27]=[C:15]3[N:14]=2)=[O:11])=[CH:8][CH:7]=1)([CH3:5])[CH3:4])#[N:2].[H][H]>CO.[Ni]>[NH2:2][CH2:1][C:3]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:12][C:13]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:16]3[N:25]=[C:26]([CH3:28])[CH:27]=[C:15]3[N:14]=2)=[O:11])=[CH:29][CH:30]=1)([CH3:4])[CH3:5]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)C#N)cc3)cc(-c3ccccc3)n2n1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)CN)cc3)cc(-c3ccccc3)n2n1
Yield: 59.3 %

Procedure:
4-(2-Cyanopropan-2-yl)-N-(2-methyl-7-phenylpyrazolo[1,5-a]pyrimidin-5-yl)benzamide (Compound 343 (Example 357), 75 mg, 0.19 mmol) was dissolved in methanol (5 ml). The solution was subjected to hydrogenation conditions in a flow-hydrogenator, using Raney nickel cartridge, with 30 bar of hydrogen pressure, 50° C. temperature and a flow rate of 0.5 ml/min. The reaction mixture was concentrated in vacuo to obtain the titled product 4-(1-amino-2-methylpropan-2-yl)-N-(2-methyl-7-phenylpyrazolo[1,5-a]pyrimidin-5-yl)benzamide (45 mg, 59% yield). 1H NMR(CHLOROFORM-d) δ: 8.59 (br. s., 1H), 8.07-8.20 (m, 3H), 7.91 (d, J=8.3 Hz, 2H), 7.46-7.61 (m, 5H), 6.29 (s, 1H), 2.87 (br. s., 2H), 2.50 (s, 5H), 1.36 (s, 8H), 0.87 (br. s., 3H); ESI-MS: m/z 400.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([OH:17])=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[C:22]#[N:23]>>[CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([O:17][CH2:19][C:20]3[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=3[C:22]#[N:23])=[CH:7][CH:8]=2)[N:3]=1
Reactant: N#Cc1ccccc1CBr
Reactant: Cc1cc(N2CCCC2)c2ccc(O)cc2n1
Product: Cc1cc(N2CCCC2)c2ccc(OCc3ccccc3C#N)cc2n1

Procedure:
In analogy to example 6 there was prepared: on reaction of 2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with 2-bromomethyl benzonitrile, whereby the product was isolated as free base, 2-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)-benzonitrile as a brown solid. ISP mass spectrum, m/e: 344.4 (M+1 calculated for C22H21N3O: 344).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([NH:7][CH3:8])=[O:6].[H-].[Na+].C([Mg]Cl)(C)C.[CH2:19]([Sn:23]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])Cl)[CH2:20][CH2:21][CH3:22]>C1COCC1>[CH3:8][NH:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][N:11]=[C:2]([Sn:23]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:19][CH2:20][CH2:21][CH3:22])[CH:3]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CNC(=O)c1ccnc(I)c1
Agent: CC(C)[Mg]Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc(C(=O)NC)ccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 30.3 %

Procedure:
In a round-bottomed flask, 2-iodo-N-methylisonicotinamide (0.18 g, 0.69 mmol) was dissolved in THF (3.9 mL) and sodium hydride (60% dispersion in mineral oil, 33 mg, 0.83 mmol) was added. The reaction mixture was stirred at room temperature for 10 min then cooled to −16° C. (NaCl/ice bath) and isopropylmagnesium chloride (2.0M solution in THF, 0.39 mL, 0.780 mmol) was added dropwise. The reaction mixture was stirred at −16° C. for 40 min then tributylchlorostannane (0.22 mL, 0.81 mmol) was slowly added. The reaction mixture was allowed to warm to room temperature and stirred for 2 h then quenched with saturated NH4Cl solution and then extracted with 50 mL EtOAc (2×). The combined organic layers were washed with 5 mL water and 5 mL brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over 12 g silica gel with EtOAc/Hexanes (contains 1% Triethylamine) (gradient: 0-30% EtOAc). All fractions containing product were combined and concentrated to afford 89 mg (31%) of N-methyl-2-tributylstannanyl-isonicotinamide as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:17]=[C:16](Br)[CH:15]=2)=[CH:9][C:8]=1[Cl:31])[CH3:2].[CH:33]#[C:34][CH2:35][CH2:36][CH3:37]>C(N(CC)CC)C.CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu](I)I>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:15]=[C:16]([C:33]#[C:34][CH2:35][CH2:36][CH3:37])[CH:17]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:19]=2)=[CH:9][C:8]=1[Cl:31])[CH3:2]
Reactant: C#CCCC
Reactant: CCOC(=O)COc1ccc(Sc2cc(Br)cc(OCCCN3CCOCC3)c2)cc1Cl
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCC#Cc1cc(OCCCN2CCOCC2)cc(Sc2ccc(OCC(=O)OCC)c(Cl)c2)c1

Procedure:
{4-[3-Bromo-5-(3-morpholin-4-yl-propoxy)-phenylsulfanyl]-2-chloro-phenoxy}-acetic acid ethyl ester (0.2 g; 0.37 mmol), 1-pentyne (0.10 g; 1.47 mmol), bis(triphenylphosphine)palladium (II) chloride (21 mg; 0.029 mmol) and copper iodide (4.2 mg; 0.022 mmol) were dissolved in a mixture of triethylamine (2 mL) and DMF (2 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 150° C. for 1 h. The reaction mixture was evaporated to dryness and extracted with ethyl acetate from a aqueous 5% citric acid solution. The crude product was dried, evaporated to dryness and purified by preparative HPLC (method B). Yield: 120 mg. HPLC-MS: m/z: 532.0 (M+); Rt: 2.02 mm.
Reaction SMILES: C[Si]([N:5]=[C:6]=[O:7])(C)C.[CH:8]1[C:16]2[C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][C:12]=2[CH:11]=[C:10]([CH:21]([NH:23][OH:24])[CH3:22])[CH:9]=1.[NH4+].[Cl-]>C1COCC1>[OH:24][N:23]([CH:21]([C:10]1[CH:9]=[CH:8][C:16]2[C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][C:12]=2[CH:11]=1)[CH3:22])[C:6]([NH2:5])=[O:7]
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(NO)c1ccc2c(c1)oc1ccccc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(c1ccc2c(c1)oc1ccccc12)N(O)C(N)=O
Yield: 80 %

Procedure:
Trimethylsilyl isocyanate (1.2 mL) was added to a solution of 1-(3-dibenzofuranyl)ethyl hydroxylamine (0.88 g, 3.87 mmole), prepared as described in Example 1, step c, in THF (6 mL). The mixture was heated at 60° for one hour and then poured into saturated NH4Cl solution. This was extracted with ethyl acetate (3×100 mL). The organic layer was concentrated in vacuo and the residue was triturated with ether to give the desired product as a white solid (0.84 g, 80%). (R1=NH2, A=--CH(CH3)--, X=O, Y=H)
Reaction SMILES: C([N:8]1[N:12]=[N:11][C:10]([C@H:13]2[O:17][C@@H:16]([N:18]3[CH:26]=[N:25][C:24]4[C:19]3=[N:20][C:21]([N:42]3[CH2:46][CH2:45][C@@H:44]([NH:47][C:48]([NH:50][C:51]5[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=5)=[O:49])[CH2:43]3)=[N:22][C:23]=4[NH:27][CH2:28][CH:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C@H:15]([OH:57])[C@@H:14]2[OH:58])=[N:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CCO.[Pd]>[OH:57][C@@H:15]1[C@H:14]([OH:58])[C@@H:13]([C:10]2[N:11]=[N:12][NH:8][N:9]=2)[O:17][C@H:16]1[N:18]1[CH:26]=[N:25][C:24]2[C:19]1=[N:20][C:21]([N:42]1[CH2:46][CH2:45][C@@H:44]([NH:47][C:48]([NH:50][C:51]3[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=3)=[O:49])[CH2:43]1)=[N:22][C:23]=2[NH:27][CH2:28][CH:29]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(Nc1cccnc1)N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4O[C@H](c5nnn(Cc6ccccc6)n5)[C@@H](O)[C@H]4O)c3n2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: O=C(Nc1cccnc1)N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4O[C@H](c5nn[nH]n5)[C@@H](O)[C@H]4O)c3n2)C1
Temperature: 50 °C

Procedure:
A solution of 1-{(R)-1-[9-[(2R,3R,4S,5R)-5-(2-Benzyl-2H-tetrazol-5-yl)-3,4-dihydroxy-tetrahydro-furan-2-yl]-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-3-pyridin-3-yl-urea in EtOH under an inert atmosphere of argon is treated with 10% palladium on carbon followed by ammonium formate. The reaction mixture is heated to 50° C. for 4 hours and then filtered through Celite®. The filtrate is concentrated in vacuo to afford the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[N+]([O-])([O-])=O.[K+].[CH3:13][O:14][C:15]1[C:20]2[CH2:21][CH2:22][CH2:23][CH:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH2:25][C:19]=2[CH:18]=[CH:17][C:16]=1[N+:32]([O-])=O>C(#N)C.C(O)C.[Pd]>[CH3:13][O:14][C:15]1[C:20]2[CH2:21][CH2:22][CH2:23][CH:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH2:25][C:19]=2[CH:18]=[CH:17][C:16]=1[NH2:32]
Reactant: COc1c([N+](=O)[O-])ccc2c1CCCC(N1CCOCC1)C2
Agent: [Pd]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: COc1c(N)ccc2c1CCCC(N1CCOCC1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.8 %

Procedure:
The reductive amination product obtained above (5.46 g, 20.87 mmol) was dissolved in dry acetonitrile (35 mL) and trifluoroacetic acid (30 mL) and cooled to −5° C. Potassium nitrate (2.11 g, 20.9 mmol) was added in one portion and the mixture was stirred for three hours while warming to room temperature. The resulting mixture was poured in ice water was extracted with dichloromethane. The dichloromethane extract was washed with saturated sodium bicarbonate solution, was dried (sodium sulfate), and was concentrated. ISCO chromatography was effected in several batches (stepwise gradient: 35 to 40 to 45 to 50 to 55 to 60% followed by 100% ethyl acetate:dichloromethane) to afford two regioisomers in order of elution: 4-(1-Methoxy-4-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-morpholine (2.41 g, 38%) and 4-(1-Methoxy-2-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-morpholine (1.41 g, 22%). The latter nitro isomer, 4-(1-Methoxy-2-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-morpholine (1.51 g, 4.939 mmol) was dissolved in ethanol (100 mL) and hydrogenated over 10% palladium on carbon (151 mg) at 50 psi using a Parr shaker for 3 hours. The palladium was removed by filtration and the ethanol was concentrated to afford a brown foam which was purified via ISCO chromatography (gradient elution: 2 to 8% methanol:dichloromethane) to afford 1-methoxy-6-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (830 mg, 61%) as a brown solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:21]=[CH:20][C:19]4[C:18]([CH3:23])([CH3:22])[CH2:17][CH2:16][C:15]([CH3:25])([CH3:24])[C:14]=4[CH:13]=3)[CH:10]=2)[C:5]([CH3:26])=[C:4]([C:27]([OH:29])=[O:28])[CH:3]=1.S(=O)(=O)(O)O.[CH3:35]O>>[CH3:35][O:28][C:27]([C:4]1[CH:3]=[C:2]([OH:1])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:21]=[CH:20][C:19]4[C:18]([CH3:22])([CH3:23])[CH2:17][CH2:16][C:15]([CH3:24])([CH3:25])[C:14]=4[CH:13]=3)[CH:10]=2)[C:5]=1[CH3:26])=[O:29]
Reactant: Cc1c(C(=O)O)cc(O)c2cc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)ccc12
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(O)c2cc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)ccc2c1C

Procedure:
8.1 g (0.0209 mole) of the acid obtained in Example 5, 100 ml of methanol and 0.6 ml (0.0105 mole) of concentrated sulfuric acid are introduced in a balloon-flask, then heated by retort for 8 hours. After dry evaporation, water is added, neutralization is effected with sodium bicarbonate, followed with extraction with dichloromethane. After drying the organic phase on magnesium sulfate, the resulting solid is evaporated and then recrystallized in acetonitrile. Yield: 7.6 g (90.5%), fusion temperature: (224°-225° C.). RF: 0.5 [Merck silica plaques, the eluent being a mixture of ether-hexane (50:50)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([OH:30])[CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC(COCCCCCCCCCCCC)CN1CCNCC1.[F:54]C1C=CC(CCl)=CC=1>[Pd]>[F:54][C:5]1[CH:6]=[CH:7][C:2]([CH2:1][N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH:15]([OH:30])[CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:12][CH2:13]2)=[CH:3][CH:4]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: CCCCCCCCCCCCOCC(O)CN1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: CCCCCCCCCCCCOCC(O)CN1CCNCC1
Product: CCCCCCCCCCCCOCC(O)CN1CCN(Cc2ccc(F)cc2)CC1

Procedure:
Following the procedures of Examples 4 and 5, 1-benzyl-4-(2-hydroxy-3-n-dodecyloxypropyl)-piperazine was converted to 1-(2-hydroxy-3-n-dodecyloxypropyl)piperazine by hydrogenolysis using a palladium on carbon catalyst. The hydrogenolysis product was reacted with 4-fluorobenzyl chloride to form 1-(4-fluorobenzyl)-4-(2-hydroxy-3-n-dodecyloxypropyl)-piperazine, mp 243°-245° C.