Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1)[CH:6]=[CH:5]2.[CH:24]1(O)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[CH:24]1([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:6]=[CH:5]3)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: OC1CCCCC1
Reactant: CCOC(=O)C1CCN(Cc2ccc3cc(O)ccc3n2)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(Cc2ccc3cc(OC4CCCCC4)ccc3n2)CC1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 423.7 %

Procedure:
Into a 25 mL round bottom flask was added ethyl 1-((6-hydroxyquinolin-2-yl)methyl)piperidine-4-carboxylate (314 mg, 0.1 mmol), cyclohexanol (200 mg, 0.2 mmol, 2 eq), PPh3 (562 mg, 0.2 mmol, 2 eq) and dry toluene (0.5 mL) under N2. Then DIAD (404 mg, 0.2 mmol, 2 eq) was quickly added in one portion at room temperature. The reaction mixture was stirred at 30° C. for 30 min. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (PE:EA=4:1) to give ethyl 1-((6-(cyclohexyloxy)quinolin-2-yl)methyl)piperidine-4-carboxylate (168 mg, yield: 43%) as slight yellow oil. ESI-MS (M+H)+: 397.2. 1H NMR (400 MHz, CDCl3) δ: 7.99 (d, J=8.4 Hz, 1H), 7.94 (d, J=9.6 Hz, 1H), 7.69-7.64 (m, 1H), 7.33 (dd, J=8.8, 2.4 Hz, 1H), 7.07 (d, J=2.0 Hz, 1H), 4.43-4.37 (m, 1H), 4.13 (q, J=7.2 Hz, 2H), 3.78 (s, 2H), 2.93-2.89 (m, 2H), 2.08-2.03 (m, 3H), 1.87-1.82 (m, 4H), 1.63-1.55 (m, 5H), 1.46-1.26 (m, 5H), 1.23 (t, J=7.2 Hz, 3H).
Reaction SMILES: O1CCN(C[CH2:8][NH:9][C:10](=[O:56])[CH2:11][CH2:12][S:13][CH2:14][C:15]2[CH:16]=[C:17]([CH:53]=[CH:54][CH:55]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:23][C:22]=2[C:33]2[CH:34]=[C:35]([CH:50]=[CH:51][N:52]=2)[C:36]([NH:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[CH:41]=2)=[O:37])=[O:19])CC1.[CH3:57][O:58][CH2:59]CN>>[CH3:57][O:58][CH2:59][CH2:8][NH:9][C:10](=[O:56])[CH2:11][CH2:12][S:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:53]=[CH:54][CH:55]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)=[CH:23][C:22]=1[C:33]1[CH:34]=[C:35]([CH:50]=[CH:51][N:52]=1)[C:36]([NH:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:47])([F:48])[F:49])[CH:41]=1)=[O:37])=[O:19]
Reactant: COCCN
Reactant: O=C(CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1)NCCN1CCOCC1
Product: COCCNC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1

Procedure:
This compound was prepared using the procedure described for the preparation of 2-(2-(3-(((3-((2-morpholinoethyl)amino)-3-oxopropyl)thio)methyl)benzamido)-5-(piperidin-1-yl)-phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide 4.16, using 2-methoxyethylamine in place of 2-morpholinoethylamine. MS (ES, m/z): 734 [M+H]+
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C@H:9]2[CH2:13][O:12][C:11](=[O:14])[NH:10]2)[CH:6]=[CH:7][CH:8]=1.Br[C:18]1[CH:19]=[CH:20][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[N:22][CH:23]=1>>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([O:24][C:21]2[N:22]=[CH:23][C:18]([N:10]3[C@@H:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=4)[CH2:13][O:12][C:11]3=[O:14])=[CH:19][CH:20]=2)=[CH:30][CH:29]=1
Reactant: Clc1ccc(Oc2ccc(Br)cn2)cc1
Reactant: O=C1N[C@@H](c2cccc(C(F)(F)F)c2)CO1
Product: O=C1OC[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)nc1

Procedure:
(S)-3-[6-(4-Chloro-phenoxy)-pyridin-3-yl]-4-(3-trifluoromethyl-phenyl)-oxazolidin-2-one is prepared from (S)-4-(3-trifluoromethyl-phenyl)-oxazolidin-2-one and 5-bromo-2-(4-chloro-phenoxy)-pyridine using the same conditions as example 4. 1H NMR (CDCl3, 400 MHz) δ 8.03 (dd, 1H), 7.88 (d, 1H), 7.62 (d, 1H), 7.45˜7.55 (m, 3H), 7.3 (d, 2H), 7.01 (d, 2H), 5.40 (dd, 1H), 4.85 (t, 1H), 4.24 (dd, 1H); HPLC-MS calculated for C21H15ClF3N3O2 (M+H+) 435.1, found 435.1.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:37](=[O:38])[N:14]2[C:15]([C:21]([O:23][CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])=[C:16]([CH2:19][OH:20])[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39]([C:41]1[CH:42]=[C:43](O)[CH:44]=[CH:45][CH:46]=1)#[N:40]>>[C:39]([C:41]1[CH:46]=[C:45]([CH:44]=[CH:43][CH:42]=1)[O:20][CH2:19][C:16]1[CH2:17][S:18][C@@H:13]2[CH:12]([NH:11][C:9](=[O:10])[CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:37](=[O:38])[N:14]2[C:15]=1[C:21]([O:23][CH:24]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:22])#[N:40]
Reactant: N#Cc1cccc(O)c1
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12
Product: N#Cc1cccc(OCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)COc4ccccc4)[C@H]3SC2)c1

Procedure:
The procedure described in Example 1(a), was repeated, but using 2.00 g of diphenylmethyl 7-phenoxyacetamido-3-hydroxymethyl-3-cephem-4-carboxylate and m-cyanophenol, to afford 490 mg of the title compound as a powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]4[C:21](=O)[C:22](=[O:27])[C:23]=4[O:24]CC)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:29][NH:30][CH3:31]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]4[C:23](=[O:24])[C:22](=[O:27])[C:21]=4[N:30]([CH3:31])[CH3:29])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1c(Nc2ccc3ncnc(Nc4cccc(Br)c4)c3c2)c(=O)c1=O
Reactant: CNC
Solvent: CCO
Product: CN(C)c1c(Nc2ccc3ncnc(Nc4cccc(Br)c4)c3c2)c(=O)c1=O
Temperature: 25 °C

Procedure:
A mixture of 0.8 g of 3-[4-(3-Bromo-phenylamino)-quinazolin-6-ylamino]4-ethoxy-cyclobut-3-ene-1,2-dione, 8 mL of 40% dimethylamine, and 8 mL of ethanol was refluxed for 2 hr. The mixture was cooled to room temperature and the solid was collected and washed with ethanol and ether giving 0.7 g of 3-[4-(3-Bromo-phenylamino)-quinazolin-6-ylamino]-4-dimethylamino-cyclobut-3-ene-1,2-dione as a yellow powder: mass spectrum (m/e): M+H 438.1, 440.1.
Reaction SMILES: C[O:2][C:3](=[O:37])[C@@H:4]([NH:14][C:15](=[O:36])[C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[NH:23][S:24]([C:27]1[C:32]2=[N:33][S:34][N:35]=[C:31]2[CH:30]=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1.N1SN=C2C(S(NC3C=C(Br)C=CC=3C(O)=O)(=O)=O)=CC=CC=12.Cl.COC(=O)[C@H](CC1C=CC(Cl)=C(Cl)C=1)N>>[N:35]1[S:34][N:33]=[C:32]2[C:27]([S:24]([NH:23][C:17]3[CH:18]=[C:19]([Br:22])[CH:20]=[CH:21][C:16]=3[C:15]([NH:14][C@@H:4]([CH2:5][C:6]3[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=3)[C:3]([OH:37])=[O:2])=[O:36])(=[O:25])=[O:26])=[CH:28][CH:29]=[CH:30][C:31]=12
Reactant: COC(=O)[C@H](Cc1ccc(Cl)c(Cl)c1)NC(=O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nsnc12
Agent: COC(=O)[C@@H](N)Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C(O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nsnc12
Product: O=C(N[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nsnc12
Yield: 95 %

Procedure:
(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-benzoylamino]-3-(3,4-dichloro-phenyl)-propionic acid methyl ester. The title compound (61 mg, 95%) was prepared from 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromobenzoic acid and (S)-3,4-dichlorophenylalanine methyl ester hydrochloride as in Example 1, Part C. 1H NMR (400 MHz, CDCl3): 11.43 (br s, 1H), 8.38 (dd, J=7.0, 1.0, 1H), 8.23 (dd, J=8.8, 1.0, 1H), 7.90 (t, J=1.0, 1H), 7.73 (dd, J=8.8, 7.0, 1H), 7.35 (d, J=8.2, 1H), 7.14 (d, J=2.0, 1H), 7.11 (d, J=1.0, 2H), 6.89 (dd, J=8.2, 2.1, 1H), 6.48 (br d, J=7.1, 1H), 5.00-4.92 (m, 1H), 3.82 (s, 3H), 3.22 (dd, J=14.0, 5.8, 1H), 3.16 (dd, J=14.0, 5.1, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:19]=[CH:18][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=3)[S:9][C:5]=2[CH:4]=1.Cl.N1C=CC=CC=1.Cl>>[OH:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]2[S:9][C:5]3[CH:4]=[C:3]([OH:2])[CH:19]=[CH:18][C:6]=3[N:7]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(-c2nc3ccc(OC)cc3s2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1ccc(-c2nc3ccc(O)cc3s2)cc1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
6-Methoxy-2-(4-methoxy-phenyl)-benzothiazole (134 mg, 0.49 mmol) and pyridine hydrochloride (1.34 g, 11.6 mmol) were heated to 200° C. under nitrogen for 40 min, and then cooled to room temp. Reaction was poured cautiously into aqueous hydrochloric acid (1M) and extracted with ethyl acetate. Ethyl acetate extracts were washed with: 1) hydrochloric acid (1.0M), 2) saturated brine and concentrated in vacuo. Residue was washed with ether/hexane (1:4), dried under vacuum yielding the title compound (119 mg, 100%) as a yellow solid. MH+=244 The starting 6-Methoxy-2-(4-methoxy-phenyl)-benzothiazole was prepared as follows:
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([CH3:26])[CH:20]=3)[CH2:13][CH2:12]2)=[N:3]1.C(N(CC)CC)C.[C:34]([Cl:42])(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1>[ClH:42].[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:34](=[O:41])[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[C:21]([CH3:26])[CH:20]=3)[CH2:15][CH2:16]2)=[N:3]1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc(CCN2CCN(c3nsc4ccccc34)CC2)ccc1N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(CCN2CCN(c3nsc4ccccc34)CC2)ccc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
To a solution of 4-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-2-methyl-phenylamine Hydrochloride (0.224 g, 0.6 mmol) in dry THF (30 mL) was added triethylamine (0.167 mL, 1.20 mmol), followed by dropwise addition of benzoyl chloride (0.07 mL, 0.6 mmol). The reaction was stirred vigorously under N2 blanket at room temperature for 2 h. The reaction was quenched with H2O (25 mL) and diluted with ethylacetate (25 mL). The layers were separated and the organics washed with 1 N HCl (20 mL), sat. Na2CO3 (20 mL), brine (20 mL), dried (MgSO4), and concentrated to a residue. After chromatographic purification (5% MeOH/CH2Cl2), N-{4-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-2-methyl-phenyl}-benzamide was precipitated as its hydrochloride salt from dioxane/HCl(gas) treatment (0.162 g, 0.355 mmol). Yield=59%. 100% purity at 254 nM; LCMS (APCI): 457.2 [M+H]+, 1H NMR (400 MHz, DMSO-d6) δ 10.81 (bs, 1H), 9.88 (s, 1H), 8.13 (d, J=8.36 Hz, 1H), 8.09 (d, J=8.36 Hz, 1H), 7.95 (d, J=8.36 Hz, 1H), 7.62–7.42 (m, 5H), 7.30 (d, J=8.02 Hz, 1H), 7.18 (s, 1H), 7.12 (d, J=8.02 Hz, 1H), 4.10 (bd, J=12.32 Hz, 2H), 3.68 (bd, J=12.32 Hz, 2H), 3.50–3.33 (m, 6H), 3.32 (s, H2O), 3.10–3.00 (m, 2H), 2.47 (DMSO), 2.21 (s, 3H).
Reaction SMILES: [C:1]([C@@H:5]1[CH2:9][C:8](=[CH2:10])[CH2:7][C@H:6]1[C:11]([O:13]C)=[O:12])([O:3]C)=[O:2].[OH-].[Na+]>>[CH2:10]=[C:8]1[CH2:7][C@@H:6]([C:11]([OH:13])=[O:12])[C@H:5]([C:1]([OH:3])=[O:2])[CH2:9]1
Reactant: C=C1C[C@@H](C(=O)OC)[C@H](C(=O)OC)C1
Agent: [Na+]
Agent: [OH-]
Product: C=C1C[C@@H](C(=O)O)[C@H](C(=O)O)C1
Yield: 77.7 %

Procedure:
A diester, trans-1,2-di-carbomethoxy-4-methylenecyclopentane, 1, (1.48 g, 7.47 mmol) prepared by the method of Trost (J. Am. Chem. Soc. 105 2315 (1983) was heated under reflux for 2 hours with 2N sodium hydroxide (11 ml, 22 mmol). The resulting solution was cooled in an ice bath and acidified with concentrated (37%) hydrochloric acid (8.0 ml) until a pH of 0.6 was attained. The resulting slurry was filtered, washed with water, and dried in vacuo to give the diacid 2 (0.987 g, 77.7%) as a colorless powder: mp 178°-179° C.; Anal. calcd for C8H10O4 : C, 56.47; H, 5.92. Found: C, 56.08; H, 5.87.
Reaction SMILES: [CH2:1]([NH:8][C:9]([N:11]1[C@H:16]2[CH2:17][N:18]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[N:40]=3)[C:19](=[O:37])[C@H:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28]CC4C=CC=CC=4)=[CH:24][C:23]=3[F:36])[N:15]2[C:14](=[O:46])[CH2:13][N:12]1[CH2:47][CH:48]=[CH2:49])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(SC)C=CC=CC=1>C(O)(C(F)(F)F)=O>[CH2:1]([NH:8][C:9]([N:11]1[C@H:16]2[CH2:17][N:18]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[N:40]=3)[C:19](=[O:37])[C@H:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=3[F:36])[N:15]2[C:14](=[O:46])[CH2:13][N:12]1[CH2:47][CH:48]=[CH2:49])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCN1CC(=O)N2[C@@H](Cc3ccc(OCc4ccccc4)cc3F)C(=O)N(Cc3cccc(F)n3)C[C@@H]2N1C(=O)NCc1ccccc1
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C=CCN1CC(=O)N2[C@@H](Cc3ccc(O)cc3F)C(=O)N(Cc3cccc(F)n3)C[C@@H]2N1C(=O)NCc1ccccc1
Yield: 99.6 %

Procedure:
To a mixed solution of (6S,9aS)-N-benzyl-6-((4-(benzyloxy)-2-fluorophenyl)methyl)-8-((6-fluoropyridin-2-yl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide (5.04 g, 7.56 mmol) described in Production Example 1-1-5 and TFA (20 mL) was added thioanisole (3.55 mL, 30.2 mmol) at room temperature. The resultant mixture was stirred at room temperature for 13 hours and 50 minutes. The reaction mixture was concentrated under a reduced pressure, sodium hydrogen carbonate and water were added to the residue, and the resultant solution was extracted with ethyl acetate. An organic layer was dried over anhydrous magnesium sulfate and then filtrated. The solvent was evaporated under a reduced pressure, and the resultant residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=20:1) to give the title compound (4.34 g, yield: quantitative).
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=1)=[O:6])[CH3:2]>C1COCC1.[Pd]>[NH2:14][C:10]1[CH:9]=[C:8]([NH:7][C:5](=[O:6])[CH2:4][N:3]([CH2:17][CH3:18])[CH2:1][CH3:2])[CH:13]=[CH:12][CH:11]=1
Reactant: CCN(CC)CC(=O)Nc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCN(CC)CC(=O)Nc1cccc(N)c1
Reaction time: 8 h

Procedure:
2-(Diethylamino)-N-(3-nitrophenyl)acetamide 4 (0.73 g, 2.90 mmol) was dissolved in anhydrous THF (20 ml) under an atmosphere of N2, then Pd/C (0.073 g) was added. The atmosphere was then saturated with H2 and the mixture stirred overnight. The crude product was filtered through celite, the celite washed with EtOAc and the organic solution evaporated in vacuo. The crude was dissolved in DCM (75 ml), washed 3 times with 5N aqueous NH4OH solution (50 ml), dried (MgSO4), filtered and the solvent evaporated in vacuo. Compound N-(3-aminophenyl)-2-(diethylamino)acetamide 5 was obtained as a yellow oil (0.58 g, 90%) without requiring any further purification; Rf 0.44 [5% MeOH in DCM]; δH (CDCl3, 400 MHz) 9.28 (1H, s, NH), 7.26-7.20 (1H, m, ArH), 7.07 (1H, t, J=8.0 Hz, ArH), 6.74-6.72 (1H, m, ArH), 6.43-6.40 (1H, m, ArH), 3.71 (2H, broad s, NH2), 3.11 (2H, s, CH2), 2.65-2.59 (4H, m, 2×CH2), 1.69 (6H, t, J=7.2 Hz, 2×CH3); δC (CDCl3, 100 MHz) 169.95 (C═O), 147.27 (Ar—C), 138.64 (Ar—C), 129.61 (Ar—CH), 110.74 (Ar—CH), 109.17 (Ar—CH), 105.92 (Ar—CH), 58.14 (CH2), 48.79 (2×CH2), 12.39 (2×CH3); HRMS m/z calc. C12H20N3O [M+H]+222.1601. found [M+H]+ 222.1694.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=2[Cl:15])=[O:7])=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>C1C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][Br:18])=[CH:10][C:9]=2[Cl:15])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)c2ccc(Cl)cc2)c(Cl)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1Cl
Yield: 49.2 %

Procedure:
A stirred refluxing solution of 4-(4-chlorobenzoyl)-3-chlorotoluene (2.65 g, 9.99 mmol) and dibenzoylperoxide (100 mg, 0.413 mmol) in benzene (100 ml) was treated in portions with an intimate mixture of N-bromosuccinimide (2.2 g, 12. mmol) and dibenzoylperoxide (100 mg, 0.413 mmol). The mixture was refluxed 1.5 hours, cooled, and filtered. The filtrate was evaporated under vacuum, triturated with diethyl ether (100 ml), and filtered. The filtrate was evaporated under vacuum and the residue was chromatographed on silica gel (500 g) eluted with 97:3 (v/v) n-hexane-ethyl acetate using a preparative highperformance liquid chromatograph to provide 1.69 g (49%) of 4-(4-chlorobenzoyl)-3-chlorobenzyl bromide, m.p. 88°-90° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].C(N(CC)CC)C.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1>O1CCCC1>[Cl:5][CH2:4][CH2:3][CH2:2][N:23]1[CH2:22][CH2:21][N:20]([C:17]2[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: ClCCCBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Fc1ccc(N2CCN(CCCCl)CC2)cc1
Reaction time: 16 h

Procedure:
26.1 g (0.166 mole) of 1-bromo-3-chloropropane and 33.6 g (0.333 mole) of triethylamine are added to 30.0 g (0.166 mole) of 1-(4-fluorophenyl)-piperazine in 50 ml of tetrahydrofuran. The reaction mixture is stirred for 16 hours at from 60° to 65° C., cooled and filtered, the solvent is stripped off under reduced pressure, and the crude product is distilled under reduced pressure from an oil pump. The product distils at 135°-145° C./0.05 mm Hg in a yield of 30.0 g (70%).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]4[C:27](=[O:28])[O:26][C:25]([CH3:30])([CH3:29])[O:24][C:23]=4[CH:31]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:34](Cl)(=[O:40])[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][N:18]([C:19]3[CH:20]=[CH:21][C:22]4[C:27](=[O:28])[O:26][C:25]([CH3:29])([CH3:30])[O:24][C:23]=4[CH:31]=3)[C:34](=[O:40])[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)OC(C)(C)OC4=O)cc2)cc1
Reactant: CCCCCC(=O)Cl
Product: CCCCCC(=O)N(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc2c(c1)OC(C)(C)OC2=O

Procedure:
The titled compound was prepared following the procedure M using 7-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one and hexanoyl chloride as all orange oil (69%). 1H NMR (CDCl3, 300 MHz) δ 7.92 (d, J=8.3 Hz, 1H), 7.41 (m, 4H), 7.14 (m, 4H), 6.78 (d, J=8.3 Hz, 1H), 6.59 (s, 1H), 4.89 (s, 2H), 2.60 (t, J=7.7 Hz, 2H), 2.14 (t, J=7.3 Hz, 2H), 1.71 (s, 6H), 1.66-1.51 (m, 4H), 1.43-1.12 (m, 8H), 0.91 (t, J=7.3 Hz, 3H). 0.84 (t, J=6.7 Hz, 3H). M+ (ESI): 538.2. HPLC, Rt: 6.34 min (Purity: 99.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14](O)=[O:15])[CH:11]=[CH:10][C:9]=2[N:17]2[CH2:20][C:19]([F:22])([F:21])[CH2:18]2)[CH:5]=[CH:6][CH:7]=1.[CH3:23][O:24][CH2:25][CH2:26][O:27][CH2:28][C:29]([NH2:32])([CH3:31])[CH3:30]>>[CH3:23][O:24][CH2:25][CH2:26][O:27][CH2:28][C:29]([NH:32][C:14]([C:12]1[CH:11]=[CH:10][C:9]([N:17]2[CH2:20][C:19]([F:22])([F:21])[CH2:18]2)=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:15])([CH3:31])[CH3:30]
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(-c2cccc(Cl)c2)n1
Reactant: COCCOCC(C)(C)N
Product: COCCOCC(C)(C)NC(=O)c1ccc(N2CC(F)(F)C2)c(-c2cccc(Cl)c2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 140 a) and 2-(2-methoxy-ethoxy)-1,1-dimethyl-ethylamine (CAN 947723-29-7) as starting materials, MS (EI): m/e=454.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[C:22]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[C:15](=O)[C:14]=4[CH:13]=[CH:12][CH:11]=3)[NH:7][C:6]=2[CH:24]=1.Cl.[NH2:26][OH:27].C([O-])(=O)C.[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[C:22]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[C:15](=[N:26][OH:27])[C:14]=4[CH:13]=[CH:12][CH:11]=3)[NH:7][C:6]=2[CH:24]=1
Reactant: NO
Reactant: O=C1c2ccccc2-c2c1cccc2-c1nc2ccc(Br)cc2[nH]1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=C1c2ccccc2-c2c1cccc2-c1nc2ccc(Br)cc2[nH]1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
Stir, at room temperature under argon, a mixture of 1.13 g of 4-(6-bromo-1H-benzimidazol-2-yl)-9H-fluoren-9-one, 0.628 g of hydroxylamine hydrochloride and 1.24 g of sodium acetate in 50 ml of ethanol. The following day, evaporate the reaction medium to dryness under vacuum, take the residue up with 100 ml of water, filter off the solid, and then wash it with 100 ml of water. After drying at 40° C. under vacuum, we obtain 1.17 g of 4-(6-bromo-1H-benzimidazol-2-yl)-9H-fluoren-9-one oxime (Z, E), with the following characteristics:
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([OH:9])=O)[CH2:5][N:4]([C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:13]=[CH:12][N:11]=2)[C:3]1=[O:20].C(N1CCOCC1)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl:52][C:53]1[C:58]([F:59])=[C:57]([F:60])[CH:56]=[CH:55][C:54]=1[CH2:61][NH2:62]>ClCCl.CN(C=O)C>[Cl:52][C:53]1[C:58]([F:59])=[C:57]([F:60])[CH:56]=[CH:55][C:54]=1[CH2:61][NH:62][C:7]([CH:6]1[CH2:5][N:4]([C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:13]=[CH:12][N:11]=2)[C:3](=[O:20])[N:2]1[CH3:1])=[O:9]
Reactant: CN1C(=O)N(c2cc(C(F)(F)F)ncn2)CC1C(=O)O
Reactant: NCc1ccc(F)c(F)c1Cl
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1C(=O)N(c2cc(C(F)(F)F)ncn2)CC1C(=O)NCc1ccc(F)c(F)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.5 %

Procedure:
To a suspension of 3-methyl-2-oxo-1-[6-(trifluoromethyl)-4-pyrimidinyl]-4-imidazolidinecarboxylic acid (200 mg, 0.612 mmol) and N-ethylmorpholine (0.465 ml, 3.67 mmol) in dichloromethane (10 ml)/DMF (1 ml) was added 1-hydroxybenzotriazole hydrate (113 mg, 0.735 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (117 mg, 0.612 mmol) and the reaction mixture was stirred for 1 hour at room temperature. 1-(2-Chloro-3,4-difluorophenyl)methanamine (131 mg, 0.612 mmol) was then added and the reaction stirred overnight. Additional 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (117 mg, 0.612 mmol) was added and the reaction mixture was stirred for 3 hours. The reaction mixture was diluted with dichloromethane and washed with saturated sodium hydrogen carbonate solution, water, 3N citric acid solution, water then brine and separated through a hydrophobic frit and the organic layer concentrated under vacuum. The residue was purified by SP4 automated silica gel chromatography eluting with 10-100% ethyl acetate in isohexane to give N-[(2-chloro-3,4-difluorophenyl)methyl]-3-methyl-2-oxo-1-[6-(trifluoromethyl)-4-pyrimidinyl]-4-imidazolidinecarboxamide (95 mg, 33.8% yield). LC/MS [M+H]+=450, retention time=2.93 minutes.