Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:22]([NH:24][NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].N1C=CC=CC=1.[CH:40]1[C:52]2[CH:51]([CH2:53][O:54][C:55]([NH:57][C:58]3([C:63](O)=[O:64])[CH2:62][CH2:61][CH2:60][CH2:59]3)=[O:56])[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:44]=2[CH:43]=[CH:42][CH:41]=1>ClCCl.C(OCC)(=O)C>[CH:40]1[C:52]2[CH:51]([CH2:53][O:54][C:55]([NH:57][C:58]3([C:63]([N:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH:24][C:22](=[O:23])[C@@H:21]([C@@H:11]([C:9](=[O:10])[NH:8][O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[CH2:12]/[CH:13]=[CH:14]/[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:30][CH:31]([CH3:33])[CH3:32])=[O:64])[CH2:59][CH2:60][CH2:61][CH2:62]3)=[O:56])[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:44]=2[CH:43]=[CH:42][CH:41]=1
Reactant: O=C(NC1(C(=O)O)CCCC1)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)C1(NC(=O)OCC2c3ccccc3-c3ccccc32)CCCC1)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.7 %

Procedure:
A solution of 0.459 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in 3 ml of dichloromethane was treated under nitrogen at room temperature with 0.119 g of pyridine and a solution of the acid chloride prepared from 0.42 g of N-(9-fluorenylmethyloxycarbonyl)-cycloleucine in 3 ml of dichloromethane. The mixture was stirred at room temperature for 16 hours and diluted with ethyl acetate. The solution was washed with 5% aqueous sodium hydrogen carbonate solution, water and saturated sodium chloride solution and then dried over anhydrous magnesium sulphate. The solvent was evaporated to give a foam, which was crystallized from diethyl ether/hexane to give 0.71 g of (E)-2′-[(1-(9-fluorenylmethyloxycarbonylamino)-1-cyclopentyl)carbonyl]-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoy]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide as a white solid.
Reaction SMILES: [C:1]([Si:5]([CH3:24])([CH3:23])[O:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:32])C(=O)C1>CC#N>[Br:32][C:18]1[CH:17]=[C:16]([CH2:15][N:12]2[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:24])[CH3:23])[CH2:14][CH2:13]2)[CH:21]=[CH:20][C:19]=1[NH2:22]
Reactant: CC(C)(C)[Si](C)(C)OCCN1CCN(Cc2ccc(N)cc2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OCCN1CCN(Cc2ccc(N)c(Br)c2)CC1
Temperature: 0 °C
Yield: 32 %

Procedure:
A solution of 4-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-piperazin-1-ylmethyl}-phenylamine (as prepared in the previous step, 204 mg, 0.582 mmol) in CH3CN (6 mL) was cooled to 0° C. and treated dropwise with NBS as a solution in CH3CN (6 mL). The solvents were evaporated in vacuo. The residue was taken up in EtOAc and washed with satd aq NaHCO3. The organic layer was dried over MgSO4 and concentrated in vacuo. Purification of the residue on a 20-g Isolute SPE column on a FlashMaster system with 25-50% EtOAc-hexane afforded the title compound (80.9 mg, 32%) as an off-white solid. Mass spectrum (ESI, m/z): Calcd. for C19H34N3OSiBr, 428.2/430.2 (M+H). found 428.1/430.0.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[C:9]([F:19])=[C:10]([OH:18])[C:11]([CH:14]3[CH2:17][CH2:16][CH2:15]3)=[CH:12][CH:13]=2)=[N:6][CH:7]=1.Cl[C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH2:28])[N:22]=1.C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CS(C)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[C:9]([F:19])=[C:10]([C:11]([CH:14]3[CH2:15][CH2:16][CH2:17]3)=[CH:12][CH:13]=2)[O:18][C:21]2[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH2:28])[N:22]=2)=[N:6][CH:7]=1
Reactant: Nc1cnc(-c2ccc(C3CCC3)c(O)c2F)cn1
Reactant: Cc1cc(Cl)nc(N)n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(Oc2c(C3CCC3)ccc(-c3cnc(N)cn3)c2F)nc(N)n1
Temperature: 140 °C
Yield: 17.2 %

Procedure:
A suspension of 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (50 mg, 0.19 mmol), 4-chloro-6-methylpyrimidin-2-amine (30 mg, 0.20 mmol), K2CO3 (53 mg, 0.39 mmol), and 18-crown-6 (3 mg, 0.01 mmol) in DMSO (2 mL) was heated for 16 hours at 140° Celsius. The reaction was then cooled to room temperature, filtered, and the filtrate directly subjected to HPLC purification to give 4-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-6-methylpyrimidin-2-amine (12 mg, 16%). MS (ESI): mass calcd. for C19H19FN6O, 366.16; m/z found, 367.3 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.27-8.22 (m, 1H), 8.11 (d, J=1.5, 1H), 7.78 (m, 1H), 7.29 (d, J=8.3, 1H), 6.67 (d, J=0.8, 1H), 3.68-3.55 (m, 1H), 2.51 (d, J=0.7, 3H), 2.31-2.13 (m, 4H), 2.11-1.98 (m, 1H), 1.91-1.81 (m, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH:17]=[C:16]([C:18]([OH:20])=O)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:21]3[CH:26]=[C:25]([C:27](=[O:32])[NH:28][CH:29]4[CH2:31][CH2:30]4)[CH:24]=[CH:23][C:22]=3[CH3:33])[CH:14]=2)[C:9]1=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][N:36]([CH3:40])[CH2:37][CH2:38][NH2:39].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[CH2:1]([N:8]1[CH:17]=[C:16]([C:18]([NH:39][CH2:38][CH2:37][N:36]([CH3:40])[CH3:35])=[O:20])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:21]3[CH:26]=[C:25]([C:27](=[O:32])[NH:28][CH:29]4[CH2:31][CH2:30]4)[CH:24]=[CH:23][C:22]=3[CH3:33])[CH:14]=2)[C:9]1=[O:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CCN
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccccc3)cc(C(=O)O)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccccc3)cc(C(=O)NCCN(C)C)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of the product of step iii) (0.48 g) and N,N-dimethylethane-1,2-diamine (0.17 mL) in THF (20 mL) was added N,N-diisopropylethylamine (0.56 mL) followed by HATU (0.60 g) and the reaction stirred at room temperature for 3 hours. The reaction mixture was concentrated to dryness and the crude product purified by SiO2 chromatography (eluting with 90:10:0.1 dichloromethane:methanol:triethylamine). The fractions containing product were concentrated to dryness and the residue triturated with acetonitrile to give the title compound as a solid (0.35 g).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].Br[CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[B:23]1[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH:4][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[B:23]1[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]1
Reactant: CC1(C)OB(c2c(CBr)ccc3ccccc23)OC1(C)C
Reactant: Cc1cc(C)c(N)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(NCc2ccc3ccccc3c2B2OC(C)(C)C(C)(C)O2)c(C)c1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A mixture of 29.2 g (216 mmol) of 2,4,6-trimethylaniline, 50.0 g (144 mmol) of 2-[2-(bromomethyl)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and 22.0 g (159 mmol) of K2CO3 in 1100 cm3 of DMF was stirred for 12 h at 80° C. The resulting mixture was poured into 2000 cm3 of water. The product was extracted with 3×400 ml of ethyl acetate. The combined extract was dried over MgSO4 and then evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 um; eluent: dichloromethane). Yield 45.0 g (78%). Anal. calc. for C26H32BNO2: C, 77.81; H, 8.04; N, 3.49. Found: C, 78.00; H, 8.24; N, 3.26. 1H NMR (CDCl3): δ 8.27 (m, 1H, 8-H in naphthyl), 7.84 (m, 1H, 5-H in naphthyl), 7.81 (d, J=8.3 Hz, 1H, 4-H in naphthyl), 7.54 (m, 1H, 7-H in naphthyl), 7.48 (m, 1H, 6-H in naphthyl), 7.37 (d, J=8.3 Hz, 1H, 3-H in naphthyl), 6.87 (s, 2H, 3, 5-H in mesityl), 4.39 (s, 2H, CH2N), 3.68 (br.s, 1H, NH), 2.31 (s, 6H, 2, 6-Me in mesityl), 2.30 (s, 3H, 4-Me in mesityl), 1.49 (s, 12H, Me in tetramethyldioxaborolane).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:18])[CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[CH:12]=[CH:11]2)[CH2:2][CH2:3][CH3:4].Br[CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[O:31][CH3:32]>CN(C)C=O>[CH2:1]([NH:5][C:6]([CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[CH:12]=[C:11]2[CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[O:31][CH3:32])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)Cc1ccc2c(ccn2C)c1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Solvent: CN(C)C=O
Product: CCCCNC(=O)Cc1ccc2c(c1)c(Cc1ccc(C(=O)OC)cc1OC)cn2C
Reaction time: 18 h
Yield: 28.9 %

Procedure:
A solution of N-butyl-1-methylindole-5-acetamide (0.46 g) and methyl 4-bromomethyl-3-methoxybenzoate (0.49 g) in dimethylformamide (10 ml) was heated at 80° under a nitrogen atmosphere for 18 hr. Additional methyl 4-bromomethyl-3-methoxybenzoate (0.49 g) was added to the reaction and stirring was continued for 18 hr at 80°. The dimethylformamide was evaporated: and the oily residue was purified by flash chromatography, eluting with 1:1 ethyl acetate:hexane to give methyl 4-(5-butylcarbamoylmethyl-1-methylindol-3-ylmethyl)-3-methoxybenzoate (0.23 g, 30%) as a white solid; NMR (250 MHz, CDCl3): 0.84(t, 3H, N(CH2)CH3), 1.35-1.16(m, 4H, NCH2 (CH2)2), 3.13(q, 2H, NCH2), 3.65(s, 2H, ArCH2CO), 3.75(s, 3H, NCH3), 3.90(s, 3H, OCH3), 3.94(s, 3H, OCH3), 4.09(s, 2H, ArCH2Ar'), 5.34(br, 1H, NH).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.I[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([C:18]2[C:19]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:15]=[CH:16][CH:17]=2)[CH:7]=1
Reactant: Cc1ccc(=O)[nH]c1
Reactant: Ic1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Product: Cc1ccc(=O)n(-c2cccc3ccccc23)c1
Yield: 68 %

Procedure:
5-Methyl-1-(1-naphthyl)-2-(1H)-pyridone is prepared by the reaction of 5-methyl-2 -(1H)-pyridone and α-iodonaphthalene following the procedure of Example 1 but substituting anhydrous sodium carbonate for the potassium carbonate; yield 68%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[C@H:9]([CH3:16])[CH2:8][NH:7][C:6]=2[CH:17]=1.I[C:19]1[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O.C(OCC)(=O)C.[Cu]I>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[C@H:9]([CH3:16])[CH2:8][N:7]([C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)[C:6]=2[CH:17]=1
Reactant: Cc1nnc2n1-c1ccc(Br)cc1NC[C@H]2C
Reactant: Cn1cc(I)cn1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1nnc2n1-c1ccc(Br)cc1N(c1cnn(C)c1)C[C@H]2C
Temperature: 150 °C

Procedure:
A mixture of (R)-8-bromo-1,4-dimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (292 mg, 1 mmol), 4-iodo-1-methyl-1H-pyrazole (312 mg, 1.5 mmol), copper (I) iodide (58 mg, 0.3 mmol), 1,10-phenanthroline (54 mg, 0.3 mmol) and potassium phosphate (424 mg, 2 mmol) in dimethyl sulfoxide (10 mL) was heated at 150° C. for 14 hours under nitrogen. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with brine (20 mL×3). The organic phase was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated to give (R)-8-bromo-1,4-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine which was used in the next step without further purification. LRMS (M+H)+: calcd 372.07. found 372.
Reaction SMILES: [CH2:1]([N:13]1[C:17](=[O:18])[C:16]2([CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]2)[NH:15][C:14]1=[O:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[O:29]1[CH2:40][CH:30]1[CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH:37]1[O:39][CH2:38]1>C(O)CCCCCCC.C(OCC)(=O)C>[CH2:1]([N:13]1[C:17](=[O:18])[C:16]2([CH2:19][C:20]([CH3:27])([CH3:26])[N:21]([CH2:38][CH:37]([OH:39])[CH2:36][O:35][CH2:34][CH2:33][O:32][CH2:31][CH:30]([OH:29])[CH2:40][N:21]3[C:22]([CH3:25])([CH3:24])[CH2:23][C:16]4([NH:15][C:14](=[O:28])[N:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:17]4=[O:18])[CH2:19][C:20]3([CH3:26])[CH3:27])[C:22]([CH3:25])([CH3:24])[CH2:23]2)[NH:15][C:14]1=[O:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN1C(=O)NC2(CC(C)(C)NC(C)(C)C2)C1=O
Reactant: C(COCC1CO1)OCC1CO1
Solvent: CCOC(C)=O
Solvent: CCCCCCCCO
Product: CCCCCCCCCCCCN1C(=O)NC2(CC(C)(C)N(CC(O)COCCOCC(O)CN3C(C)(C)CC4(CC3(C)C)NC(=O)N(CCCCCCCCCCCC)C4=O)C(C)(C)C2)C1=O
Temperature: 180 °C

Procedure:
A mixture of 8.6 g of 3-dodecyl-7,7,9,9-tetramethyl-1,3,8-triazaspiro[4.5]decane-2,4-dione and 1.7 g of ethylene glycol bis(2,3-epoxypropyl)ether in 3 ml of octanol was heated to 180° C. for 30 hours. After completion of the reaction, the reaction mixture was dissolved in ethyl acetate and subjected to column chromatography through alumina eluted successively first with diethyl ether, second with a 10:1 by volume mixture of ethyl acetate and triethylamine, and lastly with methanol. The eluate eluted with the last solvent was separated and the solvent was removed therefrom by evaporation under reduced pressure, giving the desired Compound No. 355 in the form of white crystals melting at 74°-76° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]([CH3:22])=[N:20][N:21]=2)=[CH:13][C:12]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][CH:24]=1.[CH2:32]([N:34]([CH2:39][CH3:40])[CH2:35][CH2:36][CH2:37][NH2:38])[CH3:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:32]([N:34]([CH2:39][CH3:40])[CH2:35][CH2:36][CH2:37][NH:38][C:29]([C:26]1[CH:25]=[CH:24][C:23]([C:12]2[CH:13]=[C:14]([C:17]3[O:18][C:19]([CH3:22])=[N:20][N:21]=3)[CH:15]=[CH:16][C:11]=2[CH3:10])=[CH:28][CH:27]=1)=[O:30])[CH3:33]
Reactant: CCN(CC)CCCN
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CC)CCCNC(=O)c1ccc(-c2cc(-c3nnc(C)o3)ccc2C)cc1
Temperature: 25 °C
Reaction time: 66 h
Yield: 63.7 %

Procedure:
DIPEA (130 μl, 1.0 mmol) was added to a solution of 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (100 mg, 0.34 mmol), 3-diethylaminopropylamine (49 mg, 0.37 mmol), HBTU (155 mg, 0.41 mmol) and HOBT (46 mg, 0.34 mmol) in DMF (1.0 ml). The reaction was stirred at room temperature for 66 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (5 ml) and water (5 ml) The organic phase was absorbed onto a silica flash column and eluted with DCM/ethanol/ammonia (100:8:1). The product fractions were concentrated under vacuum to give N-[3-(diethylamino)propyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide (88 mg, 64%).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[N:16]1([C:24]([O:26][CH2:27][CH:28]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]3[C:29]2=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:25])[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=O.Cl.[NH2:42][C@@H:43]([C:45]([NH2:47])=[O:46])[CH3:44].C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[N:16]1([C:24]([O:26][CH2:27][CH:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:35]3[C:40]2=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:25])[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([NH:42][C@@H:43]([C:45]([NH2:47])=[O:46])[CH3:44])=[O:20]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: C[C@@H](N)C(N)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21)C(N)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3.36 g of DCC are added to a stirred solution of 5.4 g (16 mmol) of Fmoc-Pro-OH, 2 g of HCl.H-D-Ala-NH2 and 2.24 g of HOBt in 30 ml of dimethylformamide at 0° C. The mixture is left to stir at 0° C. for 1 hour and to stand at room temperature overnight. The precipitate is filtered off with suction and the filtrate is concentrated. The residue is dissolved in ethyl acetate and extracted by shaking successively with water, twice with saturated NaHCO3 solution, water, KHSO4 buffer and water. Fmoc-Pro-D-Ala-NH2 precipitates in the ethyl acetate phase during this and is filtered off with suction. The ethyl acetate mother liquor is concentrated and triturated with diethyl ether and filtered with suction.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:5]2[N:6]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][O:12]3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: C1=COCCC1
Reactant: Fc1cc(Br)cc2nc[nH]c12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: Fc1cc(Br)cc2ncn(C3CCCCO3)c12
Temperature: 80 °C
Reaction time: 8 h
Yield: 64.2 %

Procedure:
To a solution of 5-bromo-7-fluoro-1H-benzo[d]imidazole (650 mg, 3.02 mmol, CASRN 1197944-33-2) and 3,4-dihydro-2H-pyran (1.27 g, 15.12 mmol) in THF (10 mL) was added p-TsOH.H2O (58 mg, 0.30 mmol). The reaction was stirred at 80° C. overnight, cooled and the solvent removed in vacuo. The residue was diluted with DCM (100 mL) and water (50 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with a petroleum ether/EtOAc gradient (10 to 50% EtOAc)) to afford 580 mg (64%) of 5-bromo-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole (266) as yellow solid: MS (ESI) m/z=299.1 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([OH:15])=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1.[ClH:17].[N:18]1([CH2:24][CH2:25][Cl:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[ClH:26].[ClH:17].[N:18]1([CH2:24][CH2:25][O:1][C:2]2[CH:14]=[CH:13][C:12]3[C:11]4[C:6](=[CH:7][C:8]([O:15][CH2:25][CH2:24][N:18]5[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]5)=[CH:9][CH:10]=4)[C:5](=[O:16])[C:4]=3[CH:3]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: ClCCN1CCCCC1
Reactant: O=C1c2cc(O)ccc2-c2ccc(O)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1c2cc(OCCN3CCCCC3)ccc2-c2ccc(OCCN3CCCCC3)cc21

Procedure:
A mixture of 5.3 g (0.025 mole) of 2,7-dihydroxyfluoren-9-one in 100 ml of toluene, 16.2 g (0.088 mole) of 2-piperidinoethylchloride hydrochloride and 5.0 g (0.125 mole) of sodium hydroxide in 40 ml of water is heated at reflux for 15 hours with stirring. Upon cooling, the layers are separated. The toluene layer is washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The filtrate is acidified to Congo Red with ethereal HCl, and the resulting precipitate is collected, washed with ether and recrystallized from butanone-methanol to give 2,7-bis(2-piperidinoethoxy)fluoren-9-one dihydrochloride, M.P. 304°-306° C.
Reaction SMILES: [C:1]([NH:11][C@@H:12]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C@H:13]([OH:31])[CH2:14][N:15]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:16](=[O:23])[C:17](=[N+:21]=[N-:22])C(=O)C)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[Li+].[OH-]>C1COCC1.O.O.ClCCl>[C:1]([NH:11][C@@H:12]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C@H:13]([OH:31])[CH2:14][N:15]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:16](=[O:23])[CH:17]=[N+:21]=[N-:22])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC(=O)C(=[N+]=[N-])C(=O)N(Cc1ccccc1)C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: [N-]=[N+]=CC(=O)N(Cc1ccccc1)C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 5 h
Yield: 81 %

Procedure:
The diazo ketamide (XII) (0.020 g, 0.038 mmol) was dissolved in 0.5 ml of 1:1 THF/H2O and to this LiOH (5 mg, 0.19 mmol) dissolved in 0.2 ml of water was added. The reaction mixture was stirred for 5 hrs and diluted with 2 ml of dichloromethane. The organic layer was separated, dried (Na2SO4), and concentrated. The product (XIII) was then isolated by passing through a plug of silica as an oil. 0.015 g. (81% yield). 1H NMR (500 MHz, CDCl3) δ 7.13-7.49 (m, 15H), 5.02-5.37 (m, 3H), 4.46-4.87 (m, 2H), 3.75-4.04 (m, 2H), 3.28-3.47 (m, 1H), 2.75-2.94 (m, 2H). 13CNMR (125 MHz, CDCl3) 163.4, 155.85, 140.91, 140.36, 139.22, 129.14, 128.68, 128.26, 128.17, 128.10, 127.72, 127.41, 127.64, 126.75, 78.33, 60.18, 52.04, 50.15, 46.89, 44.7, 36.43.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:12][CH2:13][CH2:14][CH3:15])[O:7][C:8]2=[O:9])=[CH:4][CH:3]=1.[C:16]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17]1>C(O)C.[Pd]>[CH2:12]([CH:6]1[C:5]2[C:10](=[CH:11][C:2]([NH:1][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:3][CH:4]=2)[C:8](=[O:9])[O:7]1)[CH2:13][CH2:14][CH3:15]
Reactant: O=C1CCCC1
Reactant: CCCCC1OC(=O)c2cc(N)ccc21
Agent: [Pd]
Solvent: CCO
Product: CCCCC1OC(=O)c2cc(NC3CCCC3)ccc21

Procedure:
Analogously to the method described in Example 14, 4.1 g (20.0 mmol) of compound obtained in Example 4 in 5 ml of cyclopentanone and 150 ml of 95% ethanol are added to 10% Pd—C catalyst and hydrogenated to give the title compound.
Reaction SMILES: [C:1]12([C:11]3[CH:22]=[CH:21][C:14]([O:15][CH2:16][CH2:17][C:18](O)=[O:19])=[C:13]([CH3:23])[CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[C:1]12([C:11]3[CH:22]=[CH:21][C:14]([O:15][CH2:16][CH2:17][C:18]([N:28]4[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]4)=[O:19])=[C:13]([CH3:23])[CH:12]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: Cc1cc(C23CC4CC(CC(C4)C2)C3)ccc1OCCC(=O)O
Reactant: CN1CCNCC1
Product: Cc1cc(C23CC4CC(CC(C4)C2)C3)ccc1OCCC(=O)N1CCN(C)CC1
Yield: 94.5 %

Procedure:
The title compound was prepared from 3-(4-(adamantan-1-yl)-2-methylphenoxy)propanoic acid (0.2 g, 0.63 mmol) and 1-methylpiperazine (0.063 g, 0.63 mmol) according to the example 1, which was given 3-(4-(adamantan-1-yl)-2-methylphenoxy)-1-(4-methylpiperazin-1-yl)propan-1-one as a white solid (0.236 g, 93.6% yield).
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8](Cl)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[NH4+:12]>>[CH:1]1([CH2:6][CH2:7][C:8]#[N:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [NH4+]
Reactant: O=C(Cl)CCC1CCCC1
Agent: [OH-]
Product: N#CCCC1CCCC1
Reaction time: 8 h

Procedure:
3-Cyclopentylpropionitrile is prepared in this example. 3-Cyclopentylpropionyl chloride (57.7 g, 0.36 mole) is added dropwise to a large excess of concentrated ammonium hydroxide (400 ml) cooled in an ice/salt bath. The heavy suspension of white solid is stirred overnight, collected by filtration, washed with cold water, and recrystallized from about 2 liters of boiling water. The lustrous white plates of the amide are dried in vacuo over P2O5 ; yield 31.6 g (62.3%); mp 122° C.