Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][C@@H:6]([CH2:8][C:9]#[N:10])[C@@H:5]([N:11]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:4][CH2:3]1.[C:26](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O.C([O-])([O-])=O.[Na+].[Na+].[CH3:48][C:49]([CH3:51])=O>ClC(Cl)C>[CH2:19]([N:11]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C@H:5]1[CH2:4][CH2:3][C@@H:2]([N:1]([CH:49]([CH3:51])[CH3:48])[CH3:26])[CH2:7][C@H:6]1[CH2:8][C:9]#[N:10])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: N#CC[C@@H]1C[C@H](N)CC[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Reactant: CC(C)=O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(C)N(C)[C@@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)[C@H](CC#N)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Examples 11p and 11q, Step 6: To a solution of 2-((1S,2S,5R)-5-amino-2-(dibenzylamino)cyclohexyl)acetonitrile (4.35 mmoles) in 40 ml of anhydrous dichloroethane was added acetone (3.5 ml), and the mixture was stirred for 30 minutes at room temperature. Then sodium triacetoxyborohydride (3 g) was added, and the mixture was stirred for 1.5 hours. To the mixture was added 37% aqueous formaldehyde (2.2 ml) and it was stirred for 15 minutes. Then additional 1.6 g of sodium triacetoxyborohydride was added, and the mixture was continued to stir for 2.5 hours. At the end of the stirring, was added saturated Na2CO3, and the product was extracted with EtOAc. The extract was washed with brine, dried over Na2SO4, and evaporated to give an oily residue. It was purified by column chromatography (silica gel, 0.5:4.5:95 cNH4OH-MeOH—CH2Cl2) to give 1 g of ((1S,2S,5R)-2-(dibenzylamino)-5-(isopropyl(methyl)amino)cyclohexyl)acetonitrile as an oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:15])=[C:4]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:6][CH:7]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:34]Br>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl.[W]>[Br:1][C:2]1[C:3]([CH2:15][Br:34])=[C:4]([NH:8][C:9](=[O:14])[C:10]([F:11])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Br)cccc1NC(=O)C(F)(F)F
Reactant: BrBr
Agent: [W]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(Nc1cccc(Br)c1CBr)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of N-(3-bromo-2-methyl-phenyl)-2,2,2-trifluoro-acetamide (2.1 g, 7.4 mmol) and benzoyl peroxide (100 mg) in carbon tetrachloride (50 mL) was heated to reflux under irradiation (150 W tungsten lamp). A solution of bromine (0.55 mL, 10.4 mmol) in carbon tetrachloride (3 mL) was then added drop-wise to the refluxing solution, and heating was pursued for 16 h. The reaction mixture was left to cool to RT and diluted with DCM. The organic layer was washed with sodium thiosulfate, and evaporated to dryness to give N-(3-bromo-2-bromomethyl-phenyl)-2,2,2-trifluoro-acetamide as a brown residue which was used without further purification (2.9 g).
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH:22]([F:24])[F:23])=[C:18]([F:25])[CH:17]=3)[O:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:27][C:28]1[N:29]=[C:30]2[S:37][CH:36]=[C:35]([CH3:38])[N:31]2[C:32](=[O:34])[CH:33]=1.O.OC1N=CN=C2C=1NC(S)=N2>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH:22]([F:24])[F:23])=[C:18]([F:25])[CH:17]=3)[O:11][C:10](=[O:12])[C:9]([CH2:27][C:28]3[N:29]=[C:30]4[S:37][CH:36]=[C:35]([CH3:38])[N:31]4[C:32](=[O:34])[CH:33]=3)=[C:8]([OH:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CC(=O)OC(CCc2ccc(C(F)F)c(F)c2)(C2CCCC2)C1
Reactant: Cc1csc2nc(CCl)cc(=O)n12
Agent: Oc1ncnc2nc(S)[nH]c12
Solvent: O
Product: Cc1csc2nc(CC3=C(O)CC(CCc4ccc(C(F)F)c(F)c4)(C4CCCC4)OC3=O)cc(=O)n12

Procedure:
The title compound was prepared as described in Example B(54) where 6-Cyclopentyl-6-{2-[4-(difluoromethyl)-3-fluorophenyl]ethyl}-dihydro-2H-pyran-2,4(3H)-dione (described in Step 3 of Example B(69)) was used in place of 6-[2-(5-Chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and 7-(Chloromethyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (prepared according to a reported procedure: Doria, G.; Passarotti, C.; Sala, R.; Magrini, R.; Sberze, P.; Tibolla, M.; Cesarani, R.; Arcari, G.; Castello, R.; Toti, D. Farmaco Ed. Sci. 1985, 40, 885) was used in place of 6-Hydroxy-8-mercaptopurine monohydrate. 1H NMR (300 MHz, DMSO-D6) δ 1.55 (m, 8H) 1.94 (m, 2H) 2.33 (m, 1H) 2.44 (d, J=1.7 Hz, 2H) 2.58 (s, 3H,) 2.58 (1H buried under singlet) 2.71 (d, J=18.0 Hz, 1H) 3.38 (dd, J=15.0, 6.0 Hz, 2H) 5.77 (s, 1H) 6.90 (m, 1H) 7.10 (m, 3H) 7.27 (s, 1H) 7.44 (t, J=7.74 Hz, 1H). MS (APCI) calcd for C27H27F3N2O4S: 532.16; found (M+H+) 533.0.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O-:6])=O.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.S([O-])(O)=O.[Na+].O.CC([N:28](C)C)=O>>[C:12]1([C:11]2[N:28]=[C:4]([OH:6])[C:3]3[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:1]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccccc1C(=O)[O-]
Reactant: CC(=O)N(C)C
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: Oc1nc(-c2ccccc2)nc2ccccc12
Temperature: 150 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A mixture of o-aminobenzoate (7 mmol), benzaldehyde (7 mmol) and sodium hydrogen sulfite (10.5 mmol) in dimethylacetamide (10 ml) was heated with stirring at 150° C. overnight. Then, the reaction mixture was poured into water (300 ml). A precipitate was formed, collected and dried. Recristallization from benzene gave the desired product in 85% yield.
Reaction SMILES: S1C=CC(CS[CH2:8][CH2:9][NH:10][C:11](=[NH:14])SC)=N1.[NH2:15][CH2:16][CH2:17][S:18][CH2:19][C:20]1[CH:24]=[CH:23][S:22][N:21]=1.[CH2:25]([NH2:27])C>>[C:25]([NH:14][C:11]([NH:10][CH2:9][CH3:8])=[N:15][CH2:16][CH2:17][S:18][CH2:19][C:20]1[CH:24]=[CH:23][S:22][N:21]=1)#[N:27]
Reactant: CSC(=N)NCCSCc1ccsn1
Reactant: CCN
Reactant: NCCSCc1ccsn1
Product: CCNC(=NCCSCc1ccsn1)NC#N

Procedure:
Reaction N-cyano-N'-[2-(3-isothiazolylmethylthio)ethyl-S-methylisothiourea, prepared from 3-[(2-aminoethyl)thiomethyl]isothiazole by the procedure of Example 3(c)(i), wth ethylamine by the procedure of Example 4 gives N-cyano-N'-ethyl-N"-[2-(3-isothiazolylmethylthio)ethyl]guanidine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:19][CH2:20][CH2:21]Br.Cl>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:21][CH2:20][CH2:19]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: BrCCCBr
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2ccc([N+](=O)[O-])cc2)CCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
10 g of ethyl 4-nitrophenylacetate are dissolved in 100 ml of DMF, added dropwise to a suspension of 4.97 g of sodium hydride in 20 ml of DMF with ice-cooling and stirred for 30 min. 6.6 ml of 1,3-dibromopropane are subsequently added, and the mixture is stirred at 23° C. for 12 h. The reaction mixture is subsequently stirred into a mixture of 100 ml of 1 N hydrochloric acid and 200 g of ice. The mixture is washed four times with 100 ml of ethyl acetate each time, the combined organic phases once with 100 ml of sodium chloride solution, dried over sodium sulfate and, after filtration, evaporated to dryness in vacuo. The residue is purified by column chromatography (reversed phase). Yield: 5.5 g (46%) of ethyl 1-(4-nitrophenyl)cyclobutanecarboxylate; LC-MS retention time: 2.21 min (“nonpolar” gradient);
Reaction SMILES: [NH2:1][CH:2]([C:11]([OH:13])=[O:12])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[ClH:14].[CH2:15](O)[CH3:16]>>[ClH:14].[NH2:1][CH:2]([CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:11]([O:13][CH2:15][CH3:16])=[O:12]
Reactant: CCO
Reactant: NC(CCc1ccccc1)C(=O)O
Agent: Cl
Product: CCOC(=O)C(N)CCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of d,l-homophenylalanine (5 g., 27.9 mmole) in absolute ethanol (60 ml.) was cooled to 0° (ice bath) and saturated with hydrochloric acid gas. The mixture was allowed to warm to room temperature and stirred overnight. A stream of nitrogen was then passed through the solution to remove the bulk of the hydrochloric acid and the mixture was evaporated to dryness. The solid residue was triturated with ether, filtered and dried to give (±)-α-aminobenzenebutanoic acid, ethyl ester, monohydrochloride as a fluffy white solid; m.p. 129°-130°. Rf (acetic acid/methanol/dichloromethane; 1:1:8)=0.63.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([N+:19]([O-])=O)=[CH:14][C:13]=2[Cl:22])[C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[H][H]>CO.[Ni]>[Cl:18][C:17]1[CH:16]=[C:15]([CH:14]=[C:13]([Cl:22])[C:12]=1[CH:9]([C:10]#[N:11])[C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[NH2:19]
Reactant: [H][H]
Reactant: N#CC(c1ccc(Cl)c(Cl)c1)c1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: [Ni]
Solvent: CO
Product: N#CC(c1ccc(Cl)c(Cl)c1)c1c(Cl)cc(N)cc1Cl
Yield: 95 %

Procedure:
In 100 ml of methanol were dissolved 7.6 g of α-(3,4-dichlorophenyl)-α-(2,6-dichloro-4-nitrophenyl)acetonitrile and 0.8 g (50%) of Raney's nickel. The solution was subjected to reduction with three times as much mol. of hydrogen gas. Insolubles were removed from the reaction mixture, then the remaining solution was concentrated to give the titled compound in a yield of 95%, m.p.191-194° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[Na+].[I-:13]>CC(C)=O>[I:13][CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5]
Reactant: OC(CCCl)c1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: OC(CCI)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
(Compound 14) (10.1 g) was dissolved in acetone (200 ml) saturated with NaI. The mixture was refluxed for 12 h and subsequently stirred at RT for 3 days. The mixture was evaporated to dryness and the residue extracted with H2O/ether. The etheral layer separated and washed with H2O and saturated NaCl-solution. Resulting in 12.5 g of 3-iodo-1-phenyl-1-propanol (compound 15).
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][O:9][N:10]2C(=O)C3=CC=CC=C3C2=O)=[C:6]([F:21])[C:5]([F:22])=[C:4]([F:23])[C:3]=1[F:24].C(N)CCC.[ClH:30].Cl.NO>C(O)C>[ClH:30].[F:1][C:2]1[C:7]([CH2:8][O:9][NH2:10])=[C:6]([F:21])[C:5]([F:22])=[C:4]([F:23])[C:3]=1[F:24]
Reactant: O=C1c2ccccc2C(=O)N1OCc1c(F)c(F)c(F)c(F)c1F
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: CCCCN
Product: NOCc1c(F)c(F)c(F)c(F)c1F
Temperature: 60 °C
Reaction time: 1 h

Procedure:
N-(Pentafluorobenzyloxy)phthalimide 15.9 g, 46 mmol), n-butylamine (3.7 g, 50 mmol) and absolute ethanol (90 ml) were placed in a dry flask under a nitrogen atmosphere. This reaction mixture was stirred at 60° C. for 1 hour, cooled and adjusted to pH 3 using dry hydrogen chloride gas. The resulting white precipitate was filtered and the crystals washed with ice-cold ethanol/ether (1:1). The filtrate was concentrated to give a second crop of crystals. The combined yield of the hydroxylamine hydrochloride was 11.15 g, 99%, m.p. (sublimed) 150°. Analysis: (Found: C, 33.7; H. 2.2; Cl, 13.9; F, 37.8; N, 5.7, C7H5ClF5NO requires C, 33.7; H, 2.0; Cl, 14.2; F, 38.1; N, 5.6%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH2:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[C:20]([C:31]([NH2:33])=[O:32])=[CH:19][N:18]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:41](OC(=O)C)(=[O:43])[CH3:42]>C(#N)C>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH2:24][CH:25]4[CH2:30][CH2:29][N:28]([C:41](=[O:43])[CH3:42])[CH2:27][CH2:26]4)[C:20]([C:31]([NH2:33])=[O:32])=[CH:19][N:18]=3)=[CH:14][CH:15]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)N1CCN(c2ccc(Nc3ncc(C(N)=O)c(NCC4CCNCC4)n3)cc2)CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(CNc2nc(Nc3ccc(N4CCN(C(C)=O)CC4)cc3)ncc2C(N)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
To a solution of 2-(4-(4-acetylpiperazin-1-yl)phenylamino)-4-(piperidin-4-ylmethylamino)pyrimidine-5-carboxamide (22 mg, 0.049 mmol) and triethylamine (0.040 mL, 0.29 mmol) in acetonitrile (2 mL) at room temperature, acetic anhydride (0.020 mL, 0.21 mmol) was added. The solution was stirred at room temperature for 1 h. The mixture was then purified by HPLC to give the titled compound (8 mg). MS 495.41 (M+H).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:43])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[N:20][CH:21]=2)[N:18]([C@@H:22]2[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]2)[CH:17]=[C:16]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:15]3=[O:33])=[C:8]([C:34]2[S:35][CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[N:38]=2)[CH:7]=1)[CH3:2].FC(F)(F)C(O)=O.[O:51]1[CH2:56][CH2:55][N:54]([CH2:57][CH:58]=O)[CH2:53][CH2:52]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH2:1]([NH:3][C:4](=[O:43])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[N:20][CH:21]=2)[N:18]([C@@H:22]2[CH2:27][CH2:26][CH2:25][N:24]([CH2:58][CH2:57][N:54]4[CH2:55][CH2:56][O:51][CH2:52][CH2:53]4)[CH2:23]2)[CH:17]=[C:16]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:15]3=[O:33])=[C:8]([C:34]2[S:35][CH:36]=[C:37]([C:39]([F:40])([F:42])[F:41])[N:38]=2)[CH:7]=1)[CH3:2]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cnc3c(c2)c(=O)c(C(=O)OCC)cn3[C@@H]2CCCNC2)cn1
Reactant: O=CCN1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cnc3c(c2)c(=O)c(C(=O)OCC)cn3[C@@H]2CCCN(CCN3CCOCC3)C2)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 0 %

Procedure:
(R)-ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-4-oxo-1-(piperidin-3-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylate (Example 27, 0.050 g, 0.08 mmol) was taken up in THF (2 mL) and 2-morpholinoacetaldehyde 2,2,2-trifluoroacetate (0.024 g, 0.10 mmol) and DIEA (0.043 mL, 0.24 mmol) were added. The mixture was stirred at RT for 15 min. then sodium triacetoxyborohydride (0.078 g, 0.37 mmol) was added and reaction was stirred at RT for 6 hrs. The reaction was then quenched with NaHCO3 and extracted with DCM three times. Organics were combined and dried over Na2SO4 then the solvent was removed in vacuo. The residue was purified by flash column chromatography on silica gel using (dichloromethane-methanol) to give (R)-ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(1-(2-morpholinoethyl)piperidin-3-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (0.026 mg, 44%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[C:9](=[O:10])[CH2:8][CH:7]1[CH2:11][C:12]([O:14]CC)=[O:13].C(O)C.[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[C:9](=[O:10])[CH2:8][CH:7]1[CH2:11][C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)CC1CC(=O)N1Cc1ccc(OC)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(CN2C(=O)CC2CC(=O)O)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
To a solution of 0.31 g (1 millimole) of ethyl [1-(2,4-dimethoxy-benzyl)-4-oxo-2-azetidinyl]-acetate and 4 ml of ethanol a solution of 0.04 g (1 millimole) of sodium hydroxide and 6 ml of water are added. The reaction mixture is stirred at room temperature for 2 hours. The solution is extracted three times with 3 ml of dichloromethane each. The aqueous layer is acidified with concentrated aqueous hydrochloric acid to pH 2 and extracted three times with 3 ml of dichloromethane each. The united organic layers are dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated. The residue is crystallized from benzene. Thus 0.27 g of the desired compound are obtained, yield: 88%, M.p.: 112° C.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)C(O)=O)C.[OH-].[K+].Cl>O.C(O)C>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:5][C:4]([OH:21])=[O:3])=[CH:19][CH:18]=1
Reactant: CCOC(=O)C(CCCCCc1ccc(Cl)cc1)C(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCCCCCc1ccc(Cl)cc1

Procedure:
80 g of 5-(4-chlorophenyl)pentylmalonic acid ethyl ester are boiled under reflux with 45 g of potassium hydroxide in 230 ml of water and 100 ml of ethanol for 5 hours; after cooling, the mixture is adjusted to pH 1-2 with concentrated hydrochloric acid and is extracted 3 times with diethyl ether. The combined organic solutions are concentrated and the residue [5-(4-chlorophenyl)pentylmalonic acid] is heated to 160° for 3.5 hours. The residue consists of 51 g of 7-(4-chlorophenyl)heptanoic acid of m.p. 75° to 78°.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10](=[O:19])[N:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[OH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>>[O:20]=[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]1[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10](=[O:19])[N:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: CN(C(=O)Oc1ccc(CO)cc1)c1ccccc1
Reactant: Oc1ccccn1
Product: CN(C(=O)Oc1ccc(Cn2ccccc2=O)cc1)c1ccccc1
Yield: 66 %

Procedure:
The title compound was prepared in 66% yield as an oil using methyl-phenyl-carbamic acid 4-hydroxymethyl-phenyl ester and 2-hydroxypyridine. 1H NMR (400 MHz; CDCl3): δ 3.42 (br s, 3H), 5.12 (s, 2H), 6.13 (t, 1H), 6.60 (d, 1H), 7.10 (br s, 2H), 7.22-7.41 (m, 9H); HPLC-MS: m/z=335.2 (M+1); Rt=2.97 min.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[CH2:11][C:12]([OH:14])=O.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:28][O:29][C:30](=[O:36])[C@@H:31]1[CH2:35][CH2:34][CH2:33][NH:32]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:28][O:29][C:30](=[O:36])[C@@H:31]1[CH2:35][CH2:34][CH2:33][N:32]1[C:12](=[O:14])[CH2:11][CH:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1
Reactant: O=C(O)CC1CCc2ccccc2C1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCN1C(=O)CC1CCc2ccccc2C1
Temperature: 25 °C
Yield: 66.8 %

Procedure:
To a solution of 3.4 g of 1,2,3,4-tetrahydronaphthalen-2-ylacetic acid in 50 ml of methylene chloride was added 14.1 g of WSC.HCl with stirring at room temperature. Then, 3.6 g of L-proline methyl ester hydrochloride and 2.2 g of triethylamine were added to the solution. The mixture was stirred for 17 hours at room temperature. The reaction mixture was washed with water, diluted hydrochloric acid, and saturated sodium hydrogen carbonate in this order. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 3.6 g of 1-(1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-proline methyl ester as a colorless oil.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][CH2:12][C@H:13]3[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])O1.Br[C:28]1[O:32][C:31]([C:33]2[CH:34]=[CH:35][C:36]([O:41][CH:42]([CH3:44])[CH3:43])=[C:37]([CH:40]=2)[C:38]#[N:39])=[N:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].CC(O)C(O)C.O>>[C:38]([C:37]1[CH:40]=[C:33]([C:31]2[O:32][C:28]([C:9]3[CH:17]=[CH:16][CH:15]=[C:14]4[C:10]=3[CH2:11][CH2:12][C@H:13]4[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[CH:29][N:30]=2)[CH:34]=[CH:35][C:36]=1[O:41][CH:42]([CH3:44])[CH3:43])#[N:39]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2c(B3OC(C)(C)C(C)(C)O3)cccc21
Reactant: CC(C)Oc1ccc(-c2ncc(Br)o2)cc1C#N
Agent: CC(O)C(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)Oc1ccc(-c2ncc(-c3cccc4c3CC[C@H]4NC(=O)OC(C)(C)C)o2)cc1C#N
Yield: 67 %

Procedure:
Prepared using General Procedure 13. A 20 mL microwave vial was charged with (R)-tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-ylcarbamate INT-32 (58.4 mg, 0.16 mmol), 5-(5-bromooxazol-2-yl)-2-isopropoxybenzonitrile INT-40 (50 mg, 0.16 mmol), potassium carbonate (68 mg, 0.5 mmol) and a 3:1 mixture of dimethylethylene glycol/H2O (2 mL). The reaction mixture was degassed by bubbling N2 gas through the stirring solution for 10 min. Pd(PPh3)4 ((3.9 mg, 0.004 mmol) was added and the solution degassed for additional 2 min. The vial was subjected to microwave irradiation at 100° C. for 30 min. The solvent was removed and the residue dissolved in EA (10 mL), washed with brine, and then dried over MgSO4. The product was purified by chromatography (EA/hexanes) to afford 50 mg (67%) of (R)-tert-butyl 4-(2-(3-cyano-4-isopropoxyphenyl)oxazol-5-yl)-2,3-dihydro-1H-inden-1-ylcarbamate INT-42 as an off-white solid. LCMS-ESI (m/z) calculated for C27H29N3O4: 459.5; found 460.2 [M+H]+, tR=4.1 min. 1H NMR (400 MHz, CDCl3) δ 8.32-8.03 (m, 2H), 7.60 (dd, J=8.6, 4.1 Hz, 1H), 7.32-7.22 (m, 3H), 7.00 (d, J=8.9 Hz, 1H), 5.19 (dd, J=15.5, 7.5 Hz, 1H), 4.82-4.56 (m, 2H), 3.12 (ddd, J=16.3, 9.0, 3.5 Hz, 1H), 2.95 (dt, J=16.3, 8.1 Hz, 1H), 2.70-2.51 (m, 1H), 1.83 (dq, J=13.1, 8.2 Hz, 1H), 1.43 (s, 9H), 1.41-1.35 (m, 6H).
Reaction SMILES: [F:1][C:2]([P:8]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])(=[O:11])[O:9]C)([F:7])[C:3]([F:6])([F:5])[F:4].[CH2:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH3:20]>CCCCCC>[F:7][C:2]([P:8]([C:12]([F:17])([F:18])[C:13]([F:16])([F:15])[F:14])(=[O:9])[O-:11])([F:1])[C:3]([F:6])([F:5])[F:4].[CH2:19]([N+:21]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH3:2])[CH3:20]
Reactant: COP(=O)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Reactant: CCN(CC)CC
Solvent: CCCCCC
Product: CC[N+](C)(CC)CC
Product: O=P([O-])(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91 %

Procedure:
Methyl bis(pentafluoroethyl)phosphinate, (C2F5)2P(O)OCH3, (1.83 g; 5.8 mmol) is slowly added dropwise to dry and cooled (0° C.) triethylamine (0.59 g; 5.9 mmol) (exothermic) in a 10 ml glass flask. A yellow solid forms. The reaction mixture is diluted with 10 ml of n-hexane, warmed to room temperature and stirred for 20 min. The readily volatile constituents are removed in vacuo (10−3 mbar) at room temperature. Triethylmethylammonium bis(pentafluoroethyl)phosphinate, [CH3N(C2H5)3][(C2F5)2P(O)O], (2.19 g; 5.3 mmol) is isolated as pale-yellow solid in a yield of 91% and a purity of 99%.