Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[CH2:25]N)=[CH:4][CH:3]=1.[C:27]([BH3-])#[N:28].[Na+]>CO.C1(=O)CCCCC1.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[CH2:25][NH:28][CH:27]2[CH2:6][CH2:7][CH2:2][CH2:3][CH2:4]2)=[CH:6][CH:7]=1
Reactant: NCc1ncnc2c1nc(-c1ccc(Cl)cc1Cl)n2-c1ccc(Cl)cc1
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O=C1CCCCC1
Product: Clc1ccc(-n2c(-c3ccc(Cl)cc3Cl)nc3c(CNC4CCCCC4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
C-[9-(4-Chlorophenyl)-8-(2,4-dichlorophenyl)-9H-purin-6-yl]-methylamine I-(16A-1)b (19 mg, 0.047 mmol) was dissolved in methanol (1 ml) and to it was added cyclohexanone (1 drop) and acetic acid (1 drop). The reaction mixture was stirred at room temperature for 0.5 hour. and then sodium cyanoborohydride was added (5 mg) and the stirring continued until the reaction was complete (2 hours). The reaction mixture was concentrated and the residue diluted with saturated NaHCO3 solution and extracted into ethyl acetate. The organic layers were combined, dried (Na2SO4), filtered, and 5% methanol in ethyl acetate as the solvent to give title compound 16A-1. The residue was dissolved in methylene chloride and treated with 2M HCl/ether to form the desired HCl salt. Ether was added to the reaction mixture to precipitate the product. The excess ether was decanted and the crystals pumped to dryness on high vacuum to afford the hydrochloride salt of compound 16A-1 (6.8 mg, 30%): +ESI MS (M+1) 486.6; 1H NMR (500 MHz, CD3OD) δ 9.07 (s, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.64 (d, J=2.1 Hz, 1H), 7.56 (dd, J=8.8, 2.1 Hz, 1H), 7.52 (d, J=8.8 Hz, 2H), 7.40 (d, J=8.8 Hz, 2H), 4.94 (s, 2H), 3.35 (m 1H), 2.28 (br d, J=12.4 Hz, 2H), 1.96 (br d, J=13.5 Hz, 2H), 1.78 (br d, J=13.0 Hz, 1H), 1.60–1.20 (m, 5H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[NH:17][N:18]=[CH:19][CH:20]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[N:17]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1cccnc1
Reactant: Fc1ccc(CBr)cc1
Product: Cc1nc(-c2ccn(Cc3ccc(F)cc3)n2)sc1C(=O)NCc1cccnc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide and 1-bromomethyl-4-fluoro-benzene as described in Example 49 and isolated as a white solid (0.072 g, 51% yield). 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.54-8.57 (m, 2H), 7.71 (d, J=8 Hz, 1H), 7.38 (d, J=4 Hz, 1H), 7.21-7.32 (m, 3H), 7.02-7.06 (m, 2H), 6.84 (d, J=2 Hz, 1H), 6.12-6.15 (m, 1H), 5.31 (s, 2H), 4.63 (d, J=8 Hz, 2H), 2.75 (s, 3H); MS (M+H)+=408.3; Rt=1.22 min; HRMS (M+H)+=408.13.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][S:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C(O)(C(F)(F)F)=[O:28].FC(F)(F)C(OO)=O.OO.[OH-].[Na+]>C(Cl)Cl>[CH3:26][N:2]([CH3:1])[CH2:3][C:4]1([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:21][CH2:22][S:23](=[O:28])[CH2:24][CH2:25]3)=[CH:14][CH:15]=2)[CH2:5][CH2:6][O:7][CH2:8][CH2:9]1
Reactant: CN(C)CC1(c2ccc(OCCCN3CCSCC3)cc2)CCOCC1
Reactant: O=C(O)C(F)(F)F
Agent: O=C(OO)C(F)(F)F
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)CC1(c2ccc(OCCCN3CCS(=O)CC3)cc2)CCOCC1
Temperature: 2.5 °C
Reaction time: 6 h
Yield: 61 %

Procedure:
Dimethyl-{4-[4-(3-thiomorpholin-4-ylpropoxy)phenyl]tetrahydro-pyran-4-ylmethyl}amine (300 mg, 0.792 mmol) and TFA (0.99 ml) were cooled to 0 to 5° C. and trifluoro-peracetic acid (4M, 0.77 ml) [4M solution prepared by the addition of 27.5% H2O2 (0.94 ml) to TFA (1.56 ml)] was added and the reaction stirred for six hours at 0 to 5° C. The mixture was diluted with DCM (6 ml), basified with NaOH (2M, 8 ml) and extracted with DCM (2×20 ml). The DCM extracts were dried over MgSO4, filtered and concentrated in vacuo at 35° C. Purification by chromatography on silica, eluant DCM:MeOH:NH3 (96:4:1) provided the title compound (200 mg, 61%) as a white solid. 1H NMR (400 MHz, CDCl3) δ7.21 (d, 2H), 6.86 (d, 2H), 4.01 (t, 2H), 3.75 (dt, 2H), 3.55 (td, 2H), 3.15-3.02 (m, 2H), 2.93-2.79 (m, 4H), 2.72 (dt, 2H), 2.64 (t, 2H), 2.40 (s, 2H), 2.16-1.82 (m, 6H), 1.97 (s, 6H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]2[O:13]CCO[CH2:9]2)[CH:5]=[CH:4][N:3]=1.[CH2:14]([NH2:16])[CH3:15]>CN1CCCC1=O>[CH2:14]([NH:16][C:2]1[CH:7]=[C:6]([C:8](=[O:13])[CH3:9])[CH:5]=[CH:4][N:3]=1)[CH3:15]
Reactant: CCN
Reactant: Clc1cc(C2COCCO2)ccn1
Solvent: CN1CCCC1=O
Product: CCNc1cc(C(C)=O)ccn1
Temperature: 165 °C

Procedure:
A mixture of 18.8 g. (94 mmoles) of 1-(2-chloro-4-pyridyl)-1-ethylenedioxyethane and 50 ml. of ethylamine in 80 ml. of N-methyl-2-pyrrolidinone was sealed in a steel bomb and heated at 165° C. for 15 hours. The bomb was cooled and the contents distilled under reduced pressure to remove excess solvent. The residue in 100 ml. of methylene chloride was extracted with 2 N hydrochloric acid (3×25 ml.). The combined acid extracts were heated at 80° C. for 3 hours and were then cooled and made basic with sodium carbonate. The basified mixture was extracted with methylene chloride (4×25 ml.), and the combined organic extracts dried over sodium sulfate and evaporated to an oil which solidified, 11.5 g. (75%), m.p. 55°-57° C. The analytical sample was recrystallized from cyclohexane, m.p. 62°-63° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1.[C:26](Cl)(=[O:29])[CH2:27][CH3:28]>>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([NH:1][C:26](=[O:29])[CH2:27][CH3:28])=[C:3]([C:17](=[O:25])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[N:4]2[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:8]=1
Reactant: CCC(=O)Cl
Reactant: CCOC(=O)n1c(C(=O)c2cccc(Cl)c2)c(N)c2ccc(Cl)cc21
Product: CCOC(=O)n1c(C(=O)c2cccc(Cl)c2)c(NC(=O)CC)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 2 (Method A) from 3-amino-6-chloro-2-(3-chlorobenzoyl)-1-(ethoxycarbonyl)indole (step 1 of Example 30) and propionyl chloride.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[C:11]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:19][C:20]([C:22]2[O:23][C:24]([C:27]#[N:28])=[CH:25][CH:26]=2)=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:29][OH:30]>CCO>[N:1]1([C:7]2[CH:12]=[C:11]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:19][C:20]([C:22]2[O:23][C:24]([C:27](=[NH:28])[NH:29][OH:30])=[CH:25][CH:26]=2)=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: N#Cc1ccc(C(=O)Nc2ccc(N3CCCCC3)cc2N2CCCCC2)o1
Solvent: CCO
Product: N=C(NO)c1ccc(C(=O)Nc2ccc(N3CCCCC3)cc2N2CCCCC2)o1
Temperature: 0 °C
Yield: 23 %

Procedure:
To a solution of 5-cyano-furan-2-carboxylic acid (2,4-di-piperidin-1-yl-phenyl)-amide (48 mg, 0.12 mmol, as prepared in the previous step) in 1 mL of EtOH at room temperature was added NH2OH (26 mg, 0.4 mmol, 50% wt/H2O) via syringe. The reaction was heated to reflux for 10 min, and then cooled to 0° C. The bright yellow precipitate was filtered, washed with cold 50% EtOH—H2O (2 mL) and dried to afford 11 mg (23%) of the title compound as a bright yellow solid. 1H-NMR (DMSO-d6; 400 MHz): δ 9.83 (s, 1H), 9.37 (s, 1H), 7.84 (d, 1H, J=9.0 Hz), 7.21 (d, 1H, J=3.5 Hz), 6.89 (d, 1H, J=3.6 Hz), 6.74 (s, 1H), 6.66 (d, 1H, J=8.8 Hz), 5.96 (br s, 2H), 3.08-3.10 (m, 4H), 2.78-2.77 (m, 4H), 1.71-1.52 (m, 12H); Mass spectrum (ESI, m/z): Calcd. for C22H29N5O3 412.2 (M+H), found 412.2;
Reaction SMILES: [C:1]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].O.NN.C(O)COCCO.[OH-].[K+]>O>[CH2:1]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)c1cccs1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: CCCCCCCCCCCCc1cccs1
Temperature: 50 °C
Yield: 66.5 %

Procedure:
In a 5 liter-five-necked flask, 266 g (1.0 mol) of 2-dodecanoylthiophene, 392.4 ml of 60% hydrazine hydrate and 3 liter of diethyleneglycol were placed and reacted for 6 hours at 195° C. with distilling-off of excessive water and hydrazine hydrate. The mixture was cooled to 50° C. and 210.6 g of KOH was added thereto, followed by heating again to react for 2.5 hours at 155° C. After the reaction, the reaction mixture was poured into 10 liter of water, extracted two times with 2 liter of isopropyl ether, followed by drying with CaCl2 and distilling-off of the solvent to obtain 229 g of a crude product. The crude product was subjected to reduced-pressure distillation in an atmosphere of nitrogen to obtain 168 g of a pure product (yield: 66.7%). b.p.: 121.5° C./0.7 mmHg
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[C:5]1[N:6]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[C:7]2[C:12]([N:13]=1)=[C:11]([NH2:14])[N:10]=[C:9]([NH:15][C@H:16]([CH3:20])[CH2:17][CH2:18][CH3:19])[N:8]=2>CO>[CH3:20][C@@H:16]([NH:15][C:9]1[N:8]=[C:7]2[C:12]([N:13]=[C:5]([O:2][CH3:1])[N:6]2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)=[C:11]([NH2:14])[N:10]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCC[C@@H](C)Nc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCC[C@@H](C)Nc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of sodium methoxide in methanol (0.5M, 9 ml, 4.5 mmol) was added to a solution of 8-bromo-N2-[(1R)-1-methylbutyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-2,6-diamine (0.844 g, 2.20 mmol) in methanol (12 ml) and the resulting solution heated under reflux for 23.5 hours. More sodium methoxide in methanol (0.5M, 4.5 ml) was then added and refluxing continued for a further 4 hours. More sodium methoxide in methanol (0.5M, 4.5 ml) was again added and refluxing continued for a further 16.5 hours when LCMS indicated reaction to be complete. The reaction mixture was cooled to room temperature, evaporated and the residue partitioned between ethyl acetate (75 ml) and water (75 ml). The aqueous phase was re-extracted with ethyl acetate (75 ml) and the combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulphate, filtered and evaporated. The residue was dissolved in dichloromethane and purified on a 100 g aminopropyl (NH2) cartridge using a 0-100% ethyl acetate in cyclohexane gradient followed by a 0-20% methanol (+1% triethylamine) gradient over 15 mins. Product-containing fractions were combined and evaporated in vacuo to give the title compound as a white foam (0.614 g).
Reaction SMILES: [C:1]([N:4]1[CH2:23][CH2:22][CH2:21][C@H:5]1[C:6]([NH:8][C@H:9]([C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=O)=[O:12])[CH3:10])=[O:7])(=[O:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:39]([O:41][C:42](=[O:56])[C:43]([C:51](=[O:55])[CH:52]([CH3:54])[OH:53])([CH2:45][C:46](=[O:50])[N:47]([CH3:49])[NH2:48])[OH:44])[CH3:40]>C(#N)C>[CH2:39]([O:41][C:42](=[O:56])[C:43]([C:51](=[O:55])[CH:52]([CH3:54])[OH:53])([CH2:45][C:46](=[O:50])[N:47]([CH3:49])[NH:48][C:15](=[O:17])[C@@H:14]1[CH2:18][CH2:19][CH2:20][N:13]1[C:11](=[O:12])[C@H:9]([CH3:10])[NH:8][C:6](=[O:7])[C@@H:5]1[CH2:21][CH2:22][CH2:23][N:4]1[C:1](=[O:3])[CH3:2])[OH:44])[CH3:40]
Reactant: CC(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CCOC(=O)C(O)(CC(=O)N(C)N)C(=O)C(C)O
Agent: CC(C)COC(=O)Cl
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CCOC(=O)C(O)(CC(=O)N(C)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(C)=O)C(=O)C(C)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 0.00185 moles of acetylprolylalanylproline and 0.20 ml of N-methylmorpholine in 20 ml of acetonitrile is cooled to -20° by means of a Dry Ice acetone bath. To this is added 0.28 ml of isobutyl chloroformate. After stirring for 10 minutes at -20° there is added 0.00185 moles of 2-azaalanyllactyllactic acid ethyl ester in 5 ml of acetonitrile. The reaction mixture is allowed to warm to room temperature after which it is stirred for 2 hours and then concentrated in vacuo. The residue is extracted between 50 ml of methylene chloride and 20 ml of cold 0.25 N hydrochloric acid. The acid layer is backwashed 2 times with 25 ml of methylene chloride. The organic extracts are combined, dried over sodium sulfate and concentrated in vacuo to give a glass. This residue is chromatographed on 75 gm of silica gel. Elution with methanol/methylene chloride (1-4%) gives pure acetylprolylalanylprolyl-2-azaalanyllactyllactic acid ethyl ester.
Reaction SMILES: CN(C=O)C.CC#N.C(Cl)(=O)C(Cl)=O.[NH:15]1[C:19]([C:20]([O-:22])=O)=[N:18][N:17]=[N:16]1.[K+].[K+].N1C(C([O-])=O)=NN=N1.[CH2:33]([O:35][C:36](=[O:57])[C@H:37]([OH:56])[CH2:38][N:39]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[C:52]([Cl:54])[CH:51]=[CH:50][C:49]=2[F:55])=[CH:44][CH:43]=1)[NH2:40])[CH3:34].N1C=CC=CC=1>>[CH2:33]([O:35][C:36](=[O:57])[C@H:37]([OH:56])[CH2:38][N:39]([CH2:41][C:42]1[CH:43]=[CH:44][C:45]([C:48]2[CH:53]=[C:52]([Cl:54])[CH:51]=[CH:50][C:49]=2[F:55])=[CH:46][CH:47]=1)[NH:40][C:20]([C:19]1[NH:18][N:17]=[N:16][N:15]=1)=[O:22])[CH3:34]
Reactant: CCOC(=O)[C@H](O)CN(N)Cc1ccc(-c2cc(Cl)ccc2F)cc1
Reactant: O=C([O-])c1nnn[nH]1
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCOC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1nnn[nH]1
Reaction time: 0.17 h
Yield: 75.6 %

Procedure:
To a stirred solution of DMF (734 μL, 9.5 mmol) in MeCN (2 mL, 50 mmol) at 0° C., was slowly added a solution of oxalyl chloride (257 μL, 3.0 mmol) in MeCN (500 μL, 9 mmol). After 10 minutes, dipotassium 1H-tetrazole-5-carboxylate (249 mg, 1.3 mmol) was added and after stirring for a further 15 minutes, was added to a solution of (R)-3-[N-(5′-chloro-2′-fluoro-biphenyl-4-ylmethyl)-hydrazino]-2-hydroxy-propionic acid ethyl ester (300 mg, 0.8 mmol) in MeCN (2 mL, 40 mmol) and pyridine (661 μL, 8.2 mmol). The mixture was stirred at 0° C. for 10 minutes then evaporated under reduced pressure and purified (Interchim reverse phase chromatography column; elute from 55-75%, both peaks coeluted together) to yield the title compound (280 mg). A portion (80 mg) was further purified by preparative HPLC to yield the title compound as a TFA salt (33 mg; purity 98%). MS m/z [M+H]+ calc'd for C20H20ClFN6O4, 463.12. found 463.4.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11](=O)[C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH:15]=[C:14]([F:25])[CH:13]=1>C1COCC1>[F:1][C:2]1[C:3]([NH:10][CH2:11][C:12]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[CH:15]=[C:14]([F:25])[CH:13]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: O=C(Nc1c(F)ccc(O)c1F)c1cc(F)cc(-c2cccc(F)c2)c1
Solvent: C1CCOC1
Product: Oc1ccc(F)c(NCc2cc(F)cc(-c3cccc(F)c3)c2)c1F
Temperature: 60 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
To a solution of N-(2,6-difluoro-3-hydroxy-phenyl)-3-fluoro-5-(3-fluorophenyl)benzamide (390 mg, 1.1 mmol, 1.0 eq) in THF (6 mL) at 0° C. was added a solution of BH3 (1M in THF, 6.47 mL, 6.5 mmol, 6.0 eq). The reaction was heated to 60° C. and stirred overnight. The reaction mixture was quenched with water and extracted with EtOAc. The organic extract was washed with 5% NaHCO3, water and brine, dried (Na2SO4) and the solvent removed in vacuo to afford a crude residue which was purified by column chromatography (petroleum ether:EtOAc 1:0 to 10:1) to give the title compound as an oil (353 mg, 94%).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[S:36])=[CH:30][CH:29]=1>C(#N)C>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:35]([NH:34][C:31]4[CH:30]=[CH:29][C:28]([C:27]([F:26])([F:37])[F:38])=[CH:33][CH:32]=4)=[S:36])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Reactant: FC(F)(F)c1ccc(N=C=S)cc1
Solvent: CC#N
Product: CN(C)CCN1C(=O)c2cccc3cc4cccc(NC(=S)Nc5ccc(C(F)(F)F)cc5)c4c(c23)C1=O
Temperature: 25 °C
Yield: 90.1 %

Procedure:
200 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.60 mmole) were dissolved in 10 ml of acetonitrile. 244 mg (2 molar equivalents) of 4-(trifluoromethyl)phenyl isothiocyanate was added and the reaction mixture was maintained at room temperature for 16 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography (SiO2, CH2Cl2/MeOH 95/5). 290 mg of the desired product (formula shown hereinabove) were isolated as a red powder (yield=90%) which was characterized as follows:
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Na].[C:13]1([C:19]2(S([O-])(=O)=O)[CH:24]=[CH:23][C:22]([CH3:25])=[C:21](CC3CCCCC3)[CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCO>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([CH2:25][CH:22]1[CH2:21][CH2:20][CH:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:24][CH2:23]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: CC1=C(CC2CCCCC2)CC(c2ccccc2)(S(=O)(=O)[O-])C=C1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CC1CCC(c2ccccc2)CC1)C(=O)OCC

Procedure:
Diethyl malonate (3.1 g, 19.7 mmol, 1.5 equiv) was added dropwise to a solution of sodium (1.25 g, 54.0 mmol, 4.0 equiv) in EtOH (50 mL). 4-Phenyl-cyclohexylmethyl-p-toluene sulfonate (˜13.1 mmol, ˜1.0 equiv, the crude product from the previous step) was added as a solution in 50 mL of EtOH. The resulting mixture was refluxed for 8 h. The reaction mixture was cooled and evaporated to dryness and then dissolved in water (150 mL) and the crude product extracted with 3×100 mL EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography on SiO2 using 10% EtOAc in hexanes to give the desired product as a colorless oil (2.79 g).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[C:15]([F:18])([F:17])[F:16])[CH2:3][CH2:2]1.[NH2:19][C@@H:20]([CH2:24][CH:25]1[CH2:27][CH2:26]1)[C:21]([NH2:23])=[O:22]>>[C:21]([C@@H:20]([NH:19][C:12]([C:10]1[CH:9]=[CH:8][C:7]([C:15]([F:18])([F:17])[F:16])=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[CH2:24][CH:25]1[CH2:27][CH2:26]1)(=[O:22])[NH2:23]
Reactant: NC(=O)[C@@H](N)CC1CC1
Reactant: O=C(O)c1ccc(C(F)(F)F)c(OCC2CC2)n1
Product: NC(=O)[C@H](CC1CC1)NC(=O)c1ccc(C(F)(F)F)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid and (S)-2-amino-3-cyclopropyl-propionamide (CAN 156077-93-9) as starting materials, MS (EI): m/e=372.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19](=[NH:22])[NH:20][OH:21])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=O)=[CH:27][CH:26]=1>>[CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]([C:19]3[N:22]=[C:32]([CH2:31][C:28]4[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=4)[O:21][N:20]=3)=[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[C:6]=2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c(NC3CCOCC3)c(C(=N)NO)cnc21
Reactant: COc1ccc(CC(=O)O)cc1
Product: CCn1ncc2c(NC3CCOCC3)c(-c3noc(Cc4ccc(OC)cc4)n3)cnc21

Procedure:
Prepared from Intermediate 138 and 4-methoxyphenylacetic acid using a similar process to that described for Example 189 using similar or the same number of moles of reagents and/or volumes of solvents. LCMS showed MH+=435; TRET=3.26 min
Reaction SMILES: C(O[C:4]([C:6]1([CH2:22][CH2:23]OC)[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH2:8][CH2:7]1)=[O:5])C.[Cl-].C[Al+]C.[CH2:30]([NH2:38])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1(C)C=CC=CC=1>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:38]([CH2:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:23][CH2:22]2)[CH2:11][CH2:10]1)(=[O:13])=[O:14]
Reactant: NCCc1ccccc1
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C1N(CCc2ccccc2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2

Procedure:
This material was prepared in analogy to example 1 step D) from 1-(2-chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester, dimethylaluminium chloride in toluene and phenethylamine. MS (ESI): 433.3 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:27]([O-])=O)[C:5]([NH:8][CH2:9][CH2:10][CH:11]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[N:6][CH:7]=1.[Cl-].[NH4+].C(O)C>[Fe].O1CCCC1>[NH2:27][C:4]1[C:5]([NH:8][CH2:9][CH2:10][CH:11]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: CC(C)(C)OC(=O)NC(CCNc1ncc(Br)cc1[N+](=O)[O-])C(=O)OC(C)(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(CCNc1ncc(Br)cc1N)C(=O)OC(C)(C)C

Procedure:
A suspension of 3.5 g of tert-butyl 4-[(5-bromo-3-nitropyridin-2-yl)amino]-2-tert-butoxycarbonylaminobutanoate, 1.23 g (22 mmol) of iron powder and 20 g (0.373 mol) of ammonium chloride in 40 ml of a 1:1 mixture of ethanol and tetrahydrofuran is heated at reflux for two hours. After this time the reaction mixture is filtered on a bed of celite, which is rinsed with 100 ml of ethanol. The filtrate is concentrated under reduced pressure and then the residue is taken up in 20 ml of water. The mixture is then extracted with three times 50 ml of ethyl acetate. The organic phases are combined, washed with 50 ml of a saturated aqueous sodium chloride solution, dried over sodium sulfate and then concentrated under reduced pressure. An oil is recovered which is purified by chromatography on a silica column, eluting with a mixture of dichloromethane and methanol. This gives 2.93 g of the expected product in the form of a solid, used as it is in the remainder of the synthesis.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:5]=[CH:6][CH:7]=1.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:31][CH:32]=[C:33]([CH2:35]Cl)[N:34]=2)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:31][CH:32]=[C:33]([CH2:35][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]4[CH:15]=[CH:14][N:13]=[CH:12]4)[CH:3]=3)[N:34]=2)=[CH:26][CH:25]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Oc1cccc(CCCn2ccnc2)c1
Reactant: ClCc1coc(-c2ccc(OCc3ccccc3)cc2)n1
Product: c1ccc(COc2ccc(-c3nc(COc4cccc(CCCn5ccnc5)c4)co3)cc2)cc1
Yield: 81 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(3-(3-hydroxyphenyl)propyl]imidazole was allowed to react with 2-(4-benzyloxyphenyl)-4-chloromethyloxazole to give 2-(4-benzyloxyphenyl)-4-[3-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 81%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 144-145° C.