Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1)#[N:2].[Li]CCCC.[Cl:18][CH2:19][CH2:20][CH2:21][CH2:22]I>C1COCC1.CCCCCC>[Cl:18][CH2:19][CH2:20][CH2:21][CH2:22][N:9]([C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)[C:10](=[O:12])[CH3:11]
Reactant: CC(=O)Nc1ccc(C#N)cc1
Reactant: ClCCCCI
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)N(CCCCCl)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9 g (54.1 mmol) of N-(4-cyanophenyl)acetamide are dissolved in 100 ml of THF. The mixture is cooled to 0° C. before the dropwise addition of 51 ml of a 1.6 N solution in hexane of nBuLi (1.5 eq.). The solution is left for one hour to return to ambient temperature and is then cooled to 0° C. before the dropwise addition of 9.9 ml of 1-chloro-4-iodobutane (81 mmol). The reaction mixture is stirred at ambient temperature for 18 h and then hydrolysed with a saturated aqueous solution of ammonium chloride (100 ml) and extracted with ethyl acetate. The organic phases are combined, dried over magnesium sulphate and concentrated. Purification by chromatography on silica (eluant: petroleum ether/ethyl acetate: 1/1) yields a yellow oil containing the expected product.
Reaction SMILES: [OH2:1].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([CH:18]=O)=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:20][C:21]([NH2:36])([CH3:35])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[C:24]=1[O:33][CH3:34]>CS(C)=O>[CH3:35][C:21]([N:36]=[C:10]([O:9][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:15]([C:14]1[CH:13]=[CH:12][CH:11]=[CH:16][CH:18]=1)=[O:1])([CH3:20])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[C:24]=1[O:33][CH3:34]
Reactant: O
Reactant: O=CC(=O)c1ccccc1OCc1ccccc1
Reactant: COc1ccc(CC(C)(C)N)c(OC)c1OC
Solvent: CS(C)=O
Product: COc1ccc(CC(C)(C)N=C(OCc2ccccc2)C(=O)c2ccccc2)c(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.4 g of 2-benzyloxyphenylglyoxal hydrate are dissolved in 3 ml of dimethylsulfoxide, and a solution of 1.9 g of α,α-dimethyl-2,3,4-trimethoxyphenethylamine in 5 ml of dimethylsulfoxide is added thereto. The mixture is stirred at 25° C. for one hour, whereby a solution of α-(α,α-dimethyl-2,3,4-trimethoxyphenethylimino)-2-benzyloxyacetophenone in dimethylsulfoxide is obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)[Cl:36].[ClH:38].CO>>[ClH:36].[ClH:38].[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:18]=[C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[N:15]([CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])[CH:16]=2)=[CH:20][C:21]=1[C:26]([F:27])([F:28])[F:29]
Reactant: ClCCl
Reactant: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Product: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.38 %

Procedure:
Combine a solution of 4-(1-(2-(dimethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester (28.00 g; 1.00 equiv; 57.79 mmol) in DCM (280.00 mL; 4.37 mol) with a 4 M solution of hydrogen chloride in methanol (50.56 mL; 3.50 equiv; 202.25 mmol). Stir the green suspension at RT for 3 h. Evaporate the solvent, and add EA (100 mL) and evaporate again. Add EA (200 mL) and stir the suspension for 30 m. Filter on a glass fritted funnel to obtain the title compound (26.00 g; 56.85 mmol; 98.38% yield) as a green solid. m/z (M+H): 385.2
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(CC)CC)[CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][C:27]=1[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:30][CH:29]=1)[N:24]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[N:23]=[C:22]2[NH:50][C:51](=[O:55])[CH2:52][CH2:53][CH3:54].C(OCC)(=O)C>O.O1CCOCC1.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>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][C:27]=2[C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:32][CH:33]=2)[N:24]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:47])([CH3:48])[CH3:49])[N:23]=[C:22]3[NH:50][C:51](=[O:55])[CH2:52][CH2:53][CH3:54])[CH:2]=1
Reactant: CCB(CC)c1cccnc1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(OCc4ccccc4)cc3)c(Br)cc12
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: C1COCCO1
Solvent: O
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(OCc4ccccc4)cc3)c(-c3cccnc3)cc12
Yield: 160.5 %

Procedure:
371 mg of 3-pyridyldiethylborane, 428 mg of sodium carbonate in 30 cm3 of water, and 258 mg of tetrakis(triphenylphosphine)palladium are added to 1 g of N-[5-bromo-6-[4-(phenylmethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, prepared in Example 63, in 100 cm3 of dioxane, and the mixture is refluxed for 18 hours. 100 cm3 of ethyl acetate and 100 cm of water are added and the reaction medium is filtered through a sinter funnel packed with Celite. The organic phase is separated out after settling of the phases has taken place, washed successively with 75 cm3 of water and with 75 cm3 of saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure (2 kPa; 50° C.) to give 1.6 g of an oil, which is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3.5 cm), eluting with a cyclohexane/ethyl acetate mixture (70/30 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.) to give 700 mg of N-[5-(3-pyridyl)-6-[4-(phenylmethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl])-1H-indazol-3-yl]butanamide in the form of a yellow oil.
Reaction SMILES: [Br:1][CH2:2][C:3]1[S:7][C:6]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:5][CH:4]=1.[C:18]1([P:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[Br-:1].[CH2:11]([O:10][C:8]([C:6]1[S:7][C:3]([CH2:2][P+:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:4][CH:5]=1)=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(OCc1ccccc1)c1ccc(CBr)s1
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)s1
Product: [Br-]
Temperature: 80 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
To a mixture of 2.18 g of benzyl 5-(bromomethyl)thiophene-2-carboxylate and 26 mL of toluene was added 1.86 g of triphenylphosphine, followed by stirring overnight at 80° C. The insoluble material was collected by filtration, thereby obtaining 2.89 g of ({5-[(benzyloxy)carbonyl]-2-thienyl}methyl)(triphenyl)phosphonium bromide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([OH:7])[OH:6].C(=O)(O)[O-].[Na+].[C:13]([O:18][CH:19]([O:21][C:22](OC1CC(=O)NC1=O)=[O:23])[CH3:20])(=[O:17])[CH:14]([CH3:16])[CH3:15]>O.C(#N)C.C(OCC)C>[C:13]([O:18][CH:19]([O:21][C:22]([NH:1][CH2:2][CH2:3][CH2:4][P:5]([OH:7])[OH:6])=[O:23])[CH3:20])(=[O:17])[CH:14]([CH3:16])[CH3:15]
Reactant: NCCCP(O)O
Reactant: CC(OC(=O)OC1CC(=O)NC1=O)OC(=O)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOCC
Product: CC(OC(=O)NCCCP(O)O)OC(=O)C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-aminopropylphosphonous acid (10 mmol) and sodium bicarbonate (20 mmol) in water (40 mL) is added a solution of compound (17) (10 mmol) in acetonitrile (20 mL) over 1 min. The reaction is stirred at ambient temperature for 16 h. The reaction mixture is diluted with diethyl ether (100 mL) and washed with 0.1 M aqueous potassium bisulfate (3×100 mL). The organic phase is separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound (31) as a white solid.
Reaction SMILES: [C:1]([NH2:7])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].I[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2>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.CN(C=O)C.CCN(CC)CC>[CH3:26][O:25][C:24]1[CH:23]=[CH:22][NH:21][C:20]=1/[CH:19]=[C:11]1\[C:12](=[O:18])[NH:13][C:14]2[C:10]\1=[C:9]([C:5]#[C:4][CH2:3][CH2:2][C:1]([NH2:7])=[O:6])[CH:17]=[CH:16][CH:15]=2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Reactant: C#CCCC(N)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCCC(N)=O)c21

Procedure:
Using Method C above, 4-pentynamide (49 mg, 0.5 mmol) (prepared from 4-pentyonic acid according to Method G above) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 2 supra) (120 mg, 0.32 mmol) using (Ph3P)2PdCl2 (12 mg) and CuI (6 mg) as catalyst in DMF (1 mL) and Et3N (1 mL) as solvent at 70° C. for 22 h to yield (Z)-5-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-4-pentynamide. (Yield 45 mg, 42%).
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1>ClCCl>[NH2:9][C:10]([NH2:12])=[S:11].[C:1]([N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Product: NC(N)=S
Product: O=C(c1ccccc1)N1CCCc2ccccc21
Yield: 93 %

Procedure:
To a 250 mL 3-neck RBF equipped with a condenser, magnetic stirrer, thermo-probe, nitrogen purge and pressure-equilibrated addition funnel was added benzoyl isothiocyanate (25.0 g, 0.150 mol) followed by dichloromethane (100 mL). The mixture was cooled in an ice-water bath at a temperature below 5° C., at which point tetrahydroquinoline (20.4 g, 0.150 mol) and dichloromethane (100 mL) were added slowly over a period of time of about 30 minutes. The ice-water bath was removed and the reaction mixture was stirred under a nitrogen purge overnight. The reaction mixture was then concentrated in vacuo at a temperature of 40° C. to provide a white solid. The solid was dried to constant weight in vacuo at a temperature of 50° C. and a pressure of <1 mTorr in a 93% yield. The solid was determined to have a melting point of 143.6° C.
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[CH:32]([C:35]1[CH:36]=[C:37]([CH:42]=[CH:43][CH:44]=1)CB(O)O)([CH3:34])[CH3:33]>COCCOC>[F:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[C:2]([C:43]2[CH:42]=[CH:37][CH:36]=[C:35]([CH:32]([CH3:34])[CH3:33])[CH:44]=2)[CH:24]=1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1Br
Reactant: CC(C)c1cccc(CB(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)c1cccc(-c2cc(F)ccc2OCC(=O)N(NC(=O)c2ccccc2)C(C)C)c1

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/2M Na2CO3 (0.215 ml, 0.427 mmol) was treated with 3-isopropylbenzylboronic acid (30 mg, 0.183 mmol) and Pd[PPh3]4 (28 mg, 0.0244 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with 30% ethyl acetate/hexanes to afford the product as a white solid. (34 mg, 62%). MS m/e 449.30 (M+H+)
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[N:11]1([CH2:17][CH2:18][NH2:19])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>>[N:11]1([CH2:17][CH2:18][NH:19][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: NCCN1CCOCC1
Reactant: O=[N+]([O-])c1ccc(I)cc1
Product: O=[N+]([O-])c1ccc(NCCN2CCOCC2)cc1

Procedure:
Using 1-iodo-4-nitro-benzene (498 mg) instead of 1-bromo-3-nitro-benzene, and 2-morpholin-4-yl-ethylamine (315 μl) instead of morpholine, in the same manner as Step A in Example 1-D-105, the desired compound was obtained (301.1 mg, 60%).
Reaction SMILES: [C:1]([N:11]1[CH2:19][CH:18]([OH:20])[CH2:17][C@H:12]1[C:13]([O:15][CH3:16])=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].N1C=CC=CC=1.[S:27](Cl)([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28]>CO>[C:1]([N:11]1[CH2:19][CH:18]([O:20][S:27]([C:30]2[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH2:17][C@H:12]1[C:13]([O:15][CH3:16])=[O:14])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@@H]1CC(O)CN1C(=O)OCc1ccccc1
Solvent: CO
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1CC(OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
A stirred solution of 14.5 g. (0.052 mole) of N-carbobenzyloxy-4-hydroxy-L-proline, methyl ester in 30 ml. of pyridine is treated dropwise at -5° to -8° with a solution of 11 g. (0.058 mole) of tosyl chloride in 15 ml. of pyridine. The pale yellow solution is stored in the cold for 3 days, then added with stirring to 300 ml. of ice-cold 2 N hydrochloric acid. The precipitated gum is extracted with 200 ml. of chloroform. The aqueous phase is extracted with additional chloroform (3×100 ml.). The organic layers are combined, dried (MgSO4), and the solvent evaporated to give a pale yellow viscous oil. The oil is dissolved in 100 ml. of methanol and diluted to 400 ml. with water to precipitate the product as an oil which gradually crystallizes on seeding, rubbing, and cooling: yield 17.4 g. (77%); m.p. 62°-65°. Following crystallization from 85 ml. of isopropanol, the colorless solid N-carbobenzyloxy-4-tosyloxy-L-proline, methyl ester weighs 15.9 g. (70%); m.p. 67°-69°; [α]D26 -30° (c=1; methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1>C(OCC)(=O)C.O.C(O)(=O)C>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=2)=[CH:15][C:16]=1[CH3:23]
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1[N+](=O)[O-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1N
Temperature: 100 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
In a solution of 1.23 g of 5-(3,5-dichlorophenyl)-3-(3-methyl-4-nitrophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole in 10 ml of ethyl acetate, 5.0 ml of water, 5.0 ml of acetic acid and 0.66 g of reduced iron were added and stirred at 100° C. for 2 hours. After the completion of the reaction, the reaction mixture was filtered through Celite, 20 ml of water was added in the filtrate, extracted with ethyl acetate (20 ml×2). The organic phases together were washed with 10 ml of saturated sodium hydrogen carbonate aqueous solution, and then with 10 ml of water, thereafter dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 1.05 g of crude aimed product as red-brown oily substance. The resulting product was used as such without purification for the next step.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:2][C:3]2[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=2[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[CH2:22][CH2:21]1
Reactant: O=[N+]([O-])c1ccc(C(F)(F)C(F)(F)F)c(CBr)c1
Reactant: CN1CCNCC1
Product: CN1CCN(Cc2cc([N+](=O)[O-])ccc2C(F)(F)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Bromomethyl-4-nitro-1-pentafluoroethyl-benzene (2.6 g) was added to N-methylpiperazine (5 ml) and stirred at RT for 3 h. The mixture was filtered and the filtrate was treated with 1-chlorobutane, extracted with 2N HCl (100 ml). The acidic solution was treated with 5N NaOH (6 ml) then extracted with EtOAc. The organic layer was removed, dried over MgSO4 and concentrated to give the compound as an oil.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[O:22][CH3:23])[CH:3]=1.[CH3:24][O:25][CH2:26][CH2:27][NH2:28]>O1CCOCC1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[O:22][CH3:23])[CH:3]=[C:2]2[NH:28][CH2:27][CH2:26][O:25][CH3:24]
Reactant: COCCN
Reactant: COc1cc(F)ccc1CNc1cc(Br)c2cc(Cl)ccc2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: COCCNc1cc(NCc2ccc(F)cc2OC)nc2ccc(Cl)cc12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
(4-Bromo-6-chloro-quinolin-2-yl)-(4-fluoro-2-methoxy-benzyl)-amine (prepared from 2-amino-6-chloro-4-hydroxyquinoline and 4-fluoro-2-methoxybenzaldehyde as described in example 30, step A and B, 328 mg, 0.828 mmol) was dissolved in 5 mL dioxane. Argon was bubbled through the solution for 2 minutes to remove oxygen. 2-Methoxyethylamine (187 mg, 2.49 mmol), sodium tert.-butylate (159 mg, 1.66 mmol), 1,1′-bis(diphenylphosphino)ferrocene (69 mg, 0.125 mmol) and 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride (34 mg, 0.042 mmol) were added. The reaction mixture was stirred in a sealed tube at 100° C. for 2 h. The solvent was evaporated and the residue purified by flash chromatography on silica gel (dichloromethane/methanol/ammonia 100:0:0->110:10:1 gradient). 6-Chloro-N2-(4-fluoro-2-methoxy-benzyl)-N4-(2-methoxy-ethyl)-quinoline-2,4-diamine was obtained as an off-white foam (285 mg, 88%), MS: m/e=390.0 (M+H+).
Reaction SMILES: [H][H].C([N:10]1[C:14]([CH2:15][CH2:16][O:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:13][N:12]=[N:11]1)C1C=CC=CC=1>C(O)(C)C.O.[Pd](Cl)Cl>[NH:10]1[C:14]([CH2:15][CH2:16][O:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:13][N:12]=[N:11]1
Reactant: O=C(O)COCCc1cnnn1Cc1ccccc1
Reactant: [H][H]
Agent: Cl[Pd]Cl
Solvent: O
Solvent: CC(C)O
Product: O=C(O)COCCc1cnn[nH]1
Yield: 120.3 %

Procedure:
Pressurize 1 atmosphere of hydrogen (g) to a flask containing [2-(1-benzyl-1H-1,2,3-triazol-5-yl)ethoxy]acetic acid (10.1 g; 1.00 equiv; 38.66 mmoles) and palladium (II) chloride (3 g; 16.92 mmoles; 3.00 g) in isopropyl alcohol (300 mL) and water (60 mL). Maintain the flask under a hydrogen atmosphere for 3 h, then filter through Celite™ and concentrate. Add toluene (2×50 mL) and concentrate to afford the title compound (7.96 g, 100%). 1H NMR (d6-DMSO): 2.86 (t, J=7 Hz, 2H), 3.65 (t, J=7 Hz, 2H), 3.98 (s, 2H), 7.77 (s, 1H), 13.4-13.6 (br s, 2H).
Reaction SMILES: [F:1][C:2]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[S:20][C:19]([CH2:21][N:22]4[CH2:25][CH:24]([C:26]([O:28]C)=[O:27])[CH2:23]4)=[CH:18][C:17]=3[CH2:30][CH3:31])[N:12]=2)=[CH:7][CH:6]=1.O.[OH-].[Li+].C(O)(=O)C>>[F:1][C:2]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[S:20][C:19]([CH2:21][N:22]4[CH2:25][CH:24]([C:26]([OH:28])=[O:27])[CH2:23]4)=[CH:18][C:17]=3[CH2:30][CH3:31])[N:12]=2)=[CH:7][CH:6]=1
Reactant: CCc1cc(CN2CC(C(=O)OC)C2)sc1-c1noc(-c2ccc(Oc3cccc(F)c3F)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCc1cc(CN2CC(C(=O)O)C2)sc1-c1noc(-c2ccc(Oc3cccc(F)c3F)cc2)n1
Yield: 39.7 %

Procedure:
The title compound (77 mg) was synthesized in a yield of 38% as a white crystalline solid by conducting the reaction similar to that mentioned in Example 2 (2e) using methyl 1-[(5-{5-[4-(2,3-difluorophenoxy)phenyl]-1,2,4-oxadiazol-3-yl}-4 ethyl-2-thienyl)methyl]azetidine-3-carboxylate (0.20 g, 0.39 mmol) that was obtained in Example 18 (18c), lithium hydroxide monohydrate (36 mg, 0.86 mmol), and acetic acid (47 μL, 0.86 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[N:30]([C:33]1[CH:34]=[C:35]([CH:41]=[CH:42][CH:43]=1)[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:31]=[O:32]>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][C:31]([NH:30][C:33]3[CH:34]=[C:35]([CH:41]=[CH:42][CH:43]=3)[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:32])[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: CCOC(=O)c1cccc(N=C=O)c1
Product: CCOC(=O)c1cccc(NC(=O)Nc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and ethyl 3-isocyanatobenzoate according to the procedure of Example 65. MS (ES) m/z 581.9.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:24][C:25]1[CH:29]=[CH:28][S:27][CH:26]=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]([CH2:24][C:25]3[CH:29]=[CH:28][S:27][CH:26]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccc(OC)cc23)CC1
Reactant: BrCc1ccsc1
Product: CCOC(=O)N1CCC(c2cn(Cc3ccsc3)c3ccc(OC)cc23)CC1
Reaction time: 15 h
Yield: 85.5 %

Procedure:
This compound was prepared following the procedure described in example 13 (part B) at room temperature for 15 hours, starting with 4 g (13.2 mmol) of 4-(5-methoxy-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester and 2.65 g (15 mmol) of 3-bromomethylthiophene. After standard work-up, 4.5 g (87% of yield) of 4-(5-methoxy-1-thiophen-3-ylmethyl-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester were obtained.