Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[N:3]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3([C:16](Cl)=[O:17])[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4]1.CC1(C)C2CCC1(CS(O)(=O)=O)C(=O)C2.[NH:34]1[CH2:38][CH2:37][C@@:36]2([C:46]3[CH:45]=[CH:44][N:43]=[CH:42][C:41]=3[C:40](=[O:47])[O:39]2)[CH2:35]1.C(Cl)Cl.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[N:3]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3([C:16]([N:34]4[CH2:38][CH2:37][C@@:36]5([C:46]6[CH:45]=[CH:44][N:43]=[CH:42][C:41]=6[C:40](=[O:47])[O:39]5)[CH2:35]4)=[O:17])[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: O=C1O[C@]2(CCNC2)c2ccncc21
Reactant: O=C(Cl)C1(c2ccc(N3CCC3)nc2)CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(N5CCC5)nc4)CC3)C2)c2ccncc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1-(6-azetidin-1-ylpyridin-3-yl)cyclopropanecarbonyl chloride dihydrochloride (64.00 mg, 0.0002067 mol) and (7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonic acid-(1R)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one (1:1) (87.3 mg, 0.000207 mol) in methylene chloride (1.00 mL, 0.0156 mol) was added N,N-diisopropylethylamine (0.144 mL, 0.000827 mol) at 0° C. The reaction mixture was stirred at rt for 1-2 h. Upon completion the reaction mixture was diluted with ethyl acetate and washed with water and brine successively, dried with sodium sulfate, filtered, and concentrated. The crude product was purified by prep-LCMS twice to obtain the product as a TFA salt. LCMS: m/z 391.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:21]1[C:29]([F:30])=[C:28]([F:31])[C:27]([N+:32]([O-:34])=[O:33])=[CH:26][C:22]=1[C:23]([OH:25])=[O:24]>C1COCC1>[F:30][C:29]1[C:21]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:2]=2[F:1])=[C:22]([CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[C:28]=1[F:31])[C:23]([OH:25])=[O:24]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)c(F)c1F
Reactant: Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1cc([N+](=O)[O-])c(F)c(F)c1Nc1ccc(I)cc1F
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-fluoro-4-iodoaniline (2.9 g, 11.8 mmoles) in 50 ml anhydrous THF at −60° C., 40 ml of a 1M solution of LHMDS in THF (40 mmoles) is added dropwise. In a separate flask, 2,3,4-trifluoro-5-nitrobenzoic acid (5 g, 22.6 mmoles), previously dissolved in THF (50 ml), is treated, at −60° C., with 25 ml of a 1M solution of LHMDS in THF (25 mmoles). Both solutions are stirred at −78° C. for 45 min and the second solution is transferred via cannula to the first reaction mixture. After completion of the addition the resulting mixture is stirred under argon at room temperature for 15 hours. The reaction mixture is quenched with water, then 1N HCl is added (pH=0-1) followed by brine (100 ml). The crude material is extracted with THF (3×100 ml), the organic layers are combined and dried (Na2SO4) and the solvent is removed to give the title compound.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[CH:23]=[CH:22][C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14][C:8]=2[CH:7]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[OH:5][C:6]1[C:23]([N+:1]([O-:4])=[O:2])=[CH:22][C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:13][CH2:14][C:8]=2[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(O)cc2CC1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cc(O)c([N+](=O)[O-])cc2CC1
Reaction time: 1.5 h

Procedure:
Nitric acid (70%, 3.44 ml) was added dropwise over 40 min with vigorous stirring to 1,1-dimethylethyl 7-hydroxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylate (14.2 g) in DCM with cooling in an ice bath. After additional 5 min silica gel (15 g) and sodium bicarbonate powder (5 g) were added and stirring was continued for 1.5 h. The mixture was filtered through a layer (1 cm) of silica gel and the solids washed with EtOAc. The resulting solution was concentrated and submitted to column chromatography to provide the title compound as a yellow solid (8.54 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.C([Li])CCC.I[C:19]1[N:20]=[C:21]2[C:27]3[CH:28]=[C:29]([C:32]([O:34][CH3:35])=[O:33])[CH:30]=[CH:31][C:26]=3[O:25][CH2:24][CH2:23][N:22]2[CH:36]=1>CCCCCC.O1CCCC1.CCOC(C)=O.[Cl-].[Cl-].[Zn+2].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:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:19]1[N:20]=[C:21]2[C:27]3[CH:28]=[C:29]([C:32]([O:34][CH3:35])=[O:33])[CH:30]=[CH:31][C:26]=3[O:25][CH2:24][CH2:23][N:22]2[CH:36]=1
Reactant: COC(=O)c1ccc2c(c1)-c1nc(I)cn1CCO2
Reactant: Clc1ccccc1-n1ccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)-c1nc(-c3nccn3-c3ccccc3Cl)cn1CCO2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2-chlorophenyl)-1H-imidazole (0.133 g, 0.743 mmol) in tetrahydrofuran (5.43 mL, 66.9 mmol); at −78° C. was added 1.60 M of n-Butyllithium in Hexane (0.464 mL) dropwise. The reaction mixture was stirred at −78° C. for 1 h then 0.50 M of Zinc dichloride in Tetrahydrofuran (1.48 mL) was added. The reaction mixture was warmed to RT 30 min then added Tetrakis(triphenylphosphine)palladium(0) (0.0780 g, 0.0675 mmol), solution of methyl 2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate (0.250 g, 0.675 mmol); in 2 ml THF. The reaction was reflux for 2 h followed by treating with additional 0.50 M of Zinc dichloride in Tetrahydrofuran 2.2 ml and refluxed 3 h. The mixture was diluted with EtOAc then washed with sat. Na2CO3, and brine. The organic layer was dried over Na2SO4, concentrated in vacuo. The crude product, methyl 2-(1-(2-chlorophenyl)-1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate, was purified by chromatography. MS: (ESI+)=421.2
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12](=O)[CH3:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:15][NH:16][S:17](Cl)(=[O:19])=[O:18].[BH4-].[Na+]>N1C=CC=CC=1>[CH3:13][CH:12]1[C:3]2[CH:4]=[CH:5][C:6]3[C:11](=[N:10][CH:9]=[CH:8][CH:7]=3)[C:2]=2[NH:1][S:17](=[O:19])(=[O:18])[N:16]1[CH3:15]
Reactant: CC(=O)c1ccc2cccnc2c1N
Reactant: CNS(=O)(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CC1c2ccc3cccnc3c2NS(=O)(=O)N1C
Yield: 14.2 %

Procedure:
In a similar fashion using route 27 general procedure 71, 1-(8-amino-quinolin-7-yl)-ethanone 411 (200 mg, 1.07 mmol), N-methylsulfamyl chloride 213 (700 mg, 5.40 mmol), NaBH4 (79 mg, 2.13 mmol) and pyridine (10 ml) gave the title compound (40 mg, 13%) after purification by column chromatography with DCM/MeOH (99:1) as the eluent.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH2:19])[S:8][C:9]=1[CH2:10][O:11][Si](C(C)(C)C)(C)C)=[O:4].O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH2:19])[S:8][C:9]=1[CH2:10][OH:11])=[O:4]
Reactant: COC(=O)c1nc(N)sc1CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1nc(N)sc1CO
Yield: 83.9 %

Procedure:
To a solution of the compound (2.03 g) obtained in Step 1 in tetrahydrofuran (40 ml) was added dropwise, with stirring under ice-cooling, 1.0M tetrabutylammonium fluoride tetrahydrofuran solution (7.38 ml). After stirring at room temperature for 1 hr, the reaction mixture was concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (ethyl acetate:methanol=9:1) to give the title compound (1.06 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[N+:17]([O-])=O)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[H][H]>C1(C)C=CC=CC=1.[Pd]>[C:1]([O:5][C:6](=[O:20])[N:7]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[NH2:17])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: COc1ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: COc1ccc(N)c(N(C)C(=O)OC(C)(C)C)c1
Temperature: 40 °C
Reaction time: 3 h
Yield: 84.9 %

Procedure:
To a suspension of N-(5-methoxy-2-nitrophenyl)-N-methylcarbamic acid t-butyl ester (5.8 g) in toluene (55 ml) was added 7.5% palladium on carbon (1.2 g, which contain 50% water) and the air of the reaction vessel was replaced with nitrogen and the mixture was stirred under a hydrogen atmosphere at 40° C. for 3 hours. After the reaction the mixture was cooled to room temperature and the hydrogen in the reaction vessel was replaced with nitrogen. The palladium on carbon was removed by filtration and the filtrate was evaporated in vacuo to 22 ml. To this solution was slowly added methylcyclohexane (44 ml) and the precipitated crystals were filtered to give the title compound (4.4 g, yield 85%).
Reaction SMILES: CC1(C)C2C=C(C#CC3C=CC(C(O)=O)=CC=3)C=CC=2C(=O)CC1.[CH3:25][C:26]1([CH3:54])[C:35]2[CH:34]=[C:33]([C:36]#[C:37][C:38]3[CH:48]=[CH:47][C:41]([C:42]([O:44]CC)=[O:43])=[CH:40][CH:39]=3)[CH:32]=[CH:31][C:30]=2[C:29](=[C:49]([CH2:52][CH3:53])[CH2:50][CH3:51])[CH2:28][CH2:27]1>>[CH3:54][C:26]1([CH3:25])[C:35]2[CH:34]=[C:33]([C:36]#[C:37][C:38]3[CH:39]=[CH:40][C:41]([C:42]([OH:44])=[O:43])=[CH:47][CH:48]=3)[CH:32]=[CH:31][C:30]=2[C:29](=[C:49]([CH2:50][CH3:51])[CH2:52][CH3:53])[CH2:28][CH2:27]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=C(CC)CC)cc1
Agent: CC1(C)CCC(=O)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Product: CCC(CC)=C1CCC(C)(C)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
Employing the same general procedure as for the preparation of 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoic acid (Compound 7), 90 mg (0.23 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5(6H)-(3-pentylidene)naphth-2-yl)ethynyl]benzoate (Compound 133) was converted to the title compound using 0.5 ml (0.5 mmol) of LiOH (1M aqueuos solution).
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([CH3:10])=[CH:9][C:2]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)#[N:5]
Reactant: C1CNCCN1
Reactant: Cc1ccc(C#N)c(Br)c1
Product: Cc1ccc(C#N)c(N2CCNCC2)c1

Procedure:
2-Bromo-4-methyl-benzonitrile was coupled to piperazine using Preparation 1A Buchwald chemistry to afford 4-(2-cyano-5-methyl-phenyl)-piperazine. 4-(2-cyano-5-methyl-phenyl)-piperazine is converted to 4(2-hydroxymethyl-5-methyl-phenyl)-piperazine in a manner similar to preparation 54A Steps 1 and 2.4-(2-Hydroxymethyl-5-methyl-phenyl)-piperazine was converted to the title compound in a manner similar to Preparation 60A except that pyrrolidine was used to displace the mesylate. LRMS (ESI+): 360.3 (M+1)
Reaction SMILES: [Na].[NH2:2][C:3]1[N:8]=[C:7](Cl)[C:6]([CH:10]=[O:11])=[C:5]([N:12]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:4]=1.[CH:27]1([CH2:33][OH:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[NH2:2][C:3]1[N:8]=[C:7]([O:34][CH2:33][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:6]([CH:10]=[O:11])=[C:5]([N:12]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:4]=1
Reactant: OCC1CCCCC1
Reactant: Nc1nc(Cl)c(C=O)c(N(Cc2ccccc2)Cc2ccccc2)n1
Agent: [Na]
Product: Nc1nc(OCC2CCCCC2)c(C=O)c(N(Cc2ccccc2)Cc2ccccc2)n1
Reaction time: 1.5 h

Procedure:
Cyclohexylmethanol (10 ml) and sodium (5 eq; 0.163 g) were reacted at 90° C. for 1 h. 2-Amino-4-chloro-6dibenzylamino-5-pyrimidine carbaldehyde (0.5 g; 1.42 mmol) was added and heating continued for 90 mins. Excess alcohol was removed by short path distillation under reduced pressure, and the product purified further by column chromatography. Product was shown to be contaminated with cyclohexylmethanol by visualisation of the alcohol with sulfuric acid spray (2%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:10])[CH:5]=[C:6](F)[CH:7]=1.[C:16]1([SH:22])C=CC=CC=1.C[S-].[Na+].[NH4+].[Cl-]>CN(C=O)C>[CH3:16][S:22][C:6]1[CH:5]=[C:4]([C:9]([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:10])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(c1cc(F)cc(F)c1)c1nccs1
Reactant: Sc1ccccc1
Agent: C[S-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CSc1cc(F)cc(C(=O)c2nccs2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (3,5-difluorophenyl)(thiazol-2-yl)methanone from Thiophenol 2, Step 2, (1.09 g, 4.84 mmol) in DMF (4.8 mL) was added sodium thiomethoxide (0.34 g, 4.84 mmol). The mixture was stirred for 4 h at r.t., then added to sat. aqueous NH4Cl (100 mL) and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous MgSO4. Evaporation of the solvent and chromatography using hexane: EtOAc (90:10) gave 0.80 g of the title product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:29](=[O:39])[N:30]([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH2:33][CH3:34])=[N:4][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=2[C:17]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20]2)=[O:18])[C:6]=1[CH3:7].[Si:40]([O:47][CH2:48][CH2:49][O:50][C:51]1[CH:60]=[C:59]2[C:54]([CH:55]=[CH:56][C:57]([S:61]([NH2:64])(=[O:63])=[O:62])=[CH:58]2)=[CH:53][CH:52]=1)([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41]>>[CH2:35]([N:30]([CH2:31][CH2:32][CH2:33][CH3:34])[C:29]([C:3]1[C:2]([Cl:1])=[C:6]([CH3:7])[N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](=[O:14])[NH:64][S:61]([C:57]3[CH:56]=[CH:55][C:54]4[C:59](=[CH:60][C:51]([O:50][CH2:49][CH2:48][O:47][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:41])[CH3:42])=[CH:52][CH:53]=4)[CH:58]=3)(=[O:63])=[O:62])=[CH:10][C:9]=2[C:17]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20]2)=[O:18])[N:4]=1)=[O:39])[CH2:36][CH2:37][CH3:38]
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc2ccc(S(N)(=O)=O)cc2c1
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)O)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccc(OCCO[Si](C)(C)C(C)(C)C)cc4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Yield: 46.4 %

Procedure:
Following a procedure analogous to that for the synthesis of Example 1,4-(4-chloro-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoic acid (Intermediate 1F, 40 mg, 0.073 mmol) and 7-(2-(tert-butyldimethylsilyloxy)ethoxy)naphthalene-2-sulfonamide (Intermediate 50B, 33 mg, 0.087 mmol) were converted to the title compound (31 mg, 47%) after purification using flash column chromatography (gradient from 0% to 3% MeOH/CH2Cl2). 1H NMR (CDCl3, 2:1 mixture of amide rotamers) δ 8.62 (s, 1H), 8.11-8.09 (m, 1H), 7.97-7.96 (m, 1H), 7.89-7.88 (m, 2H), 7.84 (d, J=8.9 Hz, 1H), 7.55-7.52 (m, 1H), 7.40-7.38 (m, 2H), 7.23-7.07 (m, 3.5H), 6.85 (d, J=7.4 Hz, 0.5H), 4.75 (br s, 1H), 4.63 (br s, 1H), 4.42 (s, 1H), 4.27-4.24 (m, 2H), 3.85-3.81 (m, 2H), 3.46 (br s, 2H), 3.18-3.15 (m, 2H), 3.02 (br s, 1.5H), 2.84 (br s, 1.5H), 2.29 (s, 2H), 2.24 (s, 1H), 1.50-1.45 (m, 1H), 1.41-1.36 (m, 1H), 1.32-1.20 (m, 6H), 1.12-0.99 (m, 1H), 0.93-0.86 (m, 12H), 0.74 (t, J=7.4 Hz, 2H), 0.68 (t, J=7.2 Hz, 1H), 0.10 (s, 6H); MS(ESI+) m/z 914.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH:17]1([N:23]2[C:31]3[C:26](=[CH:27][C:28](/[C:32](/[CH3:37])=[CH:33]/[C:34](O)=[O:35])=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:17]1([N:23]2[C:31]3[C:26](=[CH:27][C:28](/[C:32](/[CH3:37])=[CH:33]/[C:34]([NH:1][C:2]4[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=4[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:35])=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2C2CCCCC2)c1
Reactant: CCOC(=O)CCCOc1ccccc1N
Product: C/C(=C\C(=O)Nc1ccccc1OCCCC(=O)O)c1ccc2c(ccn2C2CCCCC2)c1

Procedure:
0.22 g of compound 24 was obtained in a similar manner to those described in the Examples 1 to 2 using 0.47 g of ethyl 4-(2-aminophenoxy)butyrate and 0.30 g of 3-(1-cyclohexylindol-5-yl)isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].[Br:19][CH2:20][CH2:21][CH2:22]Br.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[Br:19][CH2:20][CH2:21][CH2:22][C:4]([CH2:3][C:2]([F:18])([F:1])[C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])([C:7]#[N:8])[C:5]#[N:6]
Reactant: BrCCCBr
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#CC(C#N)(CCCBr)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
3.2 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile and 8.6 g of 1,3-dibromopropane were dissolved in 20 ml of dimethyl sulfoxide, 3.0 g of potassium carbonate was added, and the mixture was stirred at room temperature for 2 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 3.2 g of 2-(3-bromopropyl)-2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile (hereinafter, referred to as the present compound (65)).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]([NH:15][CH:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])=[O:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[N:32]=[C:33]=[O:34].C1COCC1>C(OCC)(=O)C>[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[NH:32][C:33](=[O:34])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]([NH:15][CH:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])=[O:14])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)C(NC(=O)c1nc(-c2ccc(N)cc2)no1)C(C)C
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(NC(=O)c1nc(-c2ccc(NC(=O)Nc3ccc(F)cc3F)cc2)no1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.65 %

Procedure:
Methyl 2-(3-(4-aminophenyl)-1,2,4-oxadiazole-5-carboxamido)-3 methylbutanoate and 2,4-difluoro-1-isocyanatobenzene was added to THF and stirred at room temperature overnight. After completion of the reaction, the solvent was evaporated and the crude product so obtained was dissolved in ethyl acetate and washed with water, brine, dried by sodium sulfate and concentrated to give a solid. The solid was re-crystallized from Ethyl acetate: Pet ether and was obtained in a yield of 98.65%; 1H NMR (DMSO-d6) δ: 0.970 (t, 6H C(CH3)2), 2.488 (m, 1H, CHMe2), 3.68 (s, 3H, OCH3), 4.35 (m, 1H, NHCH), 7.082 (m, 1H CH), 7.35 (m, 1H, CH), 7.67 (d, 2H, CH) 8.011 (d, 2H CH), 8.099 (m, 1H, CH), 8.96 (s, 1H, NH), 9.384 (s, 1H, NH), 9.677 (d, 1H, NH); ms (m/z) 474 (M++H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][C:11]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[C:12]([CH:15]=2)[C:13]#[N:14])[CH:5]=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[N:24][N:25]([CH2:27][CH2:28][OH:29])[CH:26]=1.Cl>O1CCOCC1>[OH:29][CH2:28][CH2:27][N:25]1[CH:26]=[C:22]([NH:21][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[N:10][C:11]([N:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)=[C:12]([CH:15]=3)[C:13]#[N:14])[CH:5]=[CH:4][N:3]=2)[CH:23]=[N:24]1
Reactant: Nc1cnn(CCO)c1
Reactant: N#Cc1cc(-c2ccnc(Cl)n2)cnc1N1CCCC1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1cc(-c2ccnc(Nc3cnn(CCO)c3)n2)cnc1N1CCCC1
Temperature: 140 °C

Procedure:
5-(2-Chloro-pyrimidin-4-yl)-2-pyrrolidin-1-yl-nicotinonitrile (9) (31 mg, 0.108 mmol) and 2-(4-amino-pyrazol-1-yl)-ethanol (32 mg, 0.252 mmol) were dissolved in 1,4-dioxane (1 mL). 4N HCl in 1,4-dioxane (30 μL, 0.120 mmol) was added and the mixture was heated at 140° C. in the microwave (250 W, stirring) for 90 minutes. The solvent was evaporated in vacuo and the residue dissolved in DMSO (1 mL). The crude product was purified twice by reversed phase preparative LC-MS. Fractions containing desired product were combined and the solvents evaporated in vacuo. The title compound was obtained as a yellow solid (3.7 mg, 9%); LCMS, Rt=7.43 min (Method C), m/z 377 (MH+).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([CH:16]([C:21]1[CH:22]=[C:23](OS(C(F)(F)F)(=O)=O)[CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[CH:26]=1)[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:45][C:46]([F:57])([F:56])[C:47]1[CH:52]=[CH:51][C:50](B(O)O)=[CH:49][CH:48]=1.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O>[CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:15])[CH:16]([C:21]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[CH:24]=[C:23]([C:50]2[CH:51]=[CH:52][C:47]([C:46]([F:57])([F:56])[F:45])=[CH:48][CH:49]=2)[CH:22]=1)[CH2:17][CH:18]([CH3:20])[CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CC(C(=O)N1C(=O)OCC1Cc1ccccc1)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)CC(C(=O)N1C(=O)OCC1Cc1ccccc1)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 95 °C
Yield: 79.8 %

Procedure:
A mixture of trifluoro-methanesulfonic acid 5-[1-(4-benzyl-2-oxo-oxazolidine-3-carbonyl)-3-methyl-butyl]-4′-trifluoromethyl-biphenyl-3-yl ester (4.03 g, 6.27 mmol), 4-(trifluoromethyl)phenylboronic acid (1.34 g, 7.05 mmol), 1,2-dimethoxyethane (24 mL) and aqueous Na2CO3 (2 M, 3.2 mL, 6.4 mmol) was stirred while purging N2 at room temperature for 10 min. To this system was added Pd(Ph3)4 (1.45 g, 1.25 mmol) and heated to reflux (95° C.) for 1 h. The red-brown mixture was diluted with EtOAc (50 mL) and washed with saturated aqueous NaHCO3 solution (3×50 mL) and brine (2×50 mL). The organic fraction was dried (Na2SO4) and concentrated in vacuo. The crude mixture was purified by ISCO column chromatography to obtain 4-benzyl-3-[2-(4,4″-bis-trifluoromethyl-[1,1′;3′,1″]terphenyl-5′-yl)-4-methyl-pentanoyl]-oxazolidin-2-one (3.2 g, 79%).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([CH:18]1[O:20][CH2:19]1)[Cl:17]>>[Cl:17][CH2:16][CH:18]([OH:20])[CH2:19][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClCC1CO1
Reactant: c1ccc(CNCc2ccccc2)cc1
Product: OC(CCl)CN(Cc1ccccc1)Cc1ccccc1
Yield: 69.7 %

Procedure:
4.93 g (0.25 mol) of dibenzylamine and 25.4 g (0.275 mol) of epichlorohydrin are stirred for 3 hours under nitrogen at 85° to 90° C. The golden yellow oil obtained is distilled under a high vacuum. 50.5 g (70%) of a colourless oil are obtained.