Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1I)[CH3:2].FC1C=CC(B(O)O)=CC=1.[N:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1[C:34]1[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=1)[CH3:2]
Reactant: OB(O)c1ccncc1
Reactant: CCc1c(I)[nH]c(C=O)c1C(=O)OCc1ccccc1
Agent: OB(O)c1ccc(F)cc1
Product: CCc1c(-c2ccncc2)[nH]c(C=O)c1C(=O)OCc1ccccc1

Procedure:
Following the procedures described in Example 5, replacing methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate with benzyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate and 4-fluorophenylboronic acid with pyridin-4-ylboronic acid, the title compound was obtained. Proton NMR for the product was consistent with the title compound. HRMS (ES) exact mass calculated for C20H19N2O3 (M+H): 335.1390. Found 335.1402
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4]([Cl:11])[CH:3]=1.[C:12]([N:19]1[CH:23]=[CH:22][CH:21]=[C:20]1B(O)O)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C([O-])([O-])=O.[Cs+].[Cs+].C1(C)C=CC=CC=1>O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCO>[Cl:11][C:4]1[CH:3]=[C:2]([C:20]2[N:19]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:23]=[CH:22][CH:21]=2)[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]=12
Reactant: Clc1cc(Cl)c2c(n1)CCC2
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)n1cccc1-c1cc(Cl)c2c(n1)CCC2
Temperature: 90 °C
Reaction time: 23 h
Yield: 32.5 %

Procedure:
A 20-mL sealed tube was charged with 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.250 g, 1.33 mmol), 1-Boc-pyrrole-2-boronic acid (0.308 g, 1.46 mmol), tetrakis(triphenylphosphine)palladium(0) (0.076 g, 0.066 mmol), and Cs2CO3 (1.30 g, 3.99 mmol). Toluene (8 ml), EtOH (2 ml) and water (4 ml) were added. The resulting mixture was stirred under Ar at 90° C. for 23 h. After cooling to room temperature, the reaction solution was diluted with water (5 mL) and ethyl acetate (60 mL). The aqueous layer was separated and the organic layer was washed with saturated sodium chloride (5 mL) then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica using hexane/ethyl acetate (100:0 to 75:250) as eluent to afford tert-butyl 2-(4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-pyrrole-1-carboxylate (0.138 g, 32%) as a yellow oil. MW=318.80. 1H NMR (CDCl3, 500 MHz) δ 7.33 (dd, J=3.5, 2.0 Hz, 1H), 7.17 (s, 1H), 6.37 (dd, J=3.0, 2.0 Hz, 1H), 6.21 (t, J=3.5 Hz, 1H), 3.09 (t, J=7.5 Hz, 2H), 3.04 (t, J=7.5 Hz, 2H), 2.17 (quin, J=7.5 Hz, 2H), 1.38 (s, 9H). MS: ESI+, m/z 319 [M+H]+ and 4-chloro-2-(1H-pyrrol-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.077 g, 26%) as an off-white solid. MW=218.68. 1H NMR (CDCl3, 500 MHz) δ 9.63 (br s, 1H), 7.30 (s, 1H), 6.87-6.85 (m, 1H), 6.65-6.62 (m, 1H), 6.29-6.25 (m, 1H), 3.01 (t, J=7.5 Hz, 2H), 2.96 (t, J=7.5 Hz, 2H), 2.13 (quin, J=7.5 Hz, 2H); ESI MS m/z 218 [M]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[O:5][C:6]1[C:7](Cl)=[N:8][CH:9]=[CH:10][C:11]=1[CH3:12].O.[NH2:19][NH2:20]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[O:5][C:6]1[C:7]([NH:19][NH2:20])=[N:8][CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: NN
Reactant: Cc1ccnc(Cl)c1Oc1cc(Cl)cc(Br)c1
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccnc(NN)c1Oc1cc(Cl)cc(Br)c1
Temperature: 100 °C

Procedure:
To a solution of 3-(3-bromo-5-chlorophenoxy)-2-chloro-4-methylpyridine (121 mg, 0.363 mmol) in DMSO (1 mL) was added hydrazine hydrate (177 μL, 3.63 mmol) and the mixture was heated at 100° C. for 18 hours. The mixture was then purified on a Luna column (10μ, C18, 250×21.2 cm) eluting with 5-95% ACN/water with 0.1% TFA) to give the title compound. LRMS (M+1)=329.8.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].C(N(CC)CC)C.[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19]>CN(C)C1C=CN=CC=1.ClCCl>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:25])[CH3:24])=[CH:4][C:3]=1[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cc(O)cc(C)c1Br
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(O[Si](C)(C)C(C)(C)C)cc(C)c1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Bromo-3,5-dimethylphenol (3.5 g), 4-(dimethylamino)pyridine (212 mg) and triethylamine (2.7 mL) are stirred in dichloromethane (25 mL) at 0° C., then tert-butyldimethylchlorosilane (19 mL) is added dropwise. The reaction mixture is warmed to ambient temperature and stirred overnight. The reaction mixture is diluted with dichloromethane, washed with aqueous HCl (1 M, 25 mL) and then with saturated aqueous NaHCO3 (25 mL). The organic phase is dried (MgSO4) and concentrated to give the title compound. Yield: 5.4 g
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[C:5]([C:17]#[N:18])=[C:4]([O:19][CH3:20])[N:3]=1.[S-2:21].[Na+].[Na+]>CN(C=O)C>[OH:16][C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:7]([C:8]#[N:9])=[C:2]([SH:21])[N:3]=[C:4]([O:19][CH3:20])[C:5]=2[C:17]#[N:18])=[CH:11][CH:12]=1
Reactant: COc1nc(Cl)c(C#N)c(-c2ccc(O)cc2)c1C#N
Reactant: [S-2]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc(S)c(C#N)c(-c2ccc(O)cc2)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.3 g (4.550 mmol) of 2-chloro-4-(4-hydroxyphenyl)-6-methoxypyridine-3,5-dicarbonitrile are initially charged in 10 ml of DMF, 426 mg (5.460 mmol) of sodium sulphide are added and the mixture is stirred at room temperature overnight. The reaction mixture is reacted further without any further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3([CH3:22])[O:21]CCO3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B(OC(C)C)(OC(C)C)O[CH:25](C)C.[Li+].CC([N-]C(C)C)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17](=[O:21])[CH3:22])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH3:25])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(C3(C)OCCO3)ccc21
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)cc(C)n2C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
To a solution of 5-(2-methyl-[1,3]dioxolan-2-yl)-indole-1-carboxylic acid tert-butyl ester [4.96 g, 16.35 mmol, Intermediate (19)] in anhydrous tetrahydrofuran (20 mL) is added triisopropyl borate (4.61 g, 24.51 mmol) and cooled to 0° C. under N2. To it is added LDA (1.8M in heptane/tetrahydrofuran/ethylbenzene, 14 mL) drop wise at 0° C. over 40 minutes periods. After another 35 minutes, the reaction is quenched by the addition of aqueous 2N hydrochloric acid at 0° C. The white solid precipitated is slowly acidified with 3N hydrochloric acid till pH=3. The mixture became solution which is extracted twice with ethyl acetate (100 mL). The combined ethyl acetate phases are dried over sodium sulfate and filtered. The solid crude is triturated with acetonitrile and water to obtain 5-acetyl-2-methyl-indole-1-carboxylic acid tert-butyl ester (4.76 g, 96%, Intermediate (20)] as light yellow solid; 1H NMR (CDCl3): δ 8.30 (2.67, 3H), 8.18 (1H, d), 7.90 (1H, d), 6.78 (1H, s), 2.61 (3H, s), 1.62 (9H, s); LC/MS: ESI+ 304 (M+H)
Reaction SMILES: [CH2:1]([C:4]1[C:9]([F:10])=[C:8]([F:11])[C:7](F)=[C:6]([F:13])[C:5]=1[F:14])[CH:2]=[CH2:3].O.[NH2:16][NH2:17]>C(O)C>[CH2:1]([C:4]1[C:9]([F:10])=[C:8]([F:11])[C:7]([NH:16][NH2:17])=[C:6]([F:13])[C:5]=1[F:14])[CH:2]=[CH2:3]
Reactant: NN
Reactant: C=CCc1c(F)c(F)c(F)c(F)c1F
Solvent: CCO
Solvent: O
Product: C=CCc1c(F)c(F)c(NN)c(F)c1F

Procedure:
Allylpentafluorobenzene [41.6 g; described by Harper et al, J. Org. Chem., 29, 2385 (1964)] was added to a solution of hydrazine hydrate (100 ml) in ethanol (150 ml) and the mixture was heated at reflux for 24 hours. The solid precipitate which formed was collected by filtration and washed with ethanol and hexane to give 4-allyl-2,3,5,6-tetrafluorophenylhydrazine (18.8 g), m.p. 82°-84° C., in the form of colourless crystals. The filtrate was evaporated to dryness and the yellow solid thus obtained was washed with ethanol and hexane to give a further quantity (22.0 g) of 4-allyl-2,3,5,6-tetrafluorophenylhydrazine, m.p. 79°-81° C., in the form of a cream-coloured solid.
Reaction SMILES: CN1C(=O)CCC1.[CH2:8]([O:10][C:11]1[N:12]=[CH:13][C:14]([NH:17][C:18](=[O:22])[O:19][CH2:20][CH3:21])=[N:15][CH:16]=1)[CH3:9].CC(C)([O-])C.[K+].[CH3:29][C@:30]1([CH2:38][N:39]2[C:43]3[CH:44]=[C:45]([C:48]#[N:49])[CH:46]=[CH:47][C:42]=3[N:41]=[CH:40]2)[CH2:37]CC[C@:32]2(O[CH2:33]2)[CH2:31]1>CC(O)C.O>[CH2:8]([O:10][C:11]1[N:12]=[CH:13][C:14]([N:17]2[CH2:21][C@@:20]3([CH2:33][CH2:32][CH2:31][C@@:30]([CH2:38][N:39]4[C:43]5[CH:44]=[C:45]([C:48]#[N:49])[CH:46]=[CH:47][C:42]=5[N:41]=[CH:40]4)([CH3:29])[CH2:37]3)[O:19][C:18]2=[O:22])=[N:15][CH:16]=1)[CH3:9]
Reactant: CCOC(=O)Nc1cnc(OCC)cn1
Reactant: C[C@]1(Cn2cnc3ccc(C#N)cc32)CCC[C@@]2(CO2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CC(C)O
Solvent: O
Product: CCOc1cnc(N2C[C@@]3(CCC[C@](C)(Cn4cnc5ccc(C#N)cc54)C3)OC2=O)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a 10 mL flask was added NMP (7.11 mL), ethyl (5-ethoxypyrazin-2-yl)carbamate (0.863 g, 4.09 mmol) and potassium tert-butoxide (0.399 g, 3.55 mmol) at RT. After stirring for ˜5 min at RT, 1-{[(3S,5S)-5-methyl-1-oxaspiro[2.5]oct-5-yl]methyl}-1H-benzimidazole-6-carbonitrile (1 g, 3.55 mmol) was added. The solution was then heated to 70° C. (oil bath) and stirred for 7 h. At 7 h, the temperature was taken to 80° C., then at 8 h, it was taken to 90° C. The mixture was allowed to stir at 90° C. for 16 h. The resulting solution was cooled to RT and added dropwise to a 50 mL solution of IPA/Water (1:1) that contained a small crystalline seed. The mixture was allowed to stir at RT overnight. The next day, the slurry was filtered, and the solids slurried in MeCN overnight. The next day, the solids were filtered off, dried under reduced pressure to give 1-(((5S,7S)-3-(5-ethoxypyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile as a very light yellow solid (968 mg, 61% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J=1.25 Hz, 1H), 8.48 (s, 1H), 8.38 (s, 1H), 8.10 (d, J=1.51 Hz, 1H), 7.83 (d, J=8.53 Hz, 1H), 7.59 (dd, J=1.25, 8.28 Hz, 1H), 4.32 (q, J=7.03 Hz, 2H), 4.16 (s, 2H), 3.80-3.88 (m, 2H), 1.98 (d, J=13.80 Hz, 1H), 1.88 (d, J=14.31 Hz, 1H), 1.64-1.73 (m, 3H), 1.49-1.53 (m, 2H), 1.34-1.38 (m, 2H), 1.32-1.38 (t, J=8.0 Hz, 2H), 1.07 (s, 3H). MS (m/z) 447.2 (M+H+).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[C:28]([CH3:29])=[C:27]([CH3:30])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:19]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]2[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:15]3[C:28]([CH3:29])=[C:27]([CH3:30])[S:26][C:16]=3[N:17]=2)[CH:21]=1
Reactant: Cc1sc2nc(-c3cccnc3)nc(Cl)c2c1C
Reactant: NCCc1ccc2c(c1)OCO2
Product: Cc1sc2nc(-c3cccnc3)nc(NCCc3ccc4c(c3)OCO4)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-3-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-methylenedioxyphenethylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: CC(C)([O-])C.[Na+].[CH:7]([NH:10][C:11]1[C:12]([NH2:18])=[CH:13][CH:14]=[C:15]([CH3:17])[CH:16]=1)([CH3:9])[CH3:8].Cl[C:20]1[N:25]=[C:24]([N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[CH2:28][CH2:27]2)[N:23]=[C:22]([N:38]([CH3:40])[CH3:39])[CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[CH:7]([NH:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=1[NH:18][C:20]1[CH:21]=[C:22]([N:38]([CH3:40])[CH3:39])[N:23]=[C:24]([N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[CH2:28][CH2:27]2)[N:25]=1)([CH3:9])[CH3:8]
Reactant: CN(C)c1cc(Cl)nc(N2CCN(c3ccccn3)CC2)n1
Reactant: Cc1ccc(N)c(NC(C)C)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Product: Cc1ccc(Nc2cc(N(C)C)nc(N3CCN(c4ccccn4)CC3)n2)c(NC(C)C)c1
Temperature: 110 °C
Yield: 22.4 %

Procedure:
Sodium tert-butoxide (100 mg, 1.04 mmol) was added to a solution of N2-isopropyl-4-methyl-1,2-benzenediamine (100 mg 0.60 mmol) and N-{6-chloro-2-[4-(2-pyridinyl)-1-piperazinyl]-4-pyrimidinyl}-N,N-dimethylamine (100 mg, 0.30 mmol) in 1,4-dioxane (10 mL). Tris(dibenzylidineacetone)dipalladium (8 mg, 0.008 mmol) and 2,2′-Bis(diphenylphosphino)-1,1′binapthyl (10 mg, 0.016 mmol) were added to this mixture and heated at 110° C. for 10 hours. The resulting mixture was cooled to room temperature, concentrated in vacuo, and purified by preparative thin-layer chromatography [eluent: hexane/EtOAc (1:1)], giving the desired product (30 mg, 23%).
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C@H:10]2[CH2:15][CH2:14][C@@H:13]([Si:16]([CH3:19])([CH3:18])[CH3:17])[CH2:12][CH2:11]2)[C:4]=1[C:20](OC)=[O:21])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C@H:10]2[CH2:15][CH2:14][C@@H:13]([Si:16]([CH3:19])([CH3:18])[CH3:17])[CH2:12][CH2:11]2)[C:4]=1[CH2:20][OH:21])[CH3:2]
Reactant: CCc1ncnc(N[C@H]2CC[C@@H]([Si](C)(C)C)CC2)c1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1ncnc(N[C@H]2CC[C@@H]([Si](C)(C)C)CC2)c1CO
Temperature: 25 °C

Procedure:
A solution of 7.0 g (20.9 mmol) of 5-methoxycarbonyl-6-ethyl-4-(cis-4-(trimethylsilyl)cyclohexylamino)pyrimidine (Example 6) in 30 ml of absolute tetrahydrofuran was added dropwise to a suspension, cooled to -30° C., of 1.03 g (27.1 mmol) of lithium aluminum hydride in 10 ml of absolute tetrahydrofuran, and the mixture was stirred at room temperature until the end of reaction. Following the hydrolysis, the mixture was subjected to extraction with diethyl ether to give, after drying and removal of the solvent, 6.13 g (19.9 mmol)=95% of the hydroxymethyl compound in the form of white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([OH:14])[CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].CN(C)C1C=CN=CC=1.CN(C1C=CN=CC=1)C.[CH3:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:35]=1[CH2:41][C:42](Cl)=[O:43]>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1([O:14][C:42](=[O:43])[CH2:41][C:35]2[CH:36]=[C:37]([CH3:40])[CH:38]=[CH:39][C:34]=2[CH3:33])[CH2:7][CH2:8][N:9]([O:12][CH3:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: Cc1ccc(C)c(CC(=O)Cl)c1
Reactant: CCOC(=O)C1(O)CCN(OC)CC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCOC(=O)C1(OC(=O)Cc2cc(C)ccc2C)CCN(OC)CC1
Temperature: 0 °C
Reaction time: 120 h

Procedure:
To a solution of 4-hydroxy-1-methoxy-piperidine-4-carboxylic acid ethyl ester (1.0 g, 4.92 mmol) in 10 ml pyridine under argon was added 4-dimethylaminopyridine DMAP (30 mg, 0.25 mmol). The solution was cooled down to 0° C., then (2,5-dimethyl-phenyl)-acetyl chloride (0.99 g, 5.4 mmol) was added dropwise. The reaction mixture was warmed up to room temperature and left stirring for 5 days. Then the reaction mixture was concentrated and the crude product was purified by column chromatography on silica gel (ethyl acetate/cyclohexane first 1:15, then 1:9) to give pure 4-[2-(2,5-dimethyl-phenyl)-acetoxy]-1-methoxy-piperidine-4-carboxylic acid ethyl ester (compound P3.2) as light yellow oil. Yield: 530 mg.
Reaction SMILES: P(Br)(Br)[Br:2].[Cl:5][C:6]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:9]([CH2:10]O)=[C:8]([CH3:17])[C:7]=1[N+:18]([O-:20])=[O:19].O>C1C=CC=CC=1>[Br:2][CH2:17][C:8]1[C:9]([CH3:10])=[CH:12][C:13]([N+:14]([O-:16])=[O:15])=[C:6]([Cl:5])[C:7]=1[N+:18]([O-:20])=[O:19]
Reactant: Cc1c(CO)cc([N+](=O)[O-])c(Cl)c1[N+](=O)[O-]
Reactant: BrP(Br)Br
Solvent: c1ccccc1
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
Phosphorus tribromide (18.0 g; 0.067 mol) is added dropwise at 10° C. to a stirred slurry of 4-chloro-2-methyl-3,5-dinitrobenzyl alcohol (50.0 g; 0.20 mol) in benzene (100 ml). The reaction mixture is allowed to warm to room temperature and then heated to reflux for 5 hours. After standing at room temperature overnight, the mixture is poured into water and extracted with ether. Insoluble material present is collected and dried to yield 18.9 g solid, melting point 115°-120° C. Removal of the ether from the extracts yields additional 38.6 g solid, melting point 106° C.-112° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:22]([C:29]1[N:30]=[C:31]([CH2:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[O:32][C:33]=1[CH2:34]Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC(C)=O>[CH2:22]([C:29]1[N:30]=[C:31]([CH2:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[O:32][C:33]=1[CH2:34][N:11]1[CH2:12][CH2:13][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:9][CH2:10]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: ClCc1oc(CC2CCCCC2)nc1Cc1ccccc1
Reactant: Fc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1ccccc1N1CCN(Cc2oc(CC3CCCCC3)nc2Cc2ccccc2)CC1
Yield: 65 %

Procedure:
A suspension containing 2-fluorophenylpiperazine (2.0 mmole), potassium carbonate (4.0 mmole), potassium iodide (1.0 mmole) and 4-benzyl-5-chloromethyl-2-cyclohexylmethyl oxazole (2.0 mmole) from example 8, was stirred in acetone (20 ml) at ambient temperature for 18 hr. The solvent was removed in vacuo, water (50 ml) added and the product extracted into ethyl acetate (3×50 ml). The combined organics were washed with water (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was purified by “flash” chromatography over silica gel to afford the titled compound as an off-white crystalline powder (1.3 mmole, 65% yield). An ethyl acetate solution (10 ml) of the product was treated with 2 equivalents of ethereal 1N-HC1 to afford the HCl salt of the titled compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[CH:16]([CH3:18])[CH3:17])=[CH:10]\[CH:11]=[CH:12]\[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[N+:19]([C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1)([O-:21])=[O:20].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](\[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)/[CH:16]([CH3:18])[CH3:17])=[CH:24][CH:23]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1ccc(/C(=C\C=C\C(=O)O)C(C)C)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(/C(=C\C=C\C(=O)Oc2ccc([N+](=O)[O-])cc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.4 %

Procedure:
As in Example 115, (2E,4Z)-5-(4-methoxyphenyl)-6-methyl-2,4-heptadienoic acid (3.2 g) and 4-nitrophenol (2.2 g) in 20 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide (2.7 g) and the mixture was stirred at room temperature for 18 hours. After the usual work up, crystallization of the crude product from 2-propanol-hexane yielded 3.55 g of (2E,4Z)-5-(4-methoxyphenyl)-6-methyl-2,4-heptadienoic acid 4-nitrophenyl ester, mp 111.5°-113° C.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:12][CH:11]([OH:13])[CH2:10][CH:9]1[C:14](=[O:26])[NH:15][C:16]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][CH:17]1[CH:19]=[CH2:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:28]1[C:37]2[C:32](=[C:33]([CH3:40])[C:34]([O:38][CH3:39])=[CH:35][CH:36]=2)[N:31]=[C:30]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[N:42]=2)[CH:29]=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>C1COCC1>[C:1]([O:5][C:6]([CH:8]1[CH2:12][CH:11]([O:13][C:28]2[C:37]3[C:32](=[C:33]([CH3:40])[C:34]([O:38][CH3:39])=[CH:35][CH:36]=3)[N:31]=[C:30]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[N:42]=3)[CH:29]=2)[CH2:10][CH:9]1[C:14](=[O:26])[NH:15][C:16]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][CH:17]1[CH:19]=[CH2:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc2c(O)cc(-c3cccc(C)n3)nc2c1C
Reactant: C=CC1CC1(NC(=O)C1CC(O)CC1C(=O)OC(C)(C)C)C(=O)OCC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3cccc(C)n3)nc3c(C)c(OC)ccc23)CC1C(=O)OC(C)(C)C)C(=O)OCC
Reaction time: 8 h
Yield: 116.4 %

Procedure:
A solution of 2-(1-ethoxycarbonyl-2-vinylcyclopropylcarbamoyl)-4-hydroxycyclo-pentanecarboxylic acid tert-butyl ester (500 mg, 1.5 mmol), prepared as described in WO2005/073195, 4-hydroxy-2-(6-methyl-2-pyridyl)-7-methoxy-8-methylquinoline (97, 504 mg, 1.8 mmol) and triphenylphosphine (990 mg, 3.75 mmol) were stirred in dry THF (40 mL) at 0° C. for 10 min. Then, DIAD (0.74 mL, 3.75 mmol) was added drop wise. The resulting reaction mixture was stirred at a temperature from 0° C. to 22° C. overnight. Then, volatiles were evaporated and the residue was purified by column chromatography on silica gel (gradient CH2Cl2/AcOEt, 1:0 to 95:5) to give 1.1 g (88%) of the title compound 98: m/z=630 (M+H)+.
Reaction SMILES: BrC1C=CC(CCCO)=CC=1.[C:12]([C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([O:24][Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])[CH:18]=[CH:17]2)#[CH:13].C(OCC)(=O)C>C1COCC1.C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:29]([Si:25]([CH:26]([CH3:27])[CH3:28])([CH:32]([CH3:34])[CH3:33])[O:24][C:19]1[CH:18]=[CH:17][C:16]2[C:21](=[CH:22][CH:23]=[C:14]([C:12]#[C:13][Si:25]([CH3:32])([CH3:29])[CH3:26])[CH:15]=2)[CH:20]=1)([CH3:31])[CH3:30]
Reactant: C#Cc1ccc2cc(O[Si](C(C)C)(C(C)C)C(C)C)ccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: OCCCc1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: CC(C)[Si](Oc1ccc2cc(C#C[Si](C)(C)C)ccc2c1)(C(C)C)C(C)C
Temperature: 70 °C
Reaction time: 5 h

Procedure:
7.0 g (32.5 mmol) of 3-(4-bromophenyl)propan-1-ol are initially introduced in 70 ml of THF and 30 ml of diisopropylamine, and, after addition of 1.0 g (1.4 mmol) of bis(triphenylphosphine)palladium(II) chloride and 0.4 g (2.1 mmol) of copper(I) iodide, 16.4 g (50.5 mmol) of (6-ethynylnaphthalen-2-yloxy)triisopropylsilane in 30 ml of THF are added dropwise at 70° C. The batch is left to stir for 5 h at 70° C., 200 ml of ethyl acetate are added, and the mixture is washed three times with water. The combined aqueous phases are extracted with ethyl acetate, and the combined org. phases are dried over sodium sulfate and evaporated in vacuo. Chromatography of the crude product on silica gel with firstly toluene and then toluene/ethyl acetate (7:3) gives 2-triisopropylsilanyloxy-6-trimethylsilanylethynylnaphthalene as a brown oil, which is employed in the next step without further purification.