Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:18][C:17](=[O:19])[C:16]4[CH:20]=[C:21](I)[CH:22]=[C:23]([CH3:24])[C:15]=4[N:14]=3)=[CH:11][C:10]([C:26]([F:29])([F:28])[F:27])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Cu][C:31]#[N:32]>O1CCCC1.C(OCC)(=O)C.[Cu]I>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:18][C:17](=[O:19])[C:16]4[CH:20]=[C:21]([C:31]#[N:32])[CH:22]=[C:23]([CH3:24])[C:15]=4[N:14]=3)=[CH:11][C:10]([C:26]([F:29])([F:28])[F:27])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(I)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Reactant: N#C[Cu]
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Reaction time: 1 h

Procedure:
To a solution of 2-[1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-6-iodo-8-methyl-4H-3,1-benzoxazin-4-one (i.e. the benzoxazinone product of Step D) (500 mg, 0.94 mmol) in tetrahydrofuran (10 mL) was added copper(I) iodide (180 mg, 0.094 mmol), tetrakis(triphenyphosphine)palladium(0) (5.4 mg, 0.047 mmol) and copper(I) cyanide (420 mg, 4.7 mmol) sequentially at room temperature. After heating the reaction mixture at reflux overnight, additional copper(I) cyanide (420 mg, 4.7 mmol), copper(I) iodide (107 mg, 0.56 mmol) and tetrakis(triphenyphosphine)palladium(0) (325 mg, 0.28 mmol) were added and the reflux was continued for 1 hour. The reaction mixture turned black in color, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The reaction mixture was then diluted with ethyl acetate (20 mL) and filtered through Celite®, followed by washing three times with 10% aqueous sodium bicarbonate solution and once with brine. The organic extract was dried (MgSO4) and concentrated under reduced pressure to afford 410 mg of the title compound as a crude yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:10](=[O:23])[NH:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH3:13])=[CH:8][CH:9]=1)=[O:4].CO>[Pd].C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:10](=[O:23])[NH:11][CH:12]([C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[CH3:13])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(C(=O)NC(C)c2ccc([N+](=O)[O-])cc2)s1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(C(=O)NC(C)c2ccc(N)cc2)s1
Reaction time: 3 h

Procedure:
A mixture of 500 mg (1.497 mmol) 5-[1-(4-Nitro-phenyl)-ethylcarbamoyl]-thiophene-2-carboxylic acid methyl ester, 200 mg palladium on charcoal (10%), 10 ml methanol and 5 ml THF was hydrogenated at 30 mbar for 3 h. The catalyst was filtered off, the solvent was evaporated to give 5-[1-(4-amino-phenyl)-ethylcarbamoyl]-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:12]([NH:14][C@@H:15]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)[CH2:16][N:17]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]3=[O:27])=[O:13])[S:10][CH:11]=2)=[C:5]([CH3:36])[N:4]=[N:3]1.C1C(=O)N([Cl:44])C(=O)C1.CCOC(C)=O>CN(C)C=O>[Cl:44][C:11]1[S:10][C:9]([C:12]([NH:14][C@@H:15]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=2)[CH2:16][N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:27])=[O:13])=[CH:8][C:7]=1[C:6]1[N:2]([CH3:1])[N:3]=[N:4][C:5]=1[CH3:36]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1nnn(C)c1-c1csc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nnn(C)c1-c1cc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Yield: 31.1 %

Procedure:
A solution of 4-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamide (254 mg, 0.454 mmol), and NCS (60.6 mg, 0.454 mmol) in N,N-Dimethylformamide (DMF) (5 mL) to was heated at 40° C. overnight. The reaction mixture was taken into EtOAc, which was washed with H2O 3× and brine, dried (Na2SO4) and concentrated. The residue was purified on a 25 g Biotage column, which was eluted with 50-100% EtOAc/hexane to give 76 mg (28%) of product as a white foamy solid and 63 mg of recovered starting material. LC-MS (ES) m/z 538.0 (M+H)+.
Reaction SMILES: [C:1](=[O:6])([O:4][CH3:5])OC.[NH:7]([CH2:11]CO)[CH2:8][CH2:9][OH:10]>>[OH:10][CH2:9][CH2:8][N:7]1[CH2:11][CH2:5][O:4][C:1]1=[O:6]
Reactant: COC(=O)OC
Reactant: OCCNCCO
Product: O=C1OCCN1CCO

Procedure:
In a preferred embodiment of this invention, equimolar amounts of dimethyl carbonate and diethanolamine are mixed and heated to reflux. The mixture is maintained at reflux until essentially all of the reactants are consumed as measured by gas chromatography. The product mixture consists of methanol and 3-(2-hydroxyethyl)-2-oxazolidinone. The methanol is removed by distillation leaving essentially pure 3-(2-hydroxyethyl)-2-oxazolidinone as confirmed by gas chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[NH:32]1[CH2:37][CH2:36][CH:35]([N:38]2[C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=3[NH:40][C:39]2=[O:47])[CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:29])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([N:32]4[CH2:33][CH2:34][CH:35]([N:38]5[C:42]6[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=6[NH:40][C:39]5=[O:47])[CH2:36][CH2:37]4)=[O:23])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCC(n2c(=O)[nH]c3ccccc32)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1,3-dihydro-1-(4-piperidinyl)benzoimidazol-2-one as in General Procedure 10 to give the title compound. LCMS: m/z=647.03 (M+H+); retention time=0.81 minutes.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[NH:5][CH:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[CH2:3]1.[Cl-].[NH4+]>C(O)C.[Fe]>[NH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:4]1[CH2:3][C:2]([CH3:1])([CH3:26])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[NH:5]1
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1ccccc1[N+](=O)[O-])N2
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1ccccc1N)N2
Temperature: 90 °C
Reaction time: 3 h
Yield: 45.4 %

Procedure:
To a stirred suspension of ethyl 4,4-dimethyl-2-(2-nitrophenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (13.0 g, 36.7 mmol) in ethanol was added iron powder (8.2 g, 146.7 mmol) and saturated aqueous ammonium chloride sat room temperature, the reaction mixture was stirred at 90° C. for 3 h. The insoluble solid was filtered off and filtrated was concentrated in vacuum and the residue was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was purified by column chromatography to give ethyl 2-(2-aminophenyl)-4,4-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as yellow solid (5.4 g, yield 45.4%). LC/MS m/e obsd. (ESI+) [(M+H)+] 325.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:23])=[CH:4][C:5]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)=[N:10][NH:9][CH:8]([CH3:21])[CH2:7][C:6]=2[CH:22]=1.[CH3:24][N:25]=[C:26]=[O:27]>>[Cl:1][C:2]1[C:3]([Cl:23])=[CH:4][C:5]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)=[N:10][N:9]([C:26](=[O:27])[NH:25][CH3:24])[CH:8]([CH3:21])[CH2:7][C:6]=2[CH:22]=1
Reactant: CN=C=O
Reactant: CC1Cc2cc(Cl)c(Cl)cc2C(c2ccc([N+](=O)[O-])cc2)=NN1
Product: CNC(=O)N1N=C(c2ccc([N+](=O)[O-])cc2)c2cc(Cl)c(Cl)cc2CC1C
Yield: 97 %

Procedure:
0.33 g (0.94 mmoles) of 7,8-dichloro-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine obtained in Example 9, Step C are reacted with methyl isocyanate according to Example 3. The crude product is purified by suspending it in hot ethanol. Thus, 0.37 g (97%) of the title compound are obtained. M.p.: 221°-223° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11](OC)[C:10]2[C:5](=[C:6]([Cl:19])[CH:7]=[C:8]([O:17][CH3:18])[C:9]=2[O:15][CH3:16])[N:4]=1.[NH3:20]>>[NH2:20][C:11]1[C:10]2[C:5](=[C:6]([Cl:19])[CH:7]=[C:8]([O:17][CH3:18])[C:9]=2[O:15][CH3:16])[N:4]=[C:3]([O:2][CH3:1])[N:12]=1
Reactant: COc1nc(OC)c2c(OC)c(OC)cc(Cl)c2n1
Reactant: N
Product: COc1nc(N)c2c(OC)c(OC)cc(Cl)c2n1

Procedure:
A mixture of 2,4,5,6-tetramethoxy-8-chloroquinazoline (2.1 g, 0.0073 moles) and saturated methanolic ammonia (60 ml) was warmed to 80° C. for 16 hours in a teflon lined acid digestion bomb. The crude reaction mixture was filtered, and the resulting solid was recrystallized twice from N,N-dimethylformamide, washed three times with methanol and dried under vacuum at 60° C. to afford the product (1.08 g), mp 203°-204° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[C:12]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Yield: 69 %

Procedure:
28 g (0.2 mole) of 3-fluoro-4-nitrophenol was dissolved in 200 mL of acetone. 56 g (0.4 mole) of K2CO3 was added, and the contents heated to 40 C for 10 min. Contents were cooled to 0 C, 25 mL (0.4 mole) of methyl iodide added, and again heated to 40 C for 3 hrs. Reaction cooled to rt, roto-evaporated to approx. 100 mL, and 200 mL of methylene chloride was added. Contents were filtered, and the filtrant was rotary-evaporated to dryness. The crystalline solid was recrystallized from 4:1 EtOH/H2O to give 23.6 g (46%) of desired product. 1H NMR (CDCl3, 400 MHz) 8.12 (m, 1H), 6.78 (m, 2H), 3.93 (s, 3H); LCMS (M+H)+ 172 found.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][N:12]=2)=[CH:6][C:5]=1[OH:22].[CH3:23][S:24][CH2:25]Cl.O>CN(C)C=O>[Cl:17][C:16]1[C:11]([C:7]2[CH:6]=[C:5]([O:22][CH2:23][S:24][CH3:25])[C:4]([Cl:3])=[CH:9][C:8]=2[F:10])=[N:12][CH:13]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:15]=1
Reactant: Oc1cc(-c2ncc(C(F)(F)F)cc2Cl)c(F)cc1Cl
Reactant: CSCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSCOc1cc(-c2ncc(C(F)(F)F)cc2Cl)c(F)cc1Cl
Reaction time: 1 h

Procedure:
0.1 g (4.4 mmol) of sodium hydride was added to a solution of 1.3 g (4 mmol) of 2-chloro-5-(3-chloro-5-trifluoromethylpyrid-2-yl)-4-fluorophenol in 50 ml of dimethylformamide. After the mixture has been stirred for 1 hour, it was treated with 0.5 g (5.2 mmol) of methylthiomethyl chloride. Then, the mixture was stirred for another hour. For working-up, the reaction mixture was treated with 50 ml of water. The product was then extracted with 100 ml of methyl tert-butyl ether. The organic phase was dried over magnesium sulfate and finally concentrated. Yield: 0.3 g.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:29])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[CH:24]=[CH:25][CH:26]2[CH2:28][CH2:27]2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH:26]1([CH:25]=[CH:24][C:18]2[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7]2)=[O:29])[CH2:27][CH2:28]1
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2C=CC2CC2)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)c1C=CC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.3 %

Procedure:
The mixture 2-[2-(-2-cyclopropyl-vinyl)-3-methyl-benzoylamino]-indan-2-carboxylic acid ethyl ester (137) (220 mg, 0.56 mmol) and KOH (600 mg, 10.7 mmol) is dissolved in EtOH (8 mL) and water (0.5 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more precipitate came out of the water. The precipitate is filtered to give a pure product (138) as white solid (209 mg, 100%).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:4]=2[N:3]1C(OCC1C=CC=CC=1)=O.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:32][C:33]1[CH:42]=[C:41]2[C:36]([CH:37]=[CH:38][C:39]([C:43]#[N:44])=[CH:40]2)=[CH:35][CH:34]=1>CN(C=O)C.C(OCC)(=O)C>[C:43]([C:39]1[CH:40]=[C:41]2[C:36]([CH:35]=[CH:34][C:33]([CH2:32][N:6]3[C:5]4[CH:7]=[CH:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:4]=4[NH:3][C:2]3=[O:1])=[CH:42]2)=[CH:37][CH:38]=1)#[N:44]
Reactant: N#Cc1ccc2ccc(CBr)cc2c1
Reactant: COC(=O)c1ccc2[nH]c(=O)n(C(=O)OCc3ccccc3)c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)[nH]c(=O)n2Cc1ccc2ccc(C#N)cc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.7 %

Procedure:
To a chilled solution of methyl 2-oxo-3-(benzyloxycarbonyl)—(3H)—benzimidazole-5-carboxylate (110 mg, 0.337 mmol) in DMF (3 mL) was added cesium carbonate (0.275 g, 0.84 mmol) followed by 7-(bromomethyl)naphthalene-2-carbonitrile (108 mg, 0.44 mmol). The reaction was stirred at room temperature for 1.5 hours, diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated in vacuo. This residue was redissolved in methanol (4 mL), CH3CN (3 mL) and IN LiOH (0.7 mL). The reaction mixture was stirred for 1 hour, acidified with 1N HCl (0.7 mL), filtered and dried to yield methyl 1-[(7-cyano(2-naphthyl))methyl]-2-oxo-(3H)—benzimidazole-5-carboxylate (84 mg, 70%) as awhite solid. ES-MS (M+H)+=358.1.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.Cl.[CH:26]([NH:29]N)([CH3:28])[CH3:27].CCN(CC)CC>C(O)C.Cl>[CH3:27][CH:26]([N:29]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1)[CH3:28]
Reactant: CC(C)NN
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)n1nccc1-c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 61.8 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (500 mg, 1.5 mmol) in ethanol (10 mL) were added isopropylhydrazine hydrochloride (246 mg, 2.2 mmol) and Et3N (0.41 mL, 3.0 mmol). The mixture was stirred at 100° C. for 5 h. The mixture was diluted with 1N HCl aqueous solution, extracted with AcOEt, washed with brine, dried over Na2SO4, concentrated in vacuo, purified by column chromatography on silica gel (hexane/AcOEt=10/90 to 0/100) and recrystallized with AcOEt/i-Pr2O to yield the title compound as a pale yellow solid (323 mg, 63%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:32])([CH3:31])[NH:9][C:10](=[O:30])[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)=[CH:14][CH:13]=1)(=O)=O.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([C:7]2[C:8]([CH3:32])([CH3:31])[NH:9][C:10](=[O:30])[C:11]=2[C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[CH:16][CH:17]=2)=[CH:39][CH:38]=1
Reactant: CC1(C)NC(=O)C(c2ccc(OCc3ccc4ccccc4n3)cc2)=C1OS(=O)(=O)C(F)(F)F
Reactant: COc1ccc(B(O)O)cc1
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: O
Solvent: C1COCCO1
Product: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)NC2(C)C)cc1
Reaction time: 0.5 h
Yield: 6.6 %

Procedure:
To a stirred solution of 2,2-dimethyl-5-oxo-4-(4-(quinolin-2-ylmethoxy)phenyl)-2,5-dihydro-1H-pyrrol-3-yl trifluoromethanesulfonate (500 mg, 1.01 mmol) in 1,4-dioxane (20 mL) were added 4-methoxyphenylboronic acid (185 mg, 1.2 mmol), Na2CO3 (256 mg, 3.04 mmol) and water (4 mL) at RT under an inert atmosphere. The mixture was stirred for 30 min and then Pd(PPh3)4 (117 mg, 0.1 mmol) was added. Stirring was continued at 80° C. for 16 h. The reaction mixture was then diluted with water and extracted with EtOAc (2×200 mL). The combined organic layers were washed with water and brine, and then dried over Na2SO4 and concentrated in vacuo to afford 4-(4-methoxyphenyl)-5,5-dimethyl-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one (30 mg, 7%) as a white solid. 1H NMR (500 MHz, CDCl3): δ 8.20-8.01 (m, 2 H), 7.87-7.62 (m, 2 H), 7.61-7.51 (m, 2 H), 7.38-7.30 (m, 2 H), 7.16-7.09 (m, 2 H), 6.91 6.80 (m, 4 H), 5.96 (bs, 1 H), 5.39 (s, 2 H), 3.81 (s, 3 H), 1.43 (s, 6 H). MS: M+H: m/z=451.2 and HPLC: 94%, (Condition-I).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@@H:10]([C:14]([OH:16])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]1([NH2:20])[CH2:19][CH2:18]1.C(N=C=NCCCN(C)C)C.Cl>ClCCl>[CH2:1]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@@H:10]([C:14]([NH:20][CH:17]2[CH2:19][CH2:18]2)=[O:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1CN(Cc2ccccc2)C[C@@H]1C(=O)O
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: C[C@H]1CN(Cc2ccccc2)C[C@@H]1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(3R,4R)-1-Benzyl-4-methyl-3-pyrrolidinecarboxylic acid (6.27 g) was suspended in dichloromethane (250 mL). To this suspension, cyclopropylamine (1.76 mL) and hydrochloric acid 1-ethyl-(3-dimethylaminopropyl)carbodiimide (12.2 g) were sequentially added and the mixture was stirred at room temperature for 4 hours. Subsequently, the reaction mixture was washed with water, was dried over anhydrous sodium sulfate, and was then concentrated under reduced pressure. The resulting residue was purified on a silica gel column (ethyl acetate: methanol=10:1) to give 3.32 g of (3R,4R)-1-benzyl-N-cyclopropyl-4-methyl-3-pyrrolidinecarboxamide as a white crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[CH2:6][CH:7]([CH:9](C)[C:10]#[N:11])[O:8][C:4]=2[C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21].B.O1CCCC1>O1CCCC1>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[CH2:6][CH:7]([CH2:9][CH2:10][NH2:11])[O:8][C:4]=2[C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21]
Reactant: CC(C#N)C1Cc2ccc(Cl)c(-c3ccccc3Cl)c2O1
Agent: B
Solvent: C1CCOC1
Product: NCCC1Cc2ccc(Cl)c(-c3ccccc3Cl)c2O1
Yield: 19 %

Procedure:
To a solution of (±)-[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanol (0.5 g, 1.69 mmol) in toluene (10 mL) was added triphenylphosphine (0.66 g, 2.54 mmol), diethyl azodicarboxylate (0.44 g, 2.54 mmol), and 2-hydroxy-2-methylpropanenitrile (0.21 g, 2.53 mmol) and the reaction mixture was allowed to stir at room temperature for 48 h. The solvent was removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:9-3:7) provided 0.22 g (43%) of (±)-{2-[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]propanenitrile. To a solution of the nitrile in tetrahydrofuran (10 mL) was added borane-tetrahydrofuran (8 mL) and the reaction mixture was heated to reflux for 3 h. The reaction mixture was quenched with 1.0 N aqueous hydrogen chloride (100 mL) and then neutralized with 1.0 N aqueous sodium hydroxide (100 mL). The aqueous layer was extracted with ethyl acetate (2×200 mL) and the combined organic extracts were washed with saturated aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent removed in vacuo. Purification by flash column chromatography (silica, 10% ammonium hydroxide in methanol:dichloromethane 1:9) provided 0.1 g (19%) of (±)-{2-[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]ethyl}amine as a white solid, hydrochloride salt. mp 211-213° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][NH2:9].C([O-])([O-])=O.[Na+].[Na+].[C:16](Cl)(=[O:18])[CH3:17]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][NH:9][C:16](=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: NCc1ccncc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)NCc1ccncc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.2 %

Procedure:
To a solution of (3-bromopyridin-4-yl) methanamine (3.5 g, 19 mmol) in DCM (880 mL) is added Na2CO3 (3.0 g, 28 mmol), then acetyl chloride (1.6 g, 21 mmol) is added at 0° C. under N2 atmosphere. The mixture is stirred at room temperature for 3 hrs and then it is diluted with DCM. The mixture is washed with water and brine, dried over Na2SO4, filtered and concentrated to give the crude product. Purification by flash column chromatography affords 2.1 g of N-(3-Bromo-pyridin-4-ylmethyl)-acetamide.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[C@@H:7]([O:8][N+:9]([O-:11])=[O:10])[CH2:6][C@H:5]([C:12]([OH:14])=[O:13])[CH2:4]1.[C:15](Cl)(=O)[C:16]([Cl:18])=O.C(=O)C>CN(C)C=O.[Cl-].[Zn+2].[Cl-]>[CH3:1][O:2][C@@H:3]1[C@@H:7]([O:8][N+:9]([O-:11])=[O:10])[CH2:6][C@H:5]([C:12]([O:14][CH:16]([Cl:18])[CH3:15])=[O:13])[CH2:4]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CO[C@H]1C[C@@H](C(=O)O)C[C@@H]1O[N+](=O)[O-]
Agent: CC=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CN(C)C=O
Product: CO[C@H]1C[C@@H](C(=O)OC(C)Cl)C[C@@H]1O[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a d-chloroform (60 mL) solution of (1R,3S,4S)-3-methoxy-4-(nitrooxy)cyclopentane carboxylic acid (4.59 g, 22.4 mmol) was added oxalyl chloride (2.40 mL, 27.4 mmol), followed by a few drops of N,N-dimethylformamide. After 60 minutes, 1H-NMR showed that the reaction was complete. To this reaction mixture was added zinc chloride (0.31 g, 2.27 mmol). The suspension was cooled to 0° C., and a d-chloroform solution (10 mL) of acetaldehyde (2.6 mL, 46.0 mmol) was slowly added to the reaction mixture over 5 minutes. The reaction was warmed up to room temperature and stirred for 17 hours. 1H-NMR confirmed that the starting acid chloride has been consumed and most of the material was converted to the desired product. The reaction mixture was concentrated in vacuo, and chromatography of the residue over silica gel, eluting with 2/98→20/80 ethyl acetate/hexanes, afforded the title compound as a colorless liquid. 1H NMR (500 MHz, CDCl3) δ 1.80 (d, J=5.9 Hz, 3H), 2.04-2.14 (m, 2H), 2.28-2.36 (m, 1H), 2.50-2.60 (m, 1H), 3.01 (quintet, J=8.3 Hz, 1H), 3.37 (s, 3H), 3.81-3.85 (m, 1H), 5.26-5.31 (m, 1H), 6.54 (q, J=5.8 Hz, 1H, D1), 6.54 (q, J=5.9 Hz, 1H, D2).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11](N1C2C(=CC=CC=2)CCC1)=[O:12].[NH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][C:36]=2[NH2:38])[CH2:31][CH2:30][CH2:29]1>CCCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:6]([C:11]([NH:38][C:36]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:37]=2[NH:28][CH2:29][CH2:30][CH2:31]3)=[O:12])=[CH:7][N:8]=[CH:9][CH:10]=1
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Reactant: Nc1cccc2c1NCCC2
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc2c1NCCC2)c1cnccc1Oc1cc(Cl)ccc1Cl

Procedure:
The title compound was prepared in analogy to Example 1, from 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and 1,2,3,4-tetrahydro-quinolin-8-ylamine (commercially available; CAS RN 54012-92-9) and using a gradient of n-heptane:ethyl acetate (100:0 to 0:100) for the chromatographic purification. Light yellow solid (88%). MS (ESI): m/z=414.077 [M+H]+.