Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1.[Li]CCCC.CN([CH:23]=[O:24])C.O>CCOCC>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][C:6]=1[CH:23]=[O:24]
Reactant: COCOc1ccc(C(F)(F)F)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: COCOc1ccc(C(F)(F)F)cc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To the solution of 4-(trifluoromethyl)phenyl methoxymethyl ether (5 g) in anhydrous ether (50 ml) was gradually added dropwise 1.6M n-BuLi (16.7 ml) at room temperature. After stirring at room temperature for 2 hours, the solution of DMF (4.13 ml) in anhydrous ether (20 ml) was added dropwise over 30 minutes, and the solution was stirred for 1 hour. To the reaction solution was added water, and the ether layer was separated. The ether layer is was washed with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by chromatography on a silica gel column (methylene chloride:hexane=1:1), to give the title compound (4.49 g; 79%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=C[C:3]=1[N+]([O-])=O.[O:20]1CCC(CCN)[CH2:22][CH2:21]1.C(N(CC)CC)C.[H][H]>[C].[Pd].O.C(#N)C>[O:20]1[CH2:3][CH2:2][CH:7]([CH2:6][CH2:5][C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:22][CH2:21]1
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Reactant: [H][H]
Reactant: NCCC1CCOCC1
Agent: [Pd]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: c1ccc2oc(CCC3CCOCC3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
2-(4-Fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (800 mg, 3.1 mmol) was added to an acetonitrile (5 mL) solution containing 2-(tetrahydropyran-4-yl)ethylamine (520 mg, 3.9 mmol) and triethylamine (500 mg, 3.9 mmol), and this was heated to reflux for 3 hours. After the reaction was complete, this was cooled to room temperature, water was added, and the precipitated crystals were filtered, washed with water and then dried. To a tetrahydrofuran solution (20 mL) of the crystals obtained was added 10% palladium-carbon (100 mg). A hydrogen atmosphere was substituted in the flask, and this was stirred overnight at room temperature. After the reaction was complete, this was filtered through Celite and the filtrate was concentrated. The residue obtained was purified by silica gel column chromatography to yield the title compound (450 mg, 43% yield) as a syrup.
Reaction SMILES: N1CCC([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C@@H:13]([NH:15][C:16](=[O:18])[CH3:17])[CH3:14])CC1.Br[C:20]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH3:31])=[CH:24][C:21]=1[C:22]#[N:23].C(=O)([O-])[O-].[K+].[K+].[NH:38]1[CH2:45][CH2:44][CH2:43][C@H:39]1[C:40](O)=O>CS(C)=O.[Cu]I.O>[C:22]([C:21]1[CH:24]=[C:25]([O:28][CH2:29][CH2:30][CH3:31])[CH:26]=[CH:27][C:20]=1[N:38]1[CH2:45][CH2:44][CH:43]([C:11]2[CH:10]=[CH:9][C:8]([C@@H:13]([NH:15][C:16](=[O:18])[CH3:17])[CH3:14])=[CH:7][CH:12]=2)[CH2:39][CH2:40]1)#[N:23]
Reactant: CCCOc1ccc(Br)c(C#N)c1
Reactant: CC(=O)N[C@@H](C)c1ccccc1C1CCNCC1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCOc1ccc(N2CCC(c3ccc([C@H](C)NC(C)=O)cc3)CC2)c(C#N)c1
Temperature: 90 °C
Reaction time: 168 h

Procedure:
100 mg (0.41 mmol) (S)—N-[1-(Piperidin-4-yl-phenyl)-ethyl]-acetamide (V.1) in 2 mL DMSO are added to a mixture of 97 mg (0.41 mmol) 2-bromo-5-propoxy-benzonitrile, 112 mg (0.82 mmol) potassium carbonate, 7.7 mg (0.041 mmol) copper(I) iodide and 9 mg (0.08 mmol) (L)-proline under inert gas atmosphere. The mixture is stirred for 7 d at 90° C. After that time, water is added and the mixture is extracted with ethyl acetate. The organic layer is dried over sodium sulphate and the solvent is removed in vacuo. The residue is purified by HPLC (column: Waters XBridge 5 μM; eluent A: water+0.3% NH4OH, eluent B: MeOH) to yield the desired product.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]([F:22])([F:21])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:11][CH:10]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24].Cl>CCCCCC.ClCCl>[CH3:24][C:23]([C:11]1[CH:10]=[C:9]([O:8][CH2:7][C:6]([F:21])([F:22])[F:5])[CH:14]=[CH:13][C:12]=1[O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[O:25]
Reactant: CC(=O)OC(C)=O
Reactant: FC(F)(F)COc1ccc(OCC(F)(F)F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Yield: 90 %

Procedure:
To a mixture of 2.43 moles (324 g.) of aluminum chloride in 648 ml. of dichloromethane is added a solution of 0.88 mole (274 g.) of 1,4-bis(2,2,2-trifluoroethoxy)benzene and 0.97 mole (92 ml.) of acetic anhydride in 800 ml. of dichloromethane over a 3 hour period while maintaining the temperature at above 0° C. The reaction mixture is then heated to its reflux temperature and stirred at reflux for 5 hours. The progress of the reaction is followed using thin-layer chromatography. The reaction mixture is placed in an ice bath and ice and 10 percent hydrochloric acid are added slowly to decompose the aluminum chloride complex. The temperature of the reaction mixture is not allowed to exceed 25° C. The organic phase is separated and washed once with 2 liters of 10 percent hydrochloric acid and then with 2 liters of water. The combined aqueous phase is extracted with several liters of dichloromethane. The organic phase is dried over magnesium sulfate, then evaporated to provide a moist residue. Hexane is added to the residue and the resulting solid is collected by filtration and washed with hexane. Upon drying, 250 g. of light yellow crystalline 2,5-bis(2,2,2-trifluoroethoxy)acetophenone is obtained. The yield is 90 percent, the m.p. is 84° to 86° C.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:8](F)[C:5]=1[C:6]#[N:7].CN(C)C=O.[CH2:19]([SH:22])[CH2:20][CH3:21].[OH-].[K+]>O>[F:1][CH:2]([F:13])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([S:22][CH2:19][CH2:20][CH3:21])[C:5]=1[C:6]#[N:7]
Reactant: CCCS
Reactant: N#Cc1c(F)cccc1OC(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCCSc1cccc(OC(F)F)c1C#N
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
180 g (0.96 mol) 2-difluoromethoxy-6-fluorobenzonitrile were introduced into 1.5 l of dimethylformamide at room temperature. 73.2 g (0.96 mol) of propanethiol were added dropwise and, after cooling to 0° C., 70 g (1.25 mol) of potassium hydroxide pellets, dissolved in 600 ml of water, were added dropwise at 0° C. The mixture was stirred for one hour and then warmed to room temperature. The reaction mixture was stirred into 3.5 l of ice-water and extracted three times with 500 ml of methyl tert.-butyl ether. The combined organic phases were washed twice with 500 ml of 1N hydrochloric acid and dried over sodium sulfate. Then, the solvent was distilled off in vacuo. The oil obtained was distilled in vacuo (b.p.: 180-185° C./0.5 mbar). Yield: 76% of theory.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.OC[CH2:27][CH2:28][NH:29][C:30]1[CH:39]=[C:38]2[C:33]([CH:34]=[C:35]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[C:47]([F:50])([F:49])[F:48])[NH:36][C:37]2=[O:40])=[CH:32][CH:31]=1>C(Cl)Cl>[Br:24][CH2:20][CH2:27][CH2:28][NH:29][C:30]1[CH:39]=[C:38]2[C:33]([CH:34]=[C:35]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[C:47]([F:50])([F:48])[F:49])[NH:36][C:37]2=[O:40])=[CH:32][CH:31]=1
Reactant: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(NCCCO)cc12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(NCCCBr)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.7 %

Procedure:
Triphenylphosphine (940 mg, 3.59 mmol) and carbon tetrabromide (1.19 g, 3.59 mmol) were added to a methylene chloride solution (10 ml) that contained the 7-(3-hydroxypropylamino)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (500 mg, 1.38 mmol) obtained in step B of Example 1-49. The obtained mixture was stirred at a room temperature for 3 hours. The reaction solvent was distilled away, and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2 to 1:1), so as to obtain 7-(3-bromopropylamino)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (245 mg, 42%).
Reaction SMILES: [OH:1][N:2]=[C:3]([O:5][CH2:6][CH3:7])[CH3:4].[H-].[Na+].Cl[C:11]1[N:16]([C:17]2[CH:22]=[C:21]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N+:30]([O-:32])=[O:31])[C:20]([Cl:33])=[CH:19][C:18]=2[F:34])[C:15](=[O:35])[CH:14]=[C:13]([C:36]([F:39])([F:38])[F:37])[N:12]=1.O>O1CCCC1>[Cl:33][C:20]1[C:21]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N+:30]([O-:32])=[O:31])=[CH:22][C:17]([N:16]2[C:15](=[O:35])[CH:14]=[C:13]([C:36]([F:38])([F:39])[F:37])[N:12]=[C:11]2[O:1][N:2]=[C:3]([O:5][CH2:6][CH3:7])[CH3:4])=[C:18]([F:34])[CH:19]=1
Reactant: CCOC(C)=NO
Reactant: O=c1cc(C(F)(F)F)nc(Cl)n1-c1cc(Oc2ccccc2[N+](=O)[O-])c(Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(C)=NOc1nc(C(F)(F)F)cc(=O)n1-c1cc(Oc2ccccc2[N+](=O)[O-])c(Cl)cc1F
Temperature: 0 °C
Yield: 85 %

Procedure:
Ethyl N-hydroxyacetimidate(0.23 g, 0.002 mol) was added dropwise to a suspension of sodium hydride(008 g, 0.002 mol) in tetrahydrofuran(5 ml) with stirring at 0° C. 2-Chloro-3-[4-chloro-2-fluoro-5-(2-nitrophenoxy)phenyl]-6-trifluoromethyl-4(3H)-pyrimidinone(0.93 g, 0.002 mol) was added to the mixture at 0° C., and the mixture was stirred at 0° C. for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate solution was concentrated and purified by column chromatography on silica gel(20% ethyl acetate/hexane) to give compound II-1 (0.90 g, yield 85%) as a white solid, m.p.152-155° C.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29](C=O)=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH3:34][NH:35][CH2:36][CH2:37][OH:38].[C:39](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:34][N:35]([CH3:39])[CH2:36][CH2:37][OH:38])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:2][CH2:3]1
Reactant: CNCCO
Reactant: O=Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CN(CCO)Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-3-carbaldehyde (200 mg) in 1,2-dichloroethane (5 mL) was added 2-(methylamino)ethanol (80 μL), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added sodium triacetoxyborohydride (280 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (181 mg, yield 80%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate. MS: 524 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][NH:27][CH2:28][CH:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:30][OH:31].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:27]([CH2:28][CH:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:30][OH:31])[CH3:26])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Reactant: CNCC(CO)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CN(C)CC(CO)c2ccccc2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 60 °C
Reaction time: 7 h
Yield: 65.6 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.25 mmol), 3-(methylamino)-2-phenylpropan-1-ol (DE 1261862 19680229 CAN 69:35694) (74 mg, 0.38 mmol) and diisopropylethylamine (67 μL, 0.38 mmol) in dry DMF (5 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 7 hours at that temperature. After cooling to room temperature, the solution was diluted with water (15 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (10 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (86 mg) as a white solid.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH2:28][OH:29])[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>O1CCCC1.CCCCCC>[Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH2:28][O:29][S:46]([CH3:45])(=[O:48])=[O:47])[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](CO)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](COS(C)(=O)=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
A solution of 1α,3β-bis(tert-butyldimethylsilyloxy)-17β-(hydroxymethyl)androsta-5,7-diene (150 mg, 0.274 mmol) and triethylamine (0.153 ml, 1.10 mmol) in tetrahydrofuran (2.3 ml) was cooled to 0° C., followed by the addition of methanesulfonyl chloride (63 μl, 0.814 mmol) and stirring at 0° C. for 1 hour. The reaction mixture was diluted with hexane, washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to remove the solvent. The thus obtained residue was purified by column chromatography (hexane:ethyl acetate=9:1) to give the titled compound (155 mg, 91%) as a colorless foam.
Reaction SMILES: [C:1]1([C@H:7]([N:9]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[O:12][CH2:11][CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.Cl.[NH2:26]O.C(=O)(O)[O-].[Na+].[CH2:33]([OH:35])[CH3:34]>>[CH3:34][C:33]1[O:35][N:26]=[C:20]([C:19]2[CH:18]=[CH:17][C:16]([CH:13]3[O:12][CH2:11][CH2:10][N:9]([C@@H:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH3:8])[CH2:15][CH2:14]3)=[CH:23][CH:22]=2)[N:21]=1
Reactant: C[C@H](c1ccccc1)N1CCOC(c2ccc(C#N)cc2)CC1
Reactant: CCO
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1nc(-c2ccc(C3CCN([C@H](C)c4ccccc4)CCO3)cc2)no1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a mixture of 4-[4-((R)-1-phenyl-ethyl)-[1,4]oxazepan-7-yl]-benzonitrile (diastereomer type A) (0.68 g, 2.2 mmol) in ethanol (5 mL) and water (3 mL) was added hydroxylamine hydrochloride (0.46 g, 6.6 mmol) and sodium bicarbonate (1.20 g, 11 mmol) at room temperature and the resulting mixture was heated to 80° C. After stirring for 2 hours, the reaction mixture was evaporated for removal of ethanol and diluted with water and chloroform. The organic phase was separated from aqueous phase and dried over anhydrous sodium sulfate. After concentration, half of the residue (0.39 g) was dissolved in xylene (3 mL) and dimethylacetamide dimethylacetal was added at room temperature. The mixture was refluxed for 3 hours and concentrated. The residual material was purified by flash column chromatography on silica gel to yield 7-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-4-((R)-1-phenyl-ethyl)-[1,4]oxazepane (diastereomer type A) (0.33 g, 0.92 mmol, 83%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH:13](C(O)=O)[NH:12]2)=[O:10])=[CH:4][CH:3]=1.[S:24]1[CH2:28][CH2:27][N:26]([C:29](C2C=CC(N)=CC=2)=[O:30])[CH2:25]1.[CH2:38]([Cl:41])[CH2:39]Cl>CN(C=O)C>[S:24]1[CH2:28][CH2:27][N:26]([C:29]([C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH:11]3[CH2:20][C:15]4[C:14](=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:13][N:12]3[C:9]([NH:8][C:5]3[CH:6]=[CH:39][C:38]([Cl:41])=[CH:3][CH:4]=3)=[O:10])=[O:10])=[CH:6][CH:7]=2)=[O:30])[CH2:25]1
Reactant: O=C(O)C1Cc2ccccc2C(C(=O)Nc2ccc(Cl)cc2)N1
Reactant: Nc1ccc(C(=O)N2CCSC2)cc1
Reactant: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(C(=O)N2CCSC2)cc1)C1Cc2ccccc2CN1C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
To a solution of 2N-(4-chlorophenylaminocarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (50 mg, 0.15 mmol) and 4-(3-thiazolidinylcarbonyl)phenylamine (30 mg, 0.14 mmol) in DMF (2 mL), EDC (54 mg, 0.28 mmol) was added. The reaction mixture was stirred at room temperature overnight. It was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a white powder (32 mg). MS 521.0 and 523.0 (M+H, Cl pattern).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]#[N:16])=[CH:9][C:8]=1[CH2:17][CH:18]([CH3:20])[CH3:19])(=O)=O.[CH2:23]([C:27]1[CH:28]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH:24]([CH3:26])[CH3:25].C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>COCCOC.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:17]([C:8]1[CH:9]=[C:10]([CH2:13][CH2:14][C:15]#[N:16])[CH:11]=[CH:12][C:7]=1[C:29]1[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:27]([CH2:23][CH:24]([CH3:26])[CH3:25])[CH:28]=1)[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)Cc1cc(CCC#N)ccc1OS(=O)(=O)C(F)(F)F
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1CC(C)C
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: ClCCl
Solvent: CCO
Solvent: COCCOC
Product: COc1ccc(-c2ccc(CCC#N)cc2CC(C)C)cc1CC(C)C
Temperature: 80 °C
Yield: 100 %

Procedure:
294.8 mg (0.88 mmol) 4-(2-Cyanoethyl)-2-isobutylphenyl-trifluormethanesulfonate (6), 312.9 mg (1.08 mmol, 1.23 eq.) 2-(3-Isobutyl-4-methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (11) and 156 mg (135 μmol, 0.15 eq.) Pd(Ph3P)4 were dissolved in 20 ml DME/EtOH (9+1). To this yellow solution 0.88 ml (1.76 mmol, 2.00 eq.) of a 2 M aq. Na2CO3-solution was added and the resulting mixture was heated at 80° C. for 17 h. After concentrating the mixture in vacuo the residue was taken up in water and extracted with CH2Cl2. The comb. org. fractions were dried over MgSO4 and evaporated. Colunm chromatography (CH2Cl2) yielded 305.9 mg (0.88 mmol, 99.45%) 3-(2,3′-Diisobutyl-4′-methoxy-biphenyl-4-yl)propionitrile (73) as a clear oil. Rf (CH2Cl2)=0.68. 1H-NMR (500 MHz, CDCl3): δ=0.67 (d, 6H, J=6.62 Hz, 2*CH3), 0.85 (d, 6H, J=6.62 Hz, CH2), 2.59 (t, 2H, J=7.41 Hz, CH2CH2CN), 2.91 (t, 2H, J=7.41 Hz, CH2CH2CN), 3.79 (s, 3H, OCH3), 6.80 (d, 1H, J=8.36 Hz), 6.94 (d, 1H, J=2.21 Hz), 6.98-7.04 (m, 3H), 7.09 (d, 1H, J=7.57 Hz). MS (EI): m/z=350 (23), 349 (90), 307 (10), 306 (35), 290 (39), 250 (15), 248 (17), 247 (100), 246 (24), 209 (21), 191 (16), 178 (10), 174 (10), 147 (10), 145 (17), 144 (19), 117 (13), 105 (25), 83 (11), 57 (18). HR-MS (EI): Calcd. for C24H31NO: 349.240564. Found: 349.240765.
Reaction SMILES: [Cl:1]C1C=CC(OC)=C([C@@]2(F)C3C(=CC(C(F)(F)F)=CC=3)N(C([NH:23][CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=O)C2=O)C=1.C(N(CC)CC)C>>[ClH:1].[C:29]([O:28][C:26](=[O:27])[CH2:25][CH2:24][NH2:23])([CH3:32])([CH3:31])[CH3:30]
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(C(=O)NCCC(=O)OC(C)(C)C)c2cc(C(F)(F)F)ccc21
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCN
Product: Cl
Yield: 65 %

Procedure:
(S)-tert-butyl 3-(3-(5-chloro-2-methoxyphenyl)-3-fluoro-2-oxo-6-(trifluoromethyl)indoline-1-carboxamido)propanoate (XVIII8): Following general procedure (F), after forming the intermediate, β-alanine t-butyl ester hydrochloride (0.278 g, 1.53 mmol) and triethylamine (0.41 mL, 2.92 mmol) were added. After work-up and purification, 0.48 g of the title compound as a white foam solid was obtained (65% yield). mp: 50–53° C. MS: 531 (MH+). Anal. Calcd. for C24H23ClF4N2O5: C, 54.30; H, 4.37; N, 5.28. Found: C, 54.21; H, 4.44; N, 5.25. 1H NMR (CDCl3): δ 1.46 (s, 9H), 2.60 (t, J=6.2, 2H), 3.53 (s, 3H), 3.70 (m, 2H), 6.77 (d, J=8.7 Hz, 1H), 7.25 (m, 1H), 7.36 (dd, J=8.8 Hz, 2.6 Hz, 1H), 7.42 (d, J=7.8 Hz, 1H), 7.79 (d, J=2.2 Hz, 1H), 8.56 (t, J=5.6 Hz, 1H), 8.63 (s, 1H). IR (KBr, cm−1): 3351, 2981, 1762, 1721, 1531, 1491, 1439, 1319, 1261, 1171, 1130, 1060.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].C(N(CC)CC)C.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[C:22](Cl)=[O:23]>ClCCl.C(OCC)(=O)C>[CH2:1]([NH:4][C:22]([C:13]1[CH:14]=[CH:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=1)=[O:23])[C:2]#[CH:3]
Reactant: C#CCN
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C#CCNC(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Propargylamine (0.80 mL) and triethylamine (1.67 mL) were added simultaneously to a solution of 2-naphthoyl chloride (2.22 g) in dichloromethane (25 mL) cooled in an ice bath. The mixture was held at 0° C. for 1 hour and allowed to warm to room temperature over 3 hours. The solution was diluted with ethyl acetate, washed in turn with water, 1N hydrochloric acid, 1N sodium hydroxide, and saturated brine. Evaporation of the dried (K2CO3) organic layer gave a residue which was crystallized from dichloromethanehexane to give 2.06 g of N-(2-propynyl)-2-naphthalenecarboxamide, mp 163°-165° C.