Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:11]=[C:12]([NH2:17])[C:13]([NH2:16])=[CH:14][CH:15]=2)[CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1.C(O)(=O)C.O=[C:23]([CH2:27][CH2:28][CH3:29])[C:24](O)=[O:25].[OH-].[Na+]>O>[N:1]1([CH:6]([C:10]2[CH:11]=[C:12]3[C:13](=[CH:14][CH:15]=2)[NH:16][C:24](=[O:25])[C:23]([CH2:27][CH2:28][CH3:29])=[N:17]3)[CH:7]([CH3:8])[CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCCC(=O)C(=O)O
Reactant: CC(C)C(c1ccc(N)c(N)c1)n1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCCc1nc2cc(C(C(C)C)n3ccnc3)ccc2[nH]c1=O
Temperature: 0 °C

Procedure:
To a stirred and cooled (0° C.) mixture of 9 parts of 4-[1-(1H-imidazol-1-yl)-2-methylpropyl]-1,2-benzenediamine in 80 parts of acetic acid and 20 parts of water were added 5 parts of 2-oxopentanoic acid. The reaction mixture was stirred for 12 hours at room temperature. The whole was poured into ice water and neutralized with a sodium hydroxide solution 3N. The product was extracted three times with 130 parts of dichloromethane. The combined extracts were dried, filtered and evaporated. For obtaining 6-[1-(1H-imidazol-1yl)-2-methylpropyl]-3-propyl-2(1H)-quinoxalinone, the residue was purified by column chromatography (HPLC) over silica gel using a mixture of dichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-butanone and 1,1'-oxybisethane. The precipitated product was filtered off and stirred in cold 4-methyl-2-pentanone. After filtration, the product was recrystallized from a mixture of methanol and 2-propanone, yielding 1.6 parts (13.2%) of the above product; mp. 259.7° C. (comp. 100).
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([F:22])[CH:14]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CCO.CC(=O)OCC>[CH2:11]([O:10][C:8](=[O:9])[CH:7]([C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([F:22])[CH:14]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:12]
Reactant: CCOC(=O)C(c1ccccc1)c1ccc([N+](=O)[O-])c(F)c1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C(c1ccccc1)c1ccc(N)c(F)c1
Yield: 97.5 %

Procedure:
Ethyl 2-phenyl-2-(3-fluoro-4-nitrophenyl)acetate was dissolved in a 1:1 mixture of EtOH and EA (465 mL) and hydrogenation was carried out in an H-cube (1 bar, 25° C., 1 mL/min and 0.25 mol/L). Following removal of the solvent and drying, 5.2 g (97.5%) of product were obtained.
Reaction SMILES: [CH:1]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]O)=[CH:17][CH:16]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.P(Br)(Br)[Br:30]>C1(C)C=CC=CC=1>[Br:30][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:16][CH:17]=1
Reactant: OCc1ccc(OC(c2ccccc2)c2ccccc2)cc1
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: BrCc1ccc(OC(c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(4-(Benzhydryloxy)phenyl)methanol (500 mg, 1.72 mmol) was dissolved in toluene (20 ml) and pyridine (139 uL, 1.72 mmol) was added. The solution was cooled to 0° C. PBr3 (163 uL, 1.72 mmol) was added dropwise over 15 min. The resulting mixture was stirred at room temperature for 1 h. It was then washed with saturated K2CO3 solution and extracted with EtOAc (3×30 mL). The EtOAc layer was washed with brine and dried (MgSO4). The solvent was evaporated off in-vacuo to obtain ((4-(bromomethyl)phenoxy)methylene)dibenzene as an oil, (450 mg, 74%). This intermediate was used in the following reaction.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:26].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>CN(C=O)C>[CH2:1]([O:3][CH:4]([C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:5][CH2:6][CH2:7][CH2:8][C:9]([OH:26])=[O:10])[CH3:2]
Reactant: CCCCCCCCCCCCC#CC(OCC)OCCCCO
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCC#CC(OCC)OCCCC(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.2 g of the product from example 22 in 15 ml of dry DMF was added in portions to a solution of pyridinium dichromate (4.4 g) in 30 ml of dry DMF. The solution was stirred at room temperature for 24 hours, then poured into water (300 ml). The aqueous mixture was extracted several times with Et2O, the combined extracts were washed with water and dried over Na2SO4. The reaction mixture was purified by column chromatography (SiO2) (1% MeOH/CHCl3). The partially purified product (0.54 g) was further purified by preparative thin layer chromatography (SiO2) (2%MeOH/CHCl3). Yield: 0.35 g.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:6]=[C:7](S(C)(=O)=O)[C:8]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][O:11][C:9]=2[N:10]=1)(=[O:4])=[O:3].[N:24]1([CH2:29][CH2:30][O:31][CH2:32][CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:28][CH2:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][S:2]([C:5]1[N:6]=[C:7]([N:36]2[CH2:37][CH2:38][CH:33]([CH2:32][O:31][CH2:30][CH2:29][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:34][CH2:35]2)[C:8]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][O:11][C:9]=2[N:10]=1)(=[O:4])=[O:3]
Reactant: C1CCN(CCOCC2CCNCC2)C1
Reactant: CS(=O)(=O)c1nc(S(C)(=O)=O)c2c(-c3ccccc3)coc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)c1nc(N2CCC(COCCN3CCCC3)CC2)c2c(-c3ccccc3)coc2n1
Temperature: 120 °C
Yield: 17.4 %

Procedure:
2,4-Bis(methylsulphonyl)-5-phenyl-furo[2,3-d]-pyrimidine (400 mg, 1.14 mmol) in acetonitrile (10.0 mL) was treated with 4-(2-pyrrolidine-1-ylethyloxymethyl)piperidine (360 mg, 1.7 mmol) and potassium carbonate (219 mg, 1.71 mmol) and heated in a microwave at 120° C. for 30 min. The reaction was concentrated in vacuum to a gum and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was separated, dried over sodium sulphate and concentrated in vacuum to a gum. The gum was purified by preparative HPLC (basic method 6) to yield methylsulfonyl-5-phenyl-4-[4-(2-pyrrolidin-1-ylethoxymethyl)-1-piperidyl]furo[2,3-d]pyrimidine (96 mg, 0.198 mmol, 17%). 1H NMR (CDCl3) δ: 1.07 (2H, m), 1.52 (2H, br d, J=8 Hz), 1.75 (5H, br s), 2.5 (4H, b s), 2.6 (2H, t, J=5 Hz), 2.8 (2H, t, J=8 Hz), 3.18 (2H, d, J=4 Hz), 3.35 (3H, s), 3.5 (2H, t, J=4 Hz), 4.05 (2H, d, J=8 Hz), 7.4 (5H, m), 7.6 (1H, s).
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH3:21][C:22]1[CH:23]=[C:24]([CH2:28][CH2:29][NH2:30])[CH:25]=[CH:26][CH:27]=1.C1COCC1.[BH3-]C#N.[Na+]>CO.Cl[Ti](Cl)(Cl)Cl>[C:22]1([CH3:21])[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][NH:30][CH:2]2[C:10]3[C:5](=[CH:6][C:7]([O:11][C:12]4[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=4)=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)[CH:23]=1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3=O)nc1
Reactant: Cc1cccc(CCN)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cccc(CCNC2CCc3cc(Oc4ccc(C(N)=O)cn4)ccc32)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 73 %

Procedure:
Add Ti(iPrO)4 (1.70 g, 6.00 mmol) to a suspension of 6-(1-oxo-indan-5-yloxy)-nicotinamide (Intermediate 4, 805 mg, 3.00 mmol), 2-(3-methylphenyl)ethylamine (446 mg, 3.30 mmol) and THF (20 ml) and stir for six hours under a nitrogen atmosphere at ambient temperature. After cooling in an ice/water bath, treat the reaction mixture with a solution of TiCl4 (1.0M/DCM, 6.00 ml, 6.00 mmol) and stir at 0-5° C. for two hours before adding NaBH3CN (377 mg, 6.00 mmol) dissolved in MeOH (5 ml). Allow the reaction mixture to warm to ambient temperature as the cold bath warms and stir overnight. Quench the reaction with 2N aq. NaOH, making the suspension basic. Stir the suspension for one hour and filter through a filter aid to remove solids, washing them with EtOAc. Separate layers in the filtrate/wash and wash the organic layer with brine before drying (MgSO4) and concentrating. Purify on silica gel (5% (1N NH3/MeOH)/45% EtOAc/DCM) to obtain 849 mg of the title compound as a light yellow solid. Mass spectrum (ion spray): m/z=388 (M+1); 1HNMR (CDCl3): 8.59 (s, 1H), 8.15 (d, 1H), 7.30 (d, 1H), 7.19 (t, 1H), 7.05-7.01 (m, 3H), 6.98 (s, 1H), 6.93 (d, 2H), 5.96 (br. s, 2H), 4.26 (t, 1H), 3.02-2.94 (m, 3H), 2.86-2.76 (m, 3H), 2.44 (m, 1H), 2.33 (s, 3H), 1.84 (m, 1H).
Reaction SMILES: S(O[CH2:12][C:13]([CH3:20])([CH3:19])[CH2:14][S:15]([NH2:18])(=[O:17])=[O:16])(C1C=CC(C)=CC=1)(=O)=O.[S-:21][C:22]#[N:23].[K+]>CN(C)C=O>[S:21]([CH2:12][C:13]([CH3:20])([CH3:19])[CH2:14][S:15]([NH2:18])(=[O:16])=[O:17])[C:22]#[N:23]
Reactant: Cc1ccc(S(=O)(=O)OCC(C)(C)CS(N)(=O)=O)cc1
Reactant: N#C[S-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(CSC#N)CS(N)(=O)=O
Yield: 21.7 %

Procedure:
A solution of 6.2 g of 3-tosyloxy-2,2-dimethyl-1-propanesulfonamide and 3.75 g of potassium thiocyanate in 30 ml of dimethylformamide was stirred at 130°-140° C. for 6 hours, and then concentrated to dryness. A mixture of dichloromethane and methanol (9:1) was added to the residue, followed by filtration to remove insoluble material. The filtrate was concentrated and the residue was subjected to a column chromatography, eluting with chloroform-ethyl acetate (2:1). The relevant fractions were concentrated to obtain 0.87 g of 3-thiocyanato-2,2-dimethyl-1-propanesulfonamide as yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=1)[CH2:9][CH2:10][CH3:11].[O-:25][C:26]#[N:27].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[CH2:8]([N:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:26]([NH2:27])=[O:25])[CH:19]=1)[CH2:9][CH2:10][CH3:11]
Reactant: N#C[O-]
Reactant: CCCCn1cccc1Cc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCn1cccc1Cc1cccc(NC(N)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
A solution of 3.5 ml (45 mmol) of trifluoroacetic acid in 25 ml of benzene was added dropwise to a suspension of 5 g (21 mmol) of 1-butyl-2-(3'-aminobenzyl)pyrrole and 2.85 g (43 mmol) of sodium cyanate in 250 ml of benzene. The reaction mixture was stirred at room temperature for 1 hour further and then poured into 600 ml of saturated sodium carbonate solution. The organic phase was separated and the aqueous phase extracted with ethyl acetate (3×300 ml). The combined extracts were washed with water (2×250 ml), dried and evaporated under reduced pressure. The residue was purified by column chromatography on 300 g of silica gel, using hexane-ethyl acetate (30:70) as eluant, thus obtaining 3.82 g (65%) of the title compound, 1-butyl-2-(3'-ureidobenzyl)pyrrole, which was recrystallized from acetone-hexane.
Reaction SMILES: [ClH:1].[CH3:2][CH:3]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)[C:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)=[O:5].[N:22]#[C:23][NH2:24].C(OCC)C>C(O)C>[ClH:1].[CH3:2][CH:3]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:23]([NH2:24])=[NH:22])=[CH:19][CH:20]=1)[C:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)=[O:5]
Reactant: Cc1ccc(OC(=O)C(C)Cc2ccc(N)cc2)cc1
Reactant: N#CN
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: Cc1ccc(OC(=O)C(C)Cc2ccc(NC(=N)N)cc2)cc1

Procedure:
In 200 ml of ethanol were dissolved 21.8 g of the p-methylphenyl α-methyl-β-(p-aminophenyl)-propionate hydrochloride obtained and 4.2 of cyanamide, and the resulting solution was subjected to reaction at 70° C. for 5 hours. After the reaction, the solvent was removed by distillation under reduced pressure, to obtain an oily product. A mixture of ethanol and diethyl ether was added thereto and the solution was cooled, upon which crystals precipitated. The crystals were collected by filtration and recrystallized from an ethanol-diethyl ether mixture, to obtain p-methylphenyl α-methyl-β-(p-guanidinophenyl)propionate hydrochloride in the form of colorless crystals. Yield: 17.4 g (70%); melting point: 146°-148° C.; IR (cm-1): 3500-2550, 1748, 1653, 1631; MS: M+ =m/e 312 (M.W. -HCl).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:4][CH:3]=1.[N+:23]([C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1)([O-:25])=[O:24]>>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH:20][C:33]([NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([N+:23]([O-:25])=[O:24])[CH:27]=2)=[O:34])=[CH:4][CH:3]=1
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Reactant: NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1
Product: O=C(NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1)Nc1cccc([N+](=O)[O-])c1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 214-b) as a starting material, and using 3-nitrophenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][C@@H:29]([CH3:34])[C:30]([O:32]C)=O)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1.[NH3:35]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][C@@H:29]([CH3:34])[C:30]([NH2:35])=[O:32])[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1
Reactant: N
Reactant: COC(=O)[C@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Product: C[C@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12)C(N)=O
Yield: 84 %

Procedure:
Using the same procedure as in Example 5, methyl (2S)-2-[(4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (250 mg, 0.55 mmol) was reacted with ammonia to give the title compound as a pale solid (210 mg, 84%); NMR Spectrum 1.67 (d, 3H), 5.14 (q, 1H), 5.77 (s, 2H), 6.94 (d, 1H), 7.02 (d, 1H), 7.30 (m, 1H), 7.36 (d, 1H), 7.55 (br s, 1H), 7.76-7.67 (m, 4H), 7.90 (br s, 1H), 8.15 (s, 1H), 8.52 (m, 3H), 10.80 (br s, 1H); Mass spectrum MH+ 440.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:17][C:18]([OH:20])=O)[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[C:36]([O:40][C:41]([N:43]1[CH2:48][CH2:47][N:46]([CH2:49][C:50]2[CH:55]=[CH:54][C:53]([CH3:56])=[C:52]([NH2:57])[CH:51]=2)[CH2:45][CH2:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37]>O1CCCC1>[C:36]([O:40][C:41]([N:43]1[CH2:44][CH2:45][N:46]([CH2:49][C:50]2[CH:55]=[CH:54][C:53]([CH3:56])=[C:52]([NH:57][C:18](=[O:20])[CH2:17][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:9]3[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=3)[CH:51]=2)[CH2:47][CH2:48]1)=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: Cc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1N
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)c1ccc(F)c(F)c1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1NC(=O)CN(C(=O)OC(C)(C)C)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of [tert-butoxycarbonyl-(3,4-difluorophenyl)-amino]-acetic acid (0.200 g) in tetrahydrofuran (2 ml) at 0° C. was added triethylamine (110 ul) followed by dropwise addition of isobutylchloroformate (100 ul). After stirring for 1 hr, triethylamine (150 ul) was added followed by 4-(3-amino-4-methyl-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (0.234 g) in tetrahydrofuran (2 ml), and the reaction warmed to room temperature and then heated at 58° C. overnight. After cooling to room temperature, the reaction mixture was filtered through Celite, the filtrate collected and the solvent removed in vacuo. Purification by NPHPLC (0-5% MeOH in CH2Cl2) afforded the sub-title compound as a pale yellow solid (0.300 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:13]([N:15]3[CH2:19][CH:18]=[CH:17][CH2:16]3)=[O:14])=[C:9]([Cl:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:41]=[CH:40][C:24]2[NH:25][C:26]([C@@H:28]([NH2:39])[CH2:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[N:27][C:23]=2[CH:22]=1.C(N(CC)CC)C>CN(C)C=O>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[C:13]([N:15]1[CH2:19][CH:18]=[CH:17][CH2:16]1)=[O:14])[N:5]=[CH:4][N:3]=[C:2]2[NH:39][C@H:28]([C:26]1[NH:25][C:24]2[CH:40]=[CH:41][C:21]([Cl:20])=[CH:22][C:23]=2[N:27]=1)[CH2:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33]
Reactant: CC(C)(C)OC(=O)CCC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C(c1cc2ncnc(Cl)c2cc1Cl)N1CC=CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCC[C@H](Nc1ncnc2cc(C(=O)N3CC=CC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 2d from 4,6-dichloro-7-(2,5-dihydropyrrol-1-yl-carbonyl)-quinazoline, (S)-1-(5-chloro-1H-benzimidazol-2-yl)-4-(tert.-butyloxycarbonyl)-butylamine and triethylamine in N,N-dimethylformamide.
Reaction SMILES: [C:1]([C:5]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:6]=1[O:7][CH:8]1[CH2:11][N:10]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=2)=[O:13])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:28][Mg]I>C(OCC)C>[C:1]([C:5]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:6]=1[O:7][CH:8]1[CH2:11][N:10]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:22])([CH3:28])[CH3:21])=[CH:16][CH:15]=2)=[O:13])[CH2:9]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)c1ccc(C(=O)N2CC(Oc3ccc(F)cc3C(C)(C)C)C2)cc1
Reactant: C[Mg]I
Solvent: CCOCC
Product: CC(C)(C)c1cc(F)ccc1OC1CN(C(=O)c2ccc(C(C)(C)O)cc2)C1
Temperature: 0 °C
Yield: 56.8 %

Procedure:
To a stirred suspension of 1-(4-(3-(2-tert-butyl-4-fluorophenoxy)azetidin-1-carbonyl)phenyl)ethanone (0.14 g, 0.37 mmol) in diethyl ether (2.0 mL) was added methyl magnesium iodide (0.25 mL, 3.0 M in diethyl ether, 0.75 mmol) dropwise at room temperature. The resulting reaction mixture was heated to reflux for 1.5 h. After this reaction mixture was cooled to 0° C., diluted with diethyl ether, quenched with 1 N hydrochloric acid (2 ml) and the reaction mixture was stirred until the solids disappeared. The organic layer was separated and washed with water (2×2.0 mL), dried (Na2SO4), filtered and the filtrate was directly purified by flash column chromatography (silica gel, 50:50 ethyl acetate/heptane) to provide (3-(2-tert-butyl-4-fluorophenoxy)azetidine-1-yl)(4-(2-hydroxypropan-2-yl)phenyl)methanone (0.081 g, 57%) as a white solid.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:16]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([NH:24][C:25]1[N:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][CH:26]=1)=[O:23]>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][CH2:7][N:6]([C:31]([C:28]3[CH:27]=[CH:26][C:25]([NH:24][C:22]([C:17]4[C:16]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:23])=[N:30][CH:29]=3)=[O:32])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)nc1
Reactant: c1ccc2c(c1)CCNc1ccccc1-2
Product: O=C(Nc1ccc(C(=O)N2CCc3ccccc3-c3ccccc32)cn1)c1ccccc1-c1ccccc1

Procedure:
As described for Example 12, 6,7-dihydro-5H-dibenz[b,d]azepine is reacted with 6-[([1,1'-biphenyl]-2-ylcarbonyl)amino]-3-pyridinecarbonyl chloride to give the product as a solid.
Reaction SMILES: C1C(C(O)=[O:8])=CC(C2C3C=CC(O)=CC=3OC3C=2C=CC(C=3)=O)=C(C(O)=O)C=1.ON1C(=O)CCC1=O.[CH:37]1([N:43]=[C:44]=[N:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>CN(C=O)C>[C:44]([NH:43][CH:37]1[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]1)([NH:45][CH:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1)=[O:8]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)c1ccc(C(=O)O)c(-c2c3ccc(=O)cc-3oc3cc(O)ccc23)c1
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5- or 6-carboxyfluorescein (0.5 mmol) in dry DMF (5 mL) were added N-hydroxysuccinimide (1.1 equiv.) and 1,3-dicylcohexylcarbodiimide (1.1 equiv.). After about 10 minutes, a white solid (dicyclohexylurea) started forming. The reaction mixture was stirred under nitrogen at room temperature overnight. TLC (9:1 CH2Cl2—MeOH) indicated complete disappearance of the starting material.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]2[CH:8]=[CH:9][NH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33]>C(OCC)(=O)C>[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:28]3[CH2:29][CH2:30][CH:25]([C:16]4[CH:17]=[CH:18][C:19]5[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH:15]=4)[CH2:26][CH2:27]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1ccc2cc(C3CCNCC3)ccc2c1
Reactant: ClCCCOc1cccc2[nH]ccc12
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: c1ccc2cc(C3CCN(CCCOc4cccc5[nH]ccc45)CC3)ccc2c1

Procedure:
The title compound was prepared in similar fashion from 1-chloro-3-(1H-indole-4-oxy)propane and 4-(2-naphthyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 57% overall yield as a white solid. mp. 145°-146° C. FDMS m/e=384 (M+ of free base).
Reaction SMILES: [CH3:1][CH2:2][OH:3].[K].Cl[C:6]1[C:7]([C:16]([F:19])([F:18])[F:17])=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[C:10]([NH2:12])[CH:11]=1.Cl>O>[CH2:2]([O:3][C:6]1[C:7]([C:16]([F:17])([F:19])[F:18])=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[C:10]([NH2:12])[CH:11]=1)[CH3:1]
Reactant: CCO
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl
Agent: [K]
Solvent: O
Product: CCOc1cc(N)c([N+](=O)[O-])cc1C(F)(F)F
Yield: 96 %

Procedure:
To EtOH (500 mL) was added potassium metal (ca. 21 g, ca. 537 mmol) and the vigorous reaction had to be cooled with an ice bath. Stirring was continued until all potassium metal was dissolved. Solid commercially available 5-chloro-2-nitro-4-trifluoromethyl-phenylamine [CAS-No. 35375-74-7] (57.74 g, 240 mmol) was added in one portion and the resulting dark red mixture was stirred at 55-60° C. for 4 days. The warm reaction mixture was slowly poured into H2O (ca. 2000 mL), adjusted pH with conc. HCl to pH 2, the yellow precipitate was filtered off, washed with H2O and dried in air at 60° C. to give a yellow solid (57.81 g, 96%), which was used without further purification. MS (ISN) 249 [M−H].
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].[F:21][C:22]([F:36])([F:35])[CH2:23][C:24]1[N:25]=[C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[S:27][CH:28]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([C:10]([N:32]2[CH2:33][CH2:34][N:29]([C:26]3[S:27][CH:28]=[C:24]([CH2:23][C:22]([F:36])([F:21])[F:35])[N:25]=3)[CH2:30][CH2:31]2)=[O:12])[CH:13]=1)(=[O:3])=[O:4]
Reactant: FC(F)(F)Cc1csc(N2CCNCC2)n1
Reactant: CC(Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Product: CC(Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nc(CC(F)(F)F)cs2)CC1)C(F)(F)F
Yield: 29 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example A2) and 1-[4-(2,2,2-trifluoro-ethyl)-thiazol-2-yl]-piperazine (Example 56(a)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in pentane to yield the title compound as a white crystalline solid (yield 29%). MS (m/e): 546.3 (M+H+, 100%).