Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:14]1[CH:26]=[CH:25][C:17]([C:18]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.O>[O:19]=[C:18]([C:17]1[CH:25]=[CH:26][C:14]([N:10]2[CH2:9][CH2:8][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11]2)=[CH:15][CH:16]=1)[CH2:20][CH2:21][C:22]([OH:24])=[O:23]
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)CCC(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1
Temperature: 120 °C
Yield: 53.5 %

Procedure:
A stirred mixture of 4-phenyl-piperidine (10.4 g, 0.064 mol), 3-(4-fluorobenzoyl)-propionic acid (12.1 g, 0.062 mol), and potassium carbonate (17.5 g, 0.13 mol) in DMSO (15 mL) was heated under an atmosphere of nitrogen at 120° C. for 18 hours. The mixture was allowed to cool, diluted with water (100 mL), and brought to pH 2 dropwise with 1 M HCl. The resulting solid was filtered, washed with water, and dried in vacuo to yield a pale orange solid as the title compound (11.2 g, %C,H,N found: 74.54, 6.98, 4.07).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[Cl:19])[NH2:15]>>[Cl:11][C:12]1[CH:13]=[C:14]([NH:15][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)c1ccc(F)cc1

Procedure:
Reaction of 4-fluorobenzoyl chloride with 3,4-dichloroaniline using Method II, step 1, gave the title amide as crystals: mp 160-161° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 7.19 (2H, m, aromatics), 7.44 (2H, m, aromatics), 7.70 (1H, broad, NH), 7.88 (3H, m, aromatics). Anal. Calcd for C13H18Cl2FNO: C, 54.96; H, 2.84; N, 4.93. Found: C, 54.96; H, 2.87; N, 4.90.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=2[F:16])=[C:6](Cl)[N:5]2[N:18]=[CH:19][N:20]=[C:4]2[N:3]=1.[F:21][C:22]([F:27])([F:26])[C@@H:23]([NH2:25])[CH3:24].O>CN(C=O)C>[Cl:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=2[F:16])=[C:6]([NH:25][C@@H:23]([CH3:24])[C:22]([F:27])([F:26])[F:21])[N:5]2[N:18]=[CH:19][N:20]=[C:4]2[N:3]=1
Reactant: C[C@H](N)C(F)(F)F
Reactant: Fc1cc(F)c(-c2c(Cl)nc3ncnn3c2Cl)c(F)c1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](Nc1c(-c2c(F)cc(F)cc2F)c(Cl)nc2ncnn12)C(F)(F)F
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a solution of 5,7-dichloro-6-(2,4,6-trifluorophenyl)-[1,2,4]triazolo[1,5-a]-pyrimidine (200 g, 0.627 mol) in anhydrous DMF (1000 mL) is added (S)-2,2,2-trifluoro-1-methyl-ethylamine (177 g, 1.57 mol). The solution is stirred from about 20° C. to about 30° C. for 24 h. The reaction mixture is added to cold water (3000 mL) slowly over 30 min. The mixture is stirred for 30 min at 10-20° C. The solid product is filtered and washed with water (2×500 mL). The crude product is dissolved into IPA (1000 mL) at 50° C. Water (2000 mL) is added to precipitate the product over 30 min. The mixture is cooled to 0° C. over 1 h and stirred for 1 h at this temperature. The solid is filtered and dried at 65° C./10 mmHg for 20 h to give a light yellow solid (204 g, 82%, 98% HPLC area purity and 99% ee).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C:11](=[O:28])[C:10]=2[C:29]2[CH:30]=[N:31][C:32]3[C:37]([CH:38]=2)=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][N:25]([S:47]([CH3:46])(=[O:49])=[O:48])[CH2:26][CH2:27]4)=[CH:15][CH:16]=3)[C:11](=[O:28])[C:10]=2[C:29]2[CH:30]=[N:31][C:32]3[C:37]([CH:38]=2)=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1C(c2cnc3ccccc3c2)=C(c2cc(F)cc(F)c2)c2ccc(OCCCN3CCNCC3)cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(CCCOc2ccc3c(c2)C(=O)C(c2cnc4ccccc4c2)=C3c2cc(F)cc(F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of 3-(3,5-difluorophenyl)-6-(3-(piperazin-1-yl)propoxy)-2-(quinolin-3-yl)-1H-inden-1-one (40 mg, 1.2 eq, 0.1 mmol) obtained in Step 3 in CH2Cl2 at 0° C. was added triethylamine (1.5 eq) and methylsulfonyl chloride (1.0 eq). The mixture was stirred for 1 h at room temperature and diluted with CH2Cl2. The mixture was washed with H2O and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexanes=1:1) to obtain the title compound (53%).
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)=[O:2].C(N(CC)CC)C.[CH3:19][N:20]([CH3:24])[C:21](Cl)=[S:22]>C(#N)C>[CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:21]([N:20]([CH3:24])[CH3:19])=[S:22])=[CH:7][CH:6]=1)=[O:2]
Reactant: CN(C)C(=S)Cl
Reactant: Nc1ccc(NNC=O)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C)C(=S)Nc1ccc(NNC=O)cc1
Temperature: 60 °C

Procedure:
1-Formyl-2-(4-aminophenyl)hydrazine (1.51 g, 0.01 mole) and triethylamine (1.0 g, 0.01 mole) were mixed with dry acetonitrile (30 ml). The mixture was kept under a nitrogen atmosphere and a solution of dimethylthiocarbamoyl chloride (1.24 g, 0.01 mole) in acetonitrile (10 ml) was added dropwise at room temperature. After the addition was complete, the reaction mixture was chilled in ice, then filtered. The solid was washed with ethanol and allowed to dry. The material was stirred in water (40 ml) and heated to 60° C. to remove any hydrochloride salts. The aqueous mixture was filtered; the solid was washed with ether and dried. This gave 0.60 g (25 percent) of product as a pale tan powder, m.p. 187°-189° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH:16]2[CH2:18][CH2:17]2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:5]2[N:19]=[CH:20][C:21]([CH:22]=[O:23])=[C:4]2[N:3]=1.[NH2:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=1[Br:33].CC(C)([O-])C.[Na+].O>C1COCC1>[Br:33][C:26]1[CH:27]=[C:28]([C:29]#[N:30])[CH:31]=[CH:32][C:25]=1[NH:24][C:2]1[CH:7]=[C:6]([N:8]([CH:16]2[CH2:18][CH2:17]2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:5]2[N:19]=[CH:20][C:21]([CH:22]=[O:23])=[C:4]2[N:3]=1
Reactant: CC(C)(C)OC(=O)N(c1cc(Cl)nc2c(C=O)cnn12)C1CC1
Reactant: N#Cc1ccc(N)c(Br)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(c1cc(Nc2ccc(C#N)cc2Br)nc2c(C=O)cnn12)C1CC1
Reaction time: 1.5 h
Yield: 31.8 %

Procedure:
Tert-butyl 5-chloro-3-formylpyrazolo[1,5-a]pyrimidin-7-yl(cyclopropyl)carbamate (225 mg, 0.67 mmol) and 4-amino-3-bromobenzonitrile (197 mg, 1 mmol) were dissolved in anhydrous THF (4.5 mL). Sodium tert-butoxide (96 mg, 1 mmol) was added in one portion. After 1.5 h, the reaction was poured into H2O (25 mL) and extracted with EtOAc (3×30 mL). The organics were washed with brine (1×100 mL), dried over MgSO4, filtered and concentrated in vacuo. The tan solid was purified via flash column chromatography (30% EtOAc/hexanes) to provide tert-butyl 5-(2-bromo-4-cyanophenylamino)-3-formylpyrazolo[1,5-a]pyrimidin-7-yl(cyclopropyl)carbamate (106 mg, 32%) as a pale yellow solid. LCMS (ES): >90% pure, m/z 497 [M+1]+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([C:18]2[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=2)=[O:17])[CH2:12][CH2:11]1.Br[C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1.CC(C)([O-])C.[Na+]>CO.O1CCOCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:28]3[N:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:20][CH:19]=2)=[O:17])[CH2:12][CH2:11]1
Reactant: O=C(c1ccc(B(O)O)cc1)N1CCC(c2nc3ccccc3[nH]2)CC1
Reactant: Brc1ncccn1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(c1ccc(-c2ncccn2)cc1)N1CCC(c2nc3ccccc3[nH]2)CC1
Temperature: 90 °C
Yield: 25.8 %

Procedure:
A mixture of (4-{[4-(1H-benzimidazol-2-yl)piperidin-1-yl]carbonyl}phenyl)boronic acid (0.349 g, 1.00 mmol), 2-bromopyrimidine (0.175 g, 1.10 mmol) and sodium tert-butoxide (0.106 g, 1.10 mmol) are suspended in a mixture of MeOH/1,4-dioxane (1 mL/2 mL). The suspension is purged with N2 before adding 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) dichloride dichloromethane complex (41 mg, 5 mol %). The reaction is heated to 90° C. for 18 h. The mixture is diluted with EtOAc, washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is triturated with MeCN and DCM to give 99 mg of [4-(1H-Benzimidazol-2-yl)piperidin-1-yl][4-(pyrimidin-2-yl)phenyl]methanone.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14](Cl)(=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.9 %

Procedure:
A solution of 1-benzylpiperazine (352 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and pentanoyl chloride (301 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:1). The fractions containing 1-(4-benzylpiperazin-1-yl)pentan-1-one are collected and the solvent is removed in vacuo to give 416 mg of colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.C(=O)(O)[O-].[K+].[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].C1C2C(=CC=CC=2)CCN1>C1C=CC=CC=1>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2)=[O:22]
Reactant: O=C(Cl)c1ccccc1F
Reactant: CN1CCc2c(N)cccc2C1
Agent: O=C([O-])O
Agent: [K+]
Agent: c1ccc2c(c1)CCNC2
Solvent: c1ccccc1
Product: CN1CCc2c(cccc2NC(=O)c2ccccc2F)C1

Procedure:
5-Amino-2-methyl-1,2,3,4-tetrahydroisoquinoline (5.0 g) prepared as in Example 4 was dissolved in dry benzene (75 ml) and 0.5 g of dry potassium bicarbonate was added. A 0.1 mole excess of 2-fluorobenzoyl chloride was dissolved in dry benzene (75 ml) and this solution was added to the solution of the tetrahydroisoquinoline. A white precipitate formed immediately. The mixture was refluxed for 1 hour to insure that the reaction had gone to completion. The precipitate was collected by vacuum filtration and washed with 10% sodium carbonate solution followed by water. The washings were discarded and the remaining residue was recrystallized from ethyl acetate to yield 6.8 g of the desired product as white crystals, m.p. 112°-112.5° C.
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([N:19]2[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]2)[N:12]=[C:11]([N:26]2[CH2:31][CH2:30][N:29]3[CH:32]=[CH:33][N:34]=[C:28]3[CH2:27]2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:43])C=1>C(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>[CH2:1]([S:8]([C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([N:19]2[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]2)[N:12]=[C:11]([N:26]2[CH2:31][CH2:30][N:29]3[CH:32]=[CH:33][N:34]=[C:28]3[CH2:27]2)[N:10]=1)=[O:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(SCc2ccccc2)nc(N2CCn3ccnc3C2)nc1N1CCC(O)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(N2CCC(O)CC2)nc(N2CCn3ccnc3C2)nc1S(=O)Cc1ccccc1
Reaction time: 1.5 h

Procedure:
To a solution of 4-benzylthio-5-methoxycarbonyl-6-(4-hydroxypiperidin-1-yl)-2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)pyrimidine (prepared in the above (5)) 93 mg in chloroform 2.5 ml is dropped a solution of m-chloroperbenzoic acid 44 mg in chloroform 4 ml over a period of 10 minutes on a ice bath, and the mixture is stirred for 1.5 hours. The mixture is diluted with an aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo to give 4-benzylsulfinyl-5-methoxycarbonyl-6-(4-hydroxypiperidin-1-yl)-2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)pyrimidine as a slightly yellow foam, 83 mg.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:6])=[CH:3]/[C:4]#[N:5].[C:7](OC1C(Cl)=CC(Cl)=CC=1Cl)(=[O:21])[CH2:8][C:9](OC1C(Cl)=CC(Cl)=CC=1Cl)=[O:10].CCOCC>COCCOCCOC>[OH:21][C:7]1[C:3]([C:4]#[N:5])=[C:2]([CH3:6])[NH:1][C:9](=[O:10])[CH:8]=1
Reactant: C/C(N)=C\C#N
Reactant: O=C(CC(=O)Oc1c(Cl)cc(Cl)cc1Cl)Oc1c(Cl)cc(Cl)cc1Cl
Solvent: CCOCC
Solvent: COCCOCCOC
Product: Cc1[nH]c(=O)cc(O)c1C#N
Temperature: 120 °C

Procedure:
A mixture of (E)-3-aminobut-2-enenitrile (9.7 g, 118 mmol) and bis(2,4,6-trichlorophenyl) malonate (58.4 g, 126 mmol) in diglyme (120 ml) was heated to 120° C. for 2.5 hr. The mixture was cooled to RT and poured into Et2O and filtered to collect the precipitate. The precipitate was washed with Et20 to obtain 4-hydroxy-2-methyl-6-oxo-1,6-dihydropyridine-3-carbonitrile. MS ESI calc'd. for C7H7N2O2 [M+H]+ 151. found 151.
Reaction SMILES: [NH2:1][C:2](=[S:18])[N:3]1[CH2:7][CH:6]2[CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][CH:5]2[CH2:4]1.Cl[CH2:20][C:21]([C:23]1[CH2:27][CH:26]([C:28]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=2[F:35])[O:25][N:24]=1)=O.N1C=CC=CC=1>C(Cl)(Cl)Cl>[F:35][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([F:34])[C:28]=1[CH:26]1[O:25][N:24]=[C:23]([C:21]2[N:1]=[C:2]([N:3]3[CH2:7][CH:6]4[CH2:8][N:9]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH2:10][CH:5]4[CH2:4]3)[S:18][CH:20]=2)[CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CC2CN(C(N)=S)CC2C1
Reactant: O=C(CCl)C1=NOC(c2c(F)cccc2F)C1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CC2CN(c3nc(C4=NOC(c5c(F)cccc5F)C4)cs3)CC2C1
Temperature: 90 °C

Procedure:
To a stirred solution of 1,1-dimethylethyl 5-(aminothioxomethyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (i.e. the product of Step A) (0.5 g, 18.42 mmol) in chloroform (20 mL) was added 2-chloro-1-[5-(2,6difluorophenyl)-4,5-dihydroisoxazol-3-yl]ethanone (i.e. the product of Step B) (0.478 g, 18.42 mmol) and pyridine (0.29 g, 37.12 mmol) at room temperature. The reaction mixture was heated at 90° C. for 5 h, cooled to room temperature and concentrated under reduced pressure. The resulting material was dissolved in ethyl acetate (100 mL) and washed with water (100 mL) and saturated aqueous sodium chloride solution (100 mL) and concentrated under reduced pressure. The resulting material was purified by column chromatography (1% methanol/chloroform as eluant) to provide the title product as white solid (0.7 g) melting at 78.9-80.2° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[C:18]([C:20]1([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)#[CH:19]>C(N(CC)CC)C.[Cu]I.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>[F:14][C:13]([F:16])([F:15])[C:12]([NH:11][CH2:10][CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:19]#[C:18][C:20]2([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:3]=1)=[O:17]
Reactant: O=C(NCCCc1cccc(Br)c1)C(F)(F)F
Reactant: C#CC1(O)CCCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: O=C(NCCCc1cccc(C#CC2(O)CCCCC2)c1)C(F)(F)F
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of bromide 10 (2.0 g, 6.45 mmol) and 1-ethynylcyclohexanol (1.2 g, 9.67 mmol) in triethylamine (40 mL) was added CuI (0.0246 g, 0.129 mmol). The mixture was degassed with argon for 2-3 min, then PdCl2(PPh3)2 (0.0905 g, 0.129 mmol) was added. The reaction mixture was degassed with argon again then stirred at 70° C. overnight under argon. After cooling to room temperature, the mixture was concentrated under reduced pressure and suspended in EtOAc-hexanes (50%, 50 mL). Solids were removed by filtration and the filtrate was concentrated under reduced pressure. Purification by flash chromatography gave 2,2,2-trifluoro-N-(3-(3-((1-hydroxycyclohexyl)ethynyl)phenyl)propyl)acetamide as a clear oil. Yield (1.74 g, 76%): 1H NMR (400 MHz, DMSO-d6) δ9.40 (brs, 1H), 7.26 (t, J=7.6 Hz, 1H), 7.17-7.24 (, 3H), 5.37 (s, 1H), 3.16 (q, J=6.8 Hz, 2H), 2.56 (t, J=7.2 Hz, 2H), 1.15-1.83 (m, 12H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][Br:15].[C:16]([O:21][CH2:22][CH3:23])(=[O:20])[CH:17]([CH3:19])[CH3:18]>C1COCC1>[CH2:22]([O:21][C:16](=[O:20])[C:17]([CH3:19])([CH3:18])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][Br:15])[CH3:23]
Reactant: BrCCCCCBr
Reactant: CCOC(=O)C(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)CCCCCBr
Temperature: 25 °C
Reaction time: 20 h
Yield: 60 %

Procedure:
Under argon atmosphere and cooling with an ice-bath, a solution of lithium diisopropylamide in THF (1.7 L, 2.0 M, 3.4 mol) was slowly dropped into a solution of 1,5-dibromopentane (950 g, 4.0 mol) and ethyl isobutyrate (396 g, 3.4 mol) in THF (5 L) while keeping the temperature below +5° C. The reaction mixture was stirred at room temperature for 20 h and quenched by slow addition of saturated ammonium chloride solution (3 L). The resulting solution was divided into three 4-L portions. Each portion was diluted with saturated ammonium chloride solution (5 L) and extracted with ethyl acetate (2×2 L). Each 4-L portion of ethyl acetate was washed with saturated sodium chloride solution (2 L), 1 N hydrochloric acid (2 L), saturated sodium chloride solution (2 L), saturated sodium bicarbonate solution (2 L), and saturated sodium chloride solution (2 L). The three separate ethyl acetate layers were combined into a single 12-L portion, dried over magnesium sulfate, and concentrated in vacuo to give the crude material (1.7 L) which was purified by vacuum distillation. Two fractions were obtained: the first boiling at 88-104° C./0.6 torr (184.2 g), the second at 105-120° C./1.4 torr (409.6 g) for a total yield of 60%. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 4.11 (q, 2H, J=7.2 Hz), 3.39 (t, 2H, J=6.8 Hz), 1.85 (m, 2H), 1.56-1.35 (m, 4H), 1.24 (t, 3H, J=7.2 Hz), 1.31-1.19 (m, 2H), 1.16 (s, 6H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 177.9, 60.2, 42.1, 40.5, 33.8, 32.6, 28.6, 25.2, 24.2, 14.3. HRMS (EI, pos): Calcd. for C11H22BrO2 (MH+): 265.0803. found: 265.0810.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@@H:20]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)[CH2:21]1)[C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17](O)=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]1[O:39][NH2:40].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[F:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][N:22]1[CH2:23][CH2:24][C@@H:20]([N:8]([C:9]2[CH:10]=[CH:11][C:12](/[CH:15]=[CH:16]/[C:17](=[O:18])[NH:40][O:39][CH:34]3[CH2:35][CH2:36][CH2:37][CH2:38][O:33]3)=[CH:13][N:14]=2)[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[CH2:21]1
Reactant: CC(C)(C)OC(=O)N(c1ccc(/C=C/C(=O)O)cn1)[C@@H]1CCN(Cc2cccc(F)c2)C1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N(c1ccc(/C=C/C(=O)NOC2CCCCO2)cn1)[C@@H]1CCN(Cc2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 0.1 %

Procedure:
To a solution of (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(3-fluorobenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylic acid (2.25 g, crude) in DMF (23 mL) was added was added O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (776 mg), HOBt (1.03 g), and EDCI (1.19 g) and the resulting mixture was stirred at ambient temperature for 3 hours. The reaction mixture was diluted with water and extracted with AcOEt. The organic phase was washed with sat NH4Cl aq solution, sat NaHCO3 aq solution, and brine, and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography eluted with AcOEt to give tert-butyl [(3R)-1-(3-fluorobenzyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)carbamate (2.51 mg) as pale yellow form.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH:31]4[CH2:33][CH2:32]4)=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:12]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:11]=1>>[CH:31]1([C:27]2[CH:28]=[C:29]([CH3:30])[C:24]([N:21]3[CH2:22][CH2:23][N:18]([C:16]([C:13]4[CH:14]=[CH:15][C:10]([N:7]5[C@H:3]([CH2:2][OH:1])[CH2:4][CH2:5][C:6]5=[O:8])=[CH:11][C:12]=4[S:34]([CH3:37])(=[O:36])=[O:35])=[O:17])[CH2:19][CH2:20]3)=[N:25][CH:26]=2)[CH2:32][CH2:33]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2S(C)(=O)=O)CC1
Reactant: O=C1CC[C@@H](CO)N1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)CC[C@H]3CO)cc2S(C)(=O)=O)CC1
Yield: 56.8 %

Procedure:
Using (S)-5-hydroxymethylpyrrolidin-2-one (127 mg) and (4-bromo-2-methanesulfonylphenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (478 mg) described in Preparation Example 126 and by the reaction and treatment in the same manner as in Example 1, the title compound (291 mg) was obtained.
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][C:9]([Mg]Br)=[CH:8][CH:7]=1.[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][C:15]1=[O:23]>C1COCC1>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:15]2([OH:23])[CH2:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:14]2)=[CH:8][CH:7]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: O=C1Cc2ccccc2C1
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: OC1(c2ccc(F)cc2)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
A suspension of anhydrous cerium chloride (43.9 g, 178.0 mmol) in THF (250 mL) was stirred at room temperature for 2 hours under nitrogen. 4-Fluorophenylmagnesium bromide (75.6 mL of 2.0M solution in diethyl ether, 151.2 mmol) was added at 0° C. and stirred for 3.5 h. A solution of 2-indanone (15.36 g, 116.4 mmol) in THF (20 mL) was added at the same temperature. After stirring at 0° C. for 3 h, the mixture was allowed to warm to room temperature and kept at ambient temperature overnight (12 h). It was then treated with 5% aqueous hydrochloric solution. The solution was extracted with diethyl ether (4*200 mL). All etheral layers were combined, washed with water (100 mL), dried over anhydrous magnesium sulphate and concentrated to give the crude product. Unreacted 2-indanone was distilled off. The residue was subjected to Kugelrohr distillation (165° C./0.3 mm Hg). 2-(4-Fluorophenyl)-2-indanol (21.62 g) was obtained in pure form. 1 H-N.M.R. (CDCl3) d 2.22 (br s, 1H), d 3.24 (d, J=16.3 Hz, 2H), d 3.47 (d, J=16.3 Hz, 2H), d 7.04 (m, 2H), d 7.20-7.28(m, 4H), d 7.52(br d, J=9.0, 5.3 Hz, 2H).