Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Br:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.[N:35]1([CH2:40]/[CH:41]=[CH:42]/[CH2:43]O)[CH2:39][CH2:38][CH2:37][CH2:36]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)[Cl:65]>>[ClH:65].[Br:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:43]/[CH:42]=[CH:41]/[CH2:40][N:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: OC/C=C/CN1CCCC1
Reactant: ClCCl
Reactant: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OC/C=C/CN1CCCC1
Product: Cl
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 32 %

Procedure:
Diethyl azodicarboxylate (1.55 ml, 9.89 mmol), 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (1.2g, 3.3 mmol), (prepared as described for the starting material in Example 48), and a solution of (E)-4-(pyrrolidin-1-yl)but-2-en-1-ol (697 mg, 4.9 mmol), (prepared as described for the starting material in Example 17), in methylene chloride (5 ml) were added successively to a solution of triphenylphosphine (2.59 g, 9.89 mmol) in methylene chloride (150 ml) cooled at 5° C. The mixture was stirred at ambient temperature for 10 minutes then methylene chloride (100 ml) was added followed successively by triphenylphosphine (432 mg, 1.6 mmol), (E)-4-(pyrrolidin-1-yl)but-2-en-1-ol (232 mg, 1.6 mmol) and diethyl azodicarboxylate (246 μl, 1.6 mmol). The mixture was stirred at ambient temperature for 30 minutes and then the solvent was removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (8/2 followed by 7/3 and 6/4). The semi-purified product was repurified by column chromatography eluting with methylene chloride/methanol (8/2 followed by 7.5/2.5). The purified product was dissolved in methylene chloride, 3.7M ethereal hydrogen chloride (3 ml) was added and the volatiles were removed by evaporation. The residue was triturated with ether, collected by filtration and dried under vacuum to give (E)-4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(4-pyrrolidin-1-ylbut-2-en-1-yloxy)quinazoline hydrochloride (600 mg, 32%).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:15]1([CH2:20][CH2:21][CH2:22]O)[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([CH2:20][CH2:21][CH2:22][O:1][C:2]2[C:7]3[C:8](=[O:14])[O:9][C:10]([CH3:12])([CH3:13])[O:11][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: OCCCC1CCCC1
Reactant: CC1(C)OC(=O)c2c(O)cccc2O1
Product: CC1(C)OC(=O)c2c(OCCCC3CCCC3)cccc2O1

Procedure:
5-(3-Cyclopentyl-propoxy)-2,2-dimethyl-benzo[1,3]dioxin-4-one was prepared from 5-hydroxy-2,2-dimethyl-benzo[1,3]dioxin-4-one and 3-Cyclopentyl-propan-1-ol under conditions analogous to example 51-a. 1H NMR (200 MHz, CDCl3): δ (ppm)=7.39 (t, J=8.4 Hz, 1H), 6.57 (d, J=8.5 Hz, 1H), 6.50 (d, J=8.2 Hz, 1H), 4.05 (t, J=7.0 Hz, 2H), 1.94-1.47 (m, 11H), 1.69 (s, 6H), 1.12 (m, 2H).
Reaction SMILES: O[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:9]([C:11]1[S:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=1)=[O:10].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CC1C=CC(C)=CC=1>N1C=CC=CC=1>[N+:16]([C:13]1[S:12][C:11]([C:9]2[O:10][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][C:7]=3[N:8]=2)=[CH:15][CH:14]=1)([O-:18])=[O:17]
Reactant: O=C(Nc1ccncc1O)c1ccc([N+](=O)[O-])s1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: c1ccncc1
Solvent: Cc1ccc(C)cc1
Product: O=[N+]([O-])c1ccc(-c2nc3ccncc3o2)s1
Temperature: 160 °C
Yield: 17.2 %

Procedure:
To a stirred solution of N-(3-hydroxypyridin-4-yl)-5-nitrothiophene-2-carboxamide (1.1 g, 4.1 mmol) in pyridine (5 mL) was added P2O5 (1.2 g, 8.3 mmol) and p-xylene (21 mL). After refluxing at 160° C. overnight, the reaction mixture was concentrated in vacuo and the residue was purified by chromatography on silica gel eluted with 5% of ethyl acetate in CH2Cl2 to give 2-(5-nitrothiophen-2-yl)oxazolo[5,4-c]pyridine as brown solid (174 mg, yield 17%). 1H NMR (400 MHz, CDCl3) δ: 8.97 (1H, s); 8.59 (1H, d, J=5.6); 7.94 (1H, d, J=4.4); 7.86 (1H, d, J=4.4), 7.69 (1H, d, J=5.6, 0.8).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH:23]([CH2:25][CH3:26])[NH:22][CH2:21][CH2:20]2>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:22]3[CH2:21][CH2:20][C:19]4[C:24](=[C:15]([F:14])[CH:16]=[CH:17][CH:18]=4)[CH:23]3[CH2:25][CH3:26])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CCC1NCCc2cccc(F)c21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CCC1c2c(F)cccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-fluoro-1-ethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.Cl[C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl.O>O1CCOCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:13](=[O:15])[O:8][C:7](=[O:9])[C:6]=2[CH:10]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(O)cc1C(=O)O
Solvent: C1COCCO1
Solvent: O
Product: O=c1[nH]c2ccc(O)cc2c(=O)o1

Procedure:
Step 1): A solution of 5-hydroxyanthranilic acid (500 mg, 3.26 mmol) and triphosgene (1.45 g, 4.9 mmol) in 1,4-dioxane (20 ml) was refluxed overnight. The reaction mixture was poured into H2O (30 ml), and then the precipitates were filtered and dried to give 6-hydroxy-1,2-dihydro-4H-3,1-benzoxazin-2,4-dione, 360 mg (62%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1B(O)O.Br[C:15]1[S:16][C:17]([Cl:20])=[CH:18][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(#N)C.O.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:20][C:17]1[S:16][C:15]([C:3]2[CH:4]=[C:5]([C:8](=[O:10])[CH3:9])[CH:6]=[CH:7][C:2]=2[F:1])=[CH:19][CH:18]=1
Reactant: Clc1ccc(Br)s1
Reactant: CC(=O)c1ccc(F)c(B(O)O)c1
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: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CC(=O)c1ccc(F)c(-c2ccc(Cl)s2)c1
Yield: 42.1 %

Procedure:
To a solution of 2-fluoro-5-acetylphenylboronic acid (5.00 g, 27.48 mmol) in ACN (80 mL) and H2O (20 mL) were added 2-bromo-5-chlorothiophene (5.43 g, 27.48 mmol), sodium carbonate (2.91 g, 27.48 mmol) and tetrakis(triphenylphosphine)palladium(0) (635 mg, 0.02 mmol). The reaction mixture was refluxed for 3 h. After cooling, ethyl acetate (150 ml) and water (150 ml) were added. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried over sodium sulfate. Evaporation and purification of the crude product by silica gel chromatography using ethyl acetate/heptane gave the desired product (2.95 g, 42%).
Reaction SMILES: O[C@@H](C1C=CC=CC=1)CNC1C=CNC(=O)C=1C1NC2C(C(O)=O)=CC=CC=2N=1.C(N)C1C=CC=CC=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.F[C:72]1[CH:73]=[C:74]([CH:105]=[CH:106][CH:107]=1)[CH2:75][NH:76][C:77]([C:79]1[C:87]2[NH:86][C:85]([C:88]3[C:89](=[O:104])[NH:90][CH:91]=[CH:92][C:93]=3[NH:94][CH2:95][C@@H:96]([OH:103])[C:97]3[CH:102]=[CH:101][CH:100]=[CH:99][CH:98]=3)=[N:84][C:83]=2[CH:82]=[CH:81][CH:80]=1)=[O:78]>CN(C=O)C>[CH2:75]([NH:76][C:77]([C:79]1[C:87]2[NH:86][C:85]([C:88]3[C:89](=[O:104])[NH:90][CH:91]=[CH:92][C:93]=3[NH:94][CH2:95][C@@H:96]([OH:103])[C:97]3[CH:102]=[CH:101][CH:100]=[CH:99][CH:98]=3)=[N:84][C:83]=2[CH:82]=[CH:81][CH:80]=1)=[O:78])[C:74]1[CH:105]=[CH:106][CH:107]=[CH:72][CH:73]=1
Reactant: O=C(NCc1cccc(F)c1)c1cccc2nc(-c3c(NC[C@@H](O)c4ccccc4)cc[nH]c3=O)[nH]c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)c1cccc2nc(-c3c(NC[C@@H](O)c4ccccc4)cc[nH]c3=O)[nH]c12
Solvent: NCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)c1cccc2nc(-c3c(NC[C@@H](O)c4ccccc4)cc[nH]c3=O)[nH]c12

Procedure:
2-[4-((S)-2-Hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazole-4-carboxylic acid benzylamide was synthesized from 2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazole-4-carboxylic acid, benzylamine, DIEA, HATU and DMF using a similar procedure as 2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazole-4-carboxylic acid 3-fluoro-benzylamide yielding 2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazole-4-carboxylic acid benzylamide. LC/MS calcd for C28H25N5O3 (m/e) 479.0, obsd 480 (M+H). 1H NMR (tautomers 1:2; DMSO-d6): 13.38-13.52 (m, 1H), 11.14-11.38 (m, 1H), 10.33-11.02 (m, 1H), 9.18-9.43 (m, 1H), 7.69-7.99 (m, 2H), 7.15-7.61 (m, 12H), 6.12-6.30 (m, 1H), 5.74-5.99 (m, 1H), 4.52-4.96 (m, 3H), 3.49-3.30 (m, 2H).
Reaction SMILES: C[CH:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7].[CH3:10]C(CC=O)C>>[CH3:10][CH2:7][C:6](=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2][CH3:9]
Reactant: CC(=O)CCCC(C)C
Reactant: CC(C)CC=O
Product: CCCCCC(=O)CC
Yield: 95.4 %

Procedure:
Quantification shows that 606.3 g 6-methylheptanone (4.73 mole) were obtained, which corresponds to a 95.4% yield of methylheptanone in relation to isovaleral. The isovaleraldehyde conversion is 99.2%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C-:9]#[N:10].[C-]#N.[Na+].O>CN(C)C=O>[C:9]([C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1)#[N:10]
Reactant: [C-]#N
Reactant: Brc1ccc(Br)nc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Br)cn1
Temperature: 150 °C
Reaction time: 7 h
Yield: 69.9 %

Procedure:
In 1 L of dimethylformamide was dissolved 100 g of 2,5-dibromopyridine, 32 g of cupper cyanide and 17.8 g of sodium cyanide were added to the solution at room temperature and the solution was stirred at the temperature of 150° C. for 7 hours for reaction. After being cooled to room temperature, the reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dehydrated, filtered and concentrated in vacuo. The title compound 54 g was obtained. Yield 70%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:17][CH:12]4[CH2:13][CH:14]([CH2:16][C:10]([C:18]5[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=5)([CH2:11]4)[CH2:9]2)[CH2:15]3)=[CH:4][CH:3]=1.[CH2:25]([CH:27]1[O:29][CH2:28]1)Cl.[OH-].[Na+].C[CH2:33][C:34]([CH3:36])=[O:35]>CC(CC(C)=O)C.CS(C)=O>[CH2:25]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[CH2:15][CH:14]4[CH2:13][CH:12]([CH2:11][C:10]([C:18]5[CH:19]=[CH:20][C:21]([O:24][CH2:33][CH:34]6[O:35][CH2:36]6)=[CH:22][CH:23]=5)([CH2:16]4)[CH2:9]2)[CH2:17]3)=[CH:6][CH:7]=1)[CH:27]1[O:29][CH2:28]1
Reactant: Oc1ccc(C23CC4CC(C2)CC(c2ccc(O)cc2)(C4)C3)cc1
Reactant: ClCC1CO1
Reactant: CCC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)CC(C)C
Solvent: CS(C)=O
Product: c1cc(C23CC4CC(C2)CC(c2ccc(OCC5CO5)cc2)(C4)C3)ccc1OCC1CO1
Temperature: 45 °C
Reaction time: 4 h
Yield: 92.9 %

Procedure:
In a separable flask having an inner volume of 300 ml, equipped with a reflux condenser, a stirrer, and a thermometer, were charged 20.0 g (0.06 mol) of 1,3-bis(4-hydroxyphenyl)adamantane, 46 g (0.50 mol) of epichlorohydrin, 30 mL of MIBK, and 60 mL of DMSO, and they were heated to 45° C. Then, 5.5 g (0.14 mol) of sodium hydroxide was added into this solution by small portions during a period of 1.5 hours. After completion of the addition, the reaction temperature was raised to 75° C., and the reaction was carried out for 4 hours. After the reaction was completed, the mixture was cooled to room temperature, added by 25 mL of MIBK, and washed with water until the aqueous layer became neutral. The resulting organic layer was concentrated to obtain pale yellow solids. The pale yellow solids were dissolved in 285 g of MEK, added by 3.4 g of 25% by mass of aqueous sodium hydroxide solution, and then the mixture was stirred for 2 hours under reflux. Thereafter, the solution was cooled to room temperature, and washed by water until the aqueous layer became neutral from alkaline. The water-washing was performed two more times, and then the organic layer was concentrated to obtain pale yellow solids, which was recrystallized by a mixed solvent of THF (tetrahydrofuran) and isopropyl ether to obtain 24.1 g of 1,3-bis(4-glycidyloxyphenyl)adamantane having the following formula (purity of 94% by LC (liquid chromatography), epoxy equivalent of 224).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16](=O)[C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:30][OH:31].[OH-].[K+]>C(O)C.CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16](=[N:30][OH:31])[C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCC1CCN(Cc2ccccc2)CC1)c1ccc(N2CCCC2)cc1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: ON=C(CCC1CCN(Cc2ccccc2)CC1)c1ccc(N2CCCC2)cc1
Temperature: 0 °C
Yield: 66.1 %

Procedure:
To a mixed solution (20 ml) containing 0.8 g of the 1-benzyl-4-[2-(4-pyrrolidinobenzoyl)ethyl]piperidine prepared in Example 59 and 0.7 g of hydroxylamine hydrochloride in ethanol was added a solution (7 mi) of 1.4 g of potassium hydroxide in methanol dropwise with warming at 50°-55° C. The mixture was further heated at 50°-55° C. for one hour, at the end of which time it was added to 200 ml of ice-water. The resulting precipitate was collected by filtration, rinsed and dissolved in dichloromethane. The solution was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to give crude crystals. Recrystallization from dichloromethane-ether yielded 0.55 g of colorless crystals melting at 153°-158° C.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:36]([OH:38])=[O:37])[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([O:27]CC4C=CC=CC=4)=[C:22]([CH3:35])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:39]=[CH:40][CH:41]=[CH:42][C:4]=2[NH:3]1.[H][H]>C(Cl)Cl.[Pd]>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:36]([OH:38])=[O:37])[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[C:22]([CH3:35])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:39]=[CH:40][CH:41]=[CH:42][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1O
Temperature: 25 °C

Procedure:
3.72 g (6.51 mmol) (R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 50 mL DCM were combined with 300 mg 10% Pd/C and shaken at RT and 3000 hPa hydrogen until the reaction came to an end. The catalyst was suction filtered and the solvent evaporated down i.vac. The residue was triturated with DIPE and suction filtered.
Reaction SMILES: C1COCC1.Cl.[CH3:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[NH2:13].C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH2:33][C:34]#[CH:35])[C:26](Cl)=[O:27]>O>[CH3:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[NH:13][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:31]([O:32][CH2:33][C:34]#[CH:35])=[C:23]([O:22][CH3:21])[CH:24]=1
Reactant: C#CCOc1ccc(C(=O)Cl)cc1OC
Reactant: CC1CCCC1N
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCOc1ccc(C(=O)NC2CCCC2C)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.7 %

Procedure:
To a mixture of 20 ml of THF, 0.50 g of 2-methylcyclopentylamine hydrochloride and 1.0 g of triethylamine was added 0.50 g of 3-methoxy-4-(2-propynyloxy)benzoyl chloride. The mixture obtained was stirred at room temperature for 3 hours. Then, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 235 mg of N-(2-methylcyclopentyl)-3-methoxy-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 18 of the present invention) represented by the formula:
Reaction SMILES: [C:1]([N:5]1[C:9]([CH:10]([CH3:12])[CH3:11])=[CH:8][C:7]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[O:22][CH2:23][C:24]([CH3:27])([CH3:26])[N:25]=3)=[CH:17][CH:16]=2)=C)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl.ClCCl.C(OCC)(=[O:36])C>C(O)C>[C:1]([N:5]1[C:9]([CH:10]([CH3:12])[CH3:11])=[CH:8][C:7]([CH:13]([OH:36])[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[O:22][CH2:23][C:24]([CH3:27])([CH3:26])[N:25]=3)=[CH:17][CH:16]=2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(c1ccc(C2=NC(C)(C)CO2)cc1)c1cc(C(C)C)n(C(C)(C)C)n1
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: CC(C)c1cc(C(O)c2ccc(C3=NC(C)(C)CO3)cc2)nn1C(C)(C)C
Temperature: 100 °C

Procedure:
To 5 ml of 130 mg of α-(1-tert-butyl-5-isopropylpyrazol-3-yl)-4-(4,4-dimethyl-1,3-oxazolin-2-yl)styrene in ethanol was added 0.4 ml of a 3N aqueous solution of an acid at room temperature. The resulting mixture was heated under reflux for 30 minutes. To the reaction mixture was added a 5N aqueous solution of sodium hydroxide to adjust its pH to 11, followed by extraction with dichloromethane. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To a solution of the residue in 3 ml of 1,4-dioxane were added 100 mg of lithium hydroxide and the resulting mixture was heated at 100° C. for 2 hours. After the completion of the reaction, a 3N aqueous solution of hydrochloric acid was added to adjust the pH to 5, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue so obtained was subjected to chromatography on a silica gel column (developing solvent: 50% dichloromethane/ethyl acetate), whereby 4 mg of the title compound were obtained as a pale yellow solid.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[Cl:23][C:24]1[C:41]([C:42]([F:45])([F:44])[F:43])=[CH:40][CH:39]=[CH:38][C:25]=1[CH2:26][N:27]1[CH:32]([CH:33]2[CH2:35][CH2:34]2)[CH2:31][NH:30][C:29](=O)[C:28]1=[O:37]>C1COCC1>[Cl:23][C:24]1[C:41]([C:42]([F:45])([F:44])[F:43])=[CH:40][CH:39]=[CH:38][C:25]=1[CH2:26][N:27]1[CH:32]([CH:33]2[CH2:35][CH2:34]2)[CH2:31][NH:30][C:29](=[S:10])[C:28]1=[O:37]
Reactant: O=C1NCC(C2CC2)N(Cc2cccc(C(F)(F)F)c2Cl)C1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: O=C1C(=S)NCC(C2CC2)N1Cc1cccc(C(F)(F)F)c1Cl
Temperature: 55 °C
Yield: 173.4 %

Procedure:
To a heterogeneous mixture of Lawesson's reagent (289 mg, 0.69 mmol) in THF (13 mL) was added Intermediate 5 (480 mg, 1.4 mmol) in one portion. The mixture was heated at 55° C. for 20 minutes and then concentrated to remove solvent. Purification by chromatography (SiO2; hexanes—100% EtOAc) afforded the desired product as a yellow solid (434 mg, 86%). MS (ESI): mass calcd. for C15H14ClF3N2OS, 362.1; m/z found, 363.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 9.40 (s, 1H), 7.63 (t, J=8.0 Hz, 2H), 7.36 (t, J=7.8 Hz, 1H), 5.23 (d, J=15.8 Hz, 1H), 4.74 (d, J=15.8 Hz, 1H), 3.73 (ddd, J=13.4, 4.0, 2.1 Hz, 1H), 3.57 (ddd, J=13.5, 5.2, 3.1 Hz, 1H), 2.81 (dd, J=8.5, 4.4 Hz, 1H), 1.24-1.11 (m, 1H), 0.79-0.67 (m, 1H), 0.63-0.55 (m, 1H), 0.51-0.45 (m, 1H), 0.21-0.08 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[S:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][C:10]=2[N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1.[CH:22]1[C:34]2[CH:33]([CH2:35][O:36][C:37](Cl)=[O:38])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1.N1C=CC=CC=1>C(Cl)Cl>[CH:22]1[C:34]2[CH:33]([CH2:35][O:36][C:37]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([S:8][C:9]4[S:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][C:10]=4[N+:19]([O-:21])=[O:20])=[CH:6][CH:7]=3)=[O:38])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(Sc2ccc(N)cc2)s1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc([N+](=O)[O-])c(Sc2ccc(NC(=O)OCC3c4ccccc4-c4ccccc43)cc2)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A suspension of the product of Example 90B (0.500 g, 1.541 mmol) and 9-fluorenylmethoxycarbonyl chloride (0.478 g, 1.849 mmol) in methylene chloride (10 mL) under a nitrogen atmosphere was treated with pyridine (0.25 mL, 3.083 mmol), and the resulting solution stirred for 18 hours at room temperature. The reaction was diluted with methylene chloride (50 mL) and washed with 1N aqueous HCl (50 mL) then water (50 mL). The organic was dried over magnesium sulfate, filtered, and concentrated by rotary evaporation. Purification by silica gel flash chromatography eluting with methylene chloride afforded the title compound as a bright yellow solid (0.842 g, quantitative). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.23 (t, J=7.17 Hz, 3 H) 4.24 (q, J=7.23 Hz, 2 H) 4.35 (t, J=6.43 Hz, 1 H) 4.57 (d, J=6.25 Hz, 2 H) 7.29-7.50 (m, 4 H) 7.69 (s, 4 H) 7.77 (d, J=7.35 Hz, 2 H) 7.92 (d, J=7.35 Hz, 2 H) 8.11 (s, 1 H) 10.15 (s, 1 H); MS (ESI+) m/z 564 (M+NH4)+, 569 (M+Na)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[N:30]=[C:31]([N:39]2[CH2:44][CH2:43][N:42]([CH2:45][CH3:46])[CH2:41][CH2:40]2)[C:32]2[C:37]([CH:38]=1)=[CH:36][CH:35]=[CH:34][CH:33]=2>C1(C)C(C)=CC=CC=1.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>[CH2:45]([N:42]1[CH2:41][CH2:40][N:39]([C:31]2[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:38]=[C:29]([C:11]3[CH:12]=[C:13]4[C:8](=[CH:9][CH:10]=3)[CH2:7][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:14]4)[N:30]=2)[CH2:44][CH2:43]1)[CH3:46]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc2c(c1)CC(C(=O)OCC)C2
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CCOC(=O)C1Cc2ccc(-c3cc4ccccc4c(N4CCN(CC)CC4)n3)cc2C1
Yield: 90.8 %

Procedure:
2-Ethoxycarbonyl -5-(tributyistannyl)indane (3.04 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (0.87 g) were heated under reflux overnight in the presence of tetrakistriphenylphosphinepalladium(0) (0.12 g) in xylene in nitrogen atmosphere. Af ter cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted with 2N hydrochloric acid, and the resulting aqueous layer was washed with ethyl acetate, adjusted to pH 10 with a 8N aqueous solution of sodium hydroxide, and then extracted with ethyl acetate. The extract was washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, to give 1-(4-ethylpiperazin-1-yl)-3-(2-ethoxycarbonylindan-5-yl)isoquinoline (1.06 g) as a brown viscous oil.