Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH:3]([O:7][CH2:8][CH2:9][O:10][CH2:11][CH3:12])/[CH:4]=[CH:5]/I.C([Li:18])(C)(C)C>CCOCC.CCCCC>[Li:18]/[CH:5]=[CH:4]/[CH:3]([O:7][CH2:8][CH2:9][O:10][CH2:11][CH3:12])[CH:2]([CH3:13])[CH3:1]
Reactant: CCOCCOC(/C=C/I)C(C)C
Reactant: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: [Li]/C=C/C(OCCOCC)C(C)C
Temperature: -78 °C

Procedure:
2.50 g (8.40 mmol) of trans-4-methyl-3α-ethoxyethoxy-1 -iodopentene was dissolved in 57 ml of anhydrous ether and cooled to -78° C. with stirring under argon atmosphere. To this solution 13.7 ml of 1.23 N t-butyllithium in pentane was injected. The resulting solution was stirred for 2.75 hours at -78° C. under argon atmosphere, yielding the lithio-anion, 1-lithio-trans-4-methyl-3α-ethoxyethoxy-1-pentene. The lithio-anion was added to a solution of 0.44 g hexamethylenephosphorous triamide copper iodide in 50 ml of anhydrous ether at -78° C. under argon. This yellow mixture was stirred for 15 minutes at -78° C. Then 1.97 g (4.22 mmol) of 15α-ethoxyethoxy-PGA2 -methyl ester in 11.5 ml ether was added dropwise and the reaction mixture was stirred at -70° C. for 15 min. The mixture was then slowly warmed to 0° C. over a period of 1.5 hr. by use of an ice water and salt bath, and stirred for 0.5 hr. The mixture was then brought to 25° C. and stirred for an additional 0.5 hr. The mixture was then processed with a 20% aqueous NH4Cl/NH4OH solution and 3.35 g of an orange oil was obtained. NMR(CDCl3) analysis revealed: δ 3.65, singlet, CO2CH3 ; δ Ξ5.45, multiplet, olefinic-H; and no absorption due to olefinic protons on the cyclopen-tenone in the PGA2 starting material. The ethoxyethoxy groups were hydrolyzed by reacting with 70 ml of 65/35 acetic acid/water and 7.0 ml THF for 17 hours at 25° C. After processing, 3.30 g of an orange oil were obtained. NMR (CDCl3) analysis showed no absorption in the δ 4.80 region. The methyl ester was hydrolyzed by reaction with 22 ml of 1N NaOH and 22 ml of THF for 19 hours at 25° C. under argon atmosphere. After processing 3.28 g of a red oil was obtained chromatographed in Silicic Acid and Celite (15%). 1.227 g (65.6%) of (-)-11α-(trans-4'-methyl-3'-β -hydroxy-1-pentenyl-11 -desoxy-PGE2 was obtained. NMR(CDCl3) analysis: δ 3.95, multiplet, 2H, CHOH; δ 5.45, multiplet, 6H, CO2H, -OH. IR analysis: λmaxCHCl3 2.68μ5.75μ, 5.85μ. Optical rotation: [α]D 25° = 36.4 ± 02° (c = 1.0, CH3OH). Mass spectoscopy: 416 (P+ - 18).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH2:19][CH3:20])([CH2:17][CH3:18])[C:11]=2[CH:21]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([SH:32])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([S:32][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH2:19][CH3:20])([CH2:17][CH3:18])[C:11]=3[CH:21]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: COc1ccc(S)cc1OC
Reactant: CCC1(CC)OC(=O)Nc2ccc(OCCCCCl)cc21
Product: CCC1(CC)OC(=O)Nc2ccc(OCCCCSc3ccc(OC)c(OC)c3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-diethyl-4H-3,1-benzoxazin-2-one and 3,4-dimethoxy-thiophenol.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6].[Br:10]N1C(=O)CCC1=O>ClC1C=CC=CC=1>[CH3:9][O:8][C:1](=[O:7])[CH:2]=[CH:3][CH:4]=[CH:5][CH2:6][Br:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: C/C=C/C=C/C(=O)OC
Solvent: Clc1ccccc1
Product: COC(=O)C=CC=CCBr
Yield: 64.9 %

Procedure:
A mixture of methyl sorbate (1.26 g, 10 mmol) and N-bromosuccinimide (1.98 g, 11.0 mmol) in chlorobenzene was irradiated with a 250 W sunlamp so as to achieve a state of reflux for 4 hours. The (cooled) mixture was then evaporated under reduced pressure to give a brown oil which was purified by column chromatography (9:1 60-80° C. petroleum ether:diethyl ether) to give the title compound (1.33 g, 65%) as a clear oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[C:10]([C:11]#[N:12])=[CH:9][N:8]=[CH:7][CH:6]=1.N1C=CN=C1.[CH:18]([Si:21](Cl)([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19]>CN(C=O)C>[CH:18]([Si:21]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[O:1][CH2:2][CH2:3][NH:4][C:5]1[C:10]([C:11]#[N:12])=[CH:9][N:8]=[CH:7][CH:6]=1)([CH3:20])[CH3:19]
Reactant: N#Cc1cnccc1NCCO
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](OCCNc1ccncc1C#N)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
To a solution of 4-(2-hydroxy-ethylamino)-nicotinonitrile (500 mg, 3.07 mmol) and imidazole (250 mg, 3.68 mmol) in DMF (15 mL) was added triisopropylsilyl chloride (0.723 mL, 3.37 mmol). The reaction mixture stirred at room temperature for 2 hours. The mixture was then partitioned between ethyl acetate and water, the organic layer isolated and washed with brine, dried (Na2SO4), filtered and concentrated. The resultant residue was purified by flash chromatography (Si-PPC, pentane:ether, gradient 50:50 to 30:70) to provide the title compound as a white solid (753 mg, 77%). LCMS (method B): RT=2.92 min, M+H+=320.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CC(C)(C)OC(=O)CN
Product: CC(C)(C)OC(=O)CNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (145 mg, 0.5 mmol) and tert-butyl 2-aminoacetate (79 mg, 0.6 mmol). The title compound was obtained as a solid (98.0 mg, 42% yield). 1H NMR (300 MHz, d6-DMSO) δ: 8.74 (2H, s), 7.95 (1H, s), 4.06 (2H, m), 1.49 (9H, s) MS m/z: 463.80, 465.75 [M+H]+.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.I[C:21]1[N:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH:24]=[N:23][C:22]=1[C:30]#[N:31].Cl.[NH2:33][C:34]1[CH:39]=[C:38]([C:40]([O:42][CH3:43])=[O:41])[CH:37]=[CH:36][C:35]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:33][C:34]1[CH:39]=[C:38]([C:40]([O:42][CH3:43])=[O:41])[CH:37]=[CH:36][C:35]=1[C:21]1[N:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH:24]=[N:23][C:22]=1[C:30]#[N:31]
Reactant: CC(C)Cn1cnc(C#N)c1I
Reactant: COC(=O)c1ccc(B(O)O)c(N)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2c(C#N)ncn2CC(C)C)c(N)c1
Temperature: 100 °C
Yield: 89 %

Procedure:
To a suspension of Pd(OAc)2 (11.2 mg, 0.05 mmol, 0.05 equiv) and PPh3 (26.2 mg, 0.1 mmol, 0.1 equiv) in DME (4 mL) were sequentially added 5-iodo-1-isobutyl-1H-imidazole-4-carbonitrile S5 (275 mg, 1 mmol, 1 equiv), 2-amino-4-methoxycarbonylphenyl-boronic acid hydrochloride salt (347 mg, 1.5 mmol, 1.5 equiv) and 1.5 M aqueous Na2CO3 (2.0 mL, 3.0 mmol, 3.0 equiv) at 25° C. The reaction was heated at 100° C. for 3 h. TLC and MS analysis indicated complete conversion of S5. The reaction was then cooled down to 25° C. and partitioned between EtOAc (50 mL) and H2O (10 mL). The aqueous layer was extracted with EtOAc (3×15 mL) and the combined organic layers were washed with saturated aqueous NaCl (20 mL), dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica gel (1/9 EtOAc/hexanes-7/3 EtOAc/hexanes, gradient) afforded the title compound (265 mg, 89%) as a light yellow foam: 1H NMR (CDCl3, 600 Hz) δ 0.71 (d, J=9.6 Hz, 3H), 0.75 (d, J=9.6 Hz, 3H), 1.75 (hept, J=9.6 Hz, 1H), 3.64-3.67 (m, 2H), 3.90 (s, 3H), 7.15 (d, J=7.8 Hz, 1H), 7.44 (d, J=7.8 Hz), 7.45 (s, 1H), 7.57 (s, 1H); 13C NMR (CDCl3, 150 Hz) δ 19.6, 19.7, 29.5, 52.3, 53.6, 117.0, 128.4, 128.5, 131.7, 131.9, 131.9, 132.0, 132.1, 133.2, 139.8, 166.5; LRMS (ESI+): calcd C16H19N4O2 [M+H]+299.2. found 299.1.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([O:14][C:15]2[CH:16]=[N:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][O:50][C:51]1[CH:56]=[C:55]([NH2:57])[CH:54]=[CH:53][N:52]=1.C(N(CC)CC)C>ClCCl>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:57][C:55]2[CH:54]=[CH:53][N:52]=[C:51]([O:50][CH3:49])[CH:56]=2)=[O:11])=[C:7]([O:14][C:15]2[CH:16]=[N:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(N)ccn1
Reactant: CC(C)(C)c1ccc(C(=O)O)c(Oc2ccc(C(F)(F)F)nc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(NC(=O)c2ccc(C(C)(C)C)cc2Oc2ccc(C(F)(F)F)nc2)ccn1
Yield: 61.5 %

Procedure:
A solution of 4-(tert-butyl)-2((6-(trifluoromethyl)pyridin-3-yl)oxy)benzoic acid (169.7 mg, 0.5 mmol), HATU (190 mg, 0.5 mmol), 2-methoxypyridin-4-amine (62.1 mg, 0.5 mmol) and tri-ethyl amine (278.8 μL, 2 mmol) in dichloromethane (5 mL) was stirred at room temperature over 72 hours. The reaction was purified by silica gel chromatography using gradient of ethyl acetate in hexanes (0-40%) to yield 4-(tert-butyl)-N-(2-methoxypyridin-4-yl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzamide (137 mg, 60%). ESI-MS m/z calc. 445.16. found 446.3 (M+1)+; Retention time: 1.87 minutes (3 minutes run).
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12])[CH:6]=[CH2:7].[OH-].[Na+].[ClH:20]>C1(C)C=CC=CC=1.CN(C)C=O>[CH2:5]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([Cl:20])=[O:12])[CH:6]=[CH2:7]
Reactant: C=CCOc1ccccc1C(=O)O
Reactant: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: C=CCOc1ccccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 2000 ml four-necked reaction flask, equipped with a magnetic stirrer, thermometer, addition funnel, condenser and a nitrogen sweep, was added 281 grams of thionyl chloride (2.38 moles), 1 ml of dimethyl formamide, and 1000 ml of toluene. 356 grams of the allyloxybenzoic acid (2.0 moles) as prepared above was added over approximately 20 minutes. The reaction temperature was kept below 20° C. with an ice/water bath. The nitrogen sweep was connected to a trap, which contained 1000 ml of a 4 M aq. NaOH solution to react with SO2 and HCl that are formed during the reaction. After the addition was complete, the solution was stirred for 3 hours at room temperature and then heated to reflux. After 3.5 hours of reflux, it was cooled to room temperature. Solvent was distilled at atmospheric pressure because removal under reduced pressure caused severe bumping. After most of the solvent was removed, the residue was transferred to a 1000 ml flask equipped with a distillation head. The product was then vacuum distilled.
Reaction SMILES: C[Li].[CH3:3][O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14](=[O:23])[CH:13]=[C:12]4[CH3:24])[CH2:9][CH2:8][C:7]=2[CH:6]=1.[Cl-].[NH4+].[C:27](OCC)(=O)C>C(OCC)C.O1CCCC1.[Cu]I>[CH3:3][O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14](=[O:23])[CH2:13][C:12]4([CH3:27])[CH3:24])[CH2:9][CH2:8][C:7]=2[CH:6]=1
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)C=C(C)[C@@H]12
Reactant: CCOC(C)=O
Agent: [Cu]I
Agent: [Cl-]
Agent: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC(C)(C)[C@@H]12
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of lithium dimethylcuprate (0.79 mmol) in dry diethyl ether (2 ml) [conventionally prepared at 0° C. from copper(I) iodide (150 mg; 0.79 mmol) and methyl lithium (1.3 ml; 1.6M; 2.08 mmol)] at -78° C., boron trifluor-ide-diethyl ether complex (0.1 ml; 0.80 mmol) was added, followed by the 15-methyl-Δ15 -17-ketone (3) (163 mg; 0.55 mmol) in dry tetrahydrofuran (2 ml). After 30 min., saturated aqueous ammonium chloride was added. The standard work-up (ethyl acetate) gave a crystalline residue, chromatography of which on silica gel (5 g), eluting with ethyl acetate-toluene (1:19) gave the 15,15-dimethylketone (4) (146 mg; 70%), m.p. 145°-148° C. (from ethyl acetate-methanol); [α]D +75° (C 1.0); νmax 1727 cm-1 (CO); δH 1.10 (3H, s, --β-Me), 1.28 and 1.29 (each 3H, s, 15α- and 15β-Me), 1.84 (1H, d, J 10.9 Hz, 14α-H), 2.09 and 2.61 (each 1H, d, J 19.4 Hz, 16α- and 16β-H), 2.93 (2H, m, 6-H2), 3.78 (3H, s, 3-OMe), 6.63 (1H, d, J 2.7 Hz, 4-H), 6.70 (1H, dd, J 8.6 and 2.7 Hz, 2-H), and 7.21 (1H, d, J 8.6 Hz, 1-H); δc 17.8 (C-18), 24.5 (15-Me), 26.0 (C-11), 28.2 (C-7), 29.8 (C-6), 34.2 (C-12), 34.6 (15-Me), 35.5 (C-15), 37.5 (C-8), 44.9 (C-9), 50.2 (C-13), 53.6 (C-16), 55.2 (3-OMe), 58.4 (C-14), 111.6 (C-2), 113.6 (C-4), 126.4 (C-1), 132.2 (C-10), 137.4 (C-5), 157.6 (C-3), and 221.4 (C-17) (Found: C, 80.5; H, 8.8%; M+, 312. C21H28O2 requires C, 80.7; H, 9.0%; M, 312).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14]([C:16]2[O:17][C:18]([Br:21])=[CH:19][CH:20]=2)=O)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2]>C(O)CO.C(O)(C)C>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:12]2[N:13]=[C:14]1[C:16]1[O:17][C:18]([Br:21])=[CH:19][CH:20]=1)[CH3:2]
Reactant: CCOC(=O)CNc1ncccc1NC(=O)c1ccc(Br)o1
Solvent: CC(C)O
Solvent: OCCO
Product: CCOC(=O)Cn1c(-c2ccc(Br)o2)nc2cccnc21
Yield: 1.1 %

Procedure:
A solution of N-[3-[(5-bromo-2-furanylcarbonyl)amino]-2-pyridinyl]glycine ethyl ester (110 g, 0.30 mole) was refluxed in ethylene glycol (510 ml) for 2 hours. A 20-ml aliquot (0.01 mole) was removed and water was added to the sample. The product was extracted twice into ethyl acetate and the combined organic layer was washed several times with water, dried over magnesium sulfate, charcoaled, filtered, and evaporated under reduced pressure to give 2.5 g of crude title compound (73% yield). The solid was dissolved in hot isopropyl alcohol, filtered while hot, brought to the cloud point by addition of water and cooled to give a solid which was purified on a column of 20 g of silica gel using 1:1 methylene chloride/ethyl acetate as the eluting solvent. Evaporation of the solvent from the pure fraction gave 1.2 g of product which was recrystallized from isopropyl alcohol/water and dried under high vacuum at room temperature overnight to give 0.88 g of title compound, mp 122.5°-125° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[NH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH2:15]1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1>CN(C)C=O.O>[C:23]([O:22][C:21](=[O:27])[NH:20][C@H:17]1[CH2:16][CH2:15][C@H:14]([NH:13][C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][N:2]=[CH:3]3)=[O:12])[CH2:19][CH2:18]1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: O=C(O)c1ccc2[nH]ncc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](NC(=O)c2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the 1H-indazole-5-carboxylic acid (200 mg, 1.23 mmol) obtained in Reference Example 1 in N,N-dimethylformamide (15 ml) were added trans-tert-butyl 4-aminocyclohexylcarbamate (317 mg, 1.48 mmol), triethylamine (0.172 ml, 1.23 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide monohydrochloride (355 mg, 1.85 mmol) and hydroxybenzotriazole (200 mg, 1.48 mmol), and the resulting mixture was stirred at room temperature for 1 hour. After the reaction solution was heated at 50° C. for 1 hour, water was added thereto at 0° C. The resulting solid was filtered and then dried under reduced pressure to obtain trans-tert-butyl-4-[(1H-indazol-5-ylcarbonyl)amino]cyclohexylcarbamate (435 mg, 98%).
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C1(C)C=CC=CC=1.C([Sn](CCCC)(CCCC)[CH:22]=[CH:23][O:24][CH2:25][CH3:26])CCC>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>[Cl:8][C:5]1[N:4]=[C:3]([NH2:9])[C:2]([CH:22]=[CH:23][O:24][CH2:25][CH3:26])=[CH:7][N:6]=1
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Reactant: Nc1nc(Cl)ncc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC=Cc1cnc(Cl)nc1N
Temperature: 110 °C
Reaction time: 15 h
Yield: 45.9 %

Procedure:
A 500 mL round bottomed flask is charged with 5-bromo-2-chloropyrimidin-4-ylamine (1) (10 g, 48 mmol), tetrakis(triphenylphosphine)palladium(0) (2.8g, 2.5 mmol), and toluene (200 mL). Tributyl-(2-ethoxyvinyl)-stannane (22 g, 60 mmol) is added and the reaction heated to 110° C. with stirring for approximately 15 hours. After cooling to room temperature, the solution is diluted with 100 mL ethyl acetate and washed with water and brine. The organic extract is dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by column chromatography (SiO2, Hexane:Ethyl acetate/5:1) provides 2 (4.4 g, 46%) as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12]C(C)C(Cl)=O)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2].[C:22]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].[Mg].C(OCC)(=O)CC(OCC)=O>CCOCC>[CH2:31]([O:30][C:22](=[O:29])[CH:23]([O:12][C:11]1[CH:18]=[CH:19][C:8]([O:7][C:6]2[CH:20]=[CH:21][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:32]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(Oc1ccc(Oc2ccc(C#N)cc2)cc1)C(=O)Cl
Agent: [Mg]
Solvent: CCOCC
Product: CCOC(=O)C(Oc1ccc(Oc2ccc(C#N)cc2)cc1)C(=O)OCC
Yield: 72 %

Procedure:
A mixture of 30 g of 2-[4'-(4"-cyano-phenoxy)-phenoxy]-propionyl chloride and 30 ml of ether is added dropwise to a 35% etheral solution of magnesium diethyl malonate prepared from 17.6 g of diethyl malonate. The addition of the acid chloride having been completed the reaction mixture is heated to boiling for an hour and worked up as described in Example 1. Thus 30 g of the desired compound are obtained in the form of a viscous oil which solidifies on standing and melts at 42°-46° C. Yield 72%.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12](F)=[C:11]([F:16])[CH:10]=1.[CH2:18]([OH:21])[C:19]#[CH:20].[H-].[Na+].Cl>CN(C=O)C>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([O:21][CH2:18][C:19]#[CH:20])=[C:11]([F:16])[CH:10]=1
Reactant: CC1CCCC1NC(=O)c1ccc(F)c(F)c1
Reactant: C#CCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCOc1ccc(C(=O)NC2CCCC2C)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.6 %

Procedure:
To 2 ml of DMF were added 0.23 g of N-(2-methylcyclopentyl)-3,4-difluorobenzamide and 0.11 g of propargyl alcohol. To the mixture obtained was added 60 mg of 60% sodium hydride (oily) at 0° C. The mixture was stirred at room temperature for 2 hours. Then, dilute hydrochloric acid was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with brine, dried on magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.11 g of N-(2-methylcyclopentyl)-3-fluoro-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 69 of the present invention) represented by the formula:
Reaction SMILES: C(OC([NH:11][C@@H:12]1[C@@H:18]2[CH:19]=[CH:20][C@@H:14]([C@@H:15]3[C@H:17]2[CH2:16]3)[C@@H:13]1[C:21]([O:23][CH3:24])=[O:22])=O)C1C=CC=CC=1.[ClH:25]>C(OCC)(=O)C.[Pd].C(OCC)C.O1CCOCC1>[ClH:25].[NH2:11][C@@H:12]1[C@@H:18]2[CH2:19][CH2:20][C@@H:14]([C@@H:15]3[C@H:17]2[CH2:16]3)[C@@H:13]1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)[C@H]1[C@H]2C=C[C@H]([C@@H]3C[C@H]23)[C@H]1NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)[C@@H]1[C@H](N)[C@@H]2CC[C@H]1[C@H]1C[C@H]12
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
rac-Methyl (1R,2R,4S,5S,6S,7R)-7-{[(benzyloxy)carbonyl]amino}tricyclo[3.2.2.02,4]non-8-ene-6-carboxylate (0.61 g, 1.85 mmol) was dissolved in ethyl acetate (10 mL). 5% Palladium on carbon (0.10 g) was added. The flask was degassed and backfilled with hydrogen gas via balloon. The mixture was stirred at 25° C. for 16 h. The mixture was passed through a plug of Celite and the filtrate was concentrated in vacuo to afford a thick clear oil. The oil was dissolved in diethyl ether (6 mL) and added dropwise, with vigorous stirring, to a mixture of a 4.0M solution of hydrochloric acid in 1,4-dioxane (0.93 mL) in diethyl ether (11 mL). The mixture was concentrated and dried in vacuo to afford the desired product, rac-Methyl (1R,2R,4S,5S,6S,7R)-7-aminotricyclo[3.2.2.02,4]nonane-6-carboxylate hydrochloride (0.43 g, 1.85 mmol, 100%), as a sticky gum. LC-MS (ESI) calcd for C11H17NO2 (free amine) 195.26, found 196.5 [M+H+].
Reaction SMILES: Cl.[OH:2][CH2:3][C@@H:4]1[O:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[C:12]([F:22])[CH:11]=2)[CH2:5]1.C(N(CC)CC)C.Cl[C:31]1[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][N:32]=1>C(#N)C>[OH:2][CH2:3][C@@H:4]1[O:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:17][CH2:18][N:19]([C:31]4[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][N:32]=4)[CH2:20][CH2:21]3)=[C:12]([F:22])[CH:11]=2)[CH2:5]1
Reactant: O=C1O[C@@H](CO)CN1c1ccc(N2CCNCC2)c(F)c1
Reactant: N#Cc1ccc(Cl)nc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1ccc(N2CCN(c3ccc(N4C[C@H](CO)OC4=O)cc3F)CC2)nc1
Reaction time: 0.17 h

Procedure:
5(R)-hydroxymethyl-3-(3-fluoro-4-(piperazin-1-yl)phenyl)oxazolidin-2-one hydrochloride (25 g, 75.4 mmol ) was suspended by stirring in acetonitrile (700 ml) under nitrogen, and triethylamine (16.8 g, 166 mmol ) added, The mixture was stirred for 10 minutes and then 2-chloro-5-cyanopyridine (10.3 g, 75.4 mmol ) added, and the mixture heated under reflux for 18 hours. After cooling, the resultant solid was filtered, washed with water (3×500 ml) and diethyl ether (2×500 ml) to give 5(R)-hydroxymethyl-3-(4-(4-(5-cyanopyrid-2-yl)piperazin-1-yl)-3-fluorophenyl)-oxazolidin-2-one. A further crop was obtained by evaporation of the mother liquors to give a total yield of 23.2 g. MS: ESP+ (M+H)+=398.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:27][C:28]1[O:32][N:31]=[C:30]([CH2:33]OS(C)(=O)=O)[CH:29]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:33][C:30]2[CH:29]=[C:28]([CH3:27])[O:32][N:31]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Reactant: Cc1cc(COS(C)(=O)=O)no1
Product: Cc1cc(Cn2cc(C(=O)N3CCC4(CC3)OCc3ccccc34)c3ccc(Cl)cc32)no1

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (prepared according to example 69) with methanesulfonic acid 5-methyl-isoxazol-3-ylmethyl ester (described in WO 2004092172) gave the title compound. ES-MS m/e (%): 462.2(M+H+).