Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:23])[C:8](=O)[CH2:9][C:10](=O)[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[CH:9]=[C:10]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[NH:3][N:2]=1)=[O:23])[CH3:5]
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)CCc1ccc(OC)cc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(CCc2ccc(OC)cc2)[nH]n1

Procedure:
Hydrazine hydrate (0.513 mL, 10.6 mmol) was added to a stirring room temperature solution of 22 (2.9241 g, 10.5 mmol) in EtOH (10.6 mL, 1 M) under N2. The reaction was then heated to reflux until judged complete by HPLC (45 min): The reaction was concentrated and crystallized from EtOH to obtain 23. 1H (CDCl3, 400 MHz): δ 11.67 (1H, broad s), 7.06 (2H, d, J=8.3 Hz), 6.78 (2H, d, J=8.3 Hz), 6.57 (1H, s), 4.30 (2H, q, J=7.0 Hz), 3.76 (3H, s), 2.98 (2H, t, J=7.7 Hz), 2.88 (2H, t, J=7.7 Hz), 1.30 (3H, t, J=7.1 Hz) ppm. 13C (CDCl3, 100 MHz): δ 162.20, 158.13, 147.05, 141.79, 132.94, 129.42, 113.98, 106.61, 61.02, 55.36, 34.65, 28.23, 14.37 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 55.36, 14.37; CH2 carbons: 61.02, 34.65, 28.23; CH carbons: 129.42, 113.98, 106.61 ppm. HPLC: 9.200 min.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([C:29]1[N:30]=[C:31]([NH:34]C=O)[S:32][CH:33]=1)[C:7]([NH:9][CH:10]1[C:27](=[O:28])[N:12]2[C:13]([C:24]([O-:26])=[O:25])=[C:14]([CH2:17][N+:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[C:2]#[CH:3].Cl.O.[OH-].[Na+]>CO>[CH2:1]([O:4][N:5]=[C:6]([C:29]1[N:30]=[C:31]([NH2:34])[S:32][CH:33]=1)[C:7]([NH:9][CH:10]1[C:27](=[O:28])[N:12]2[C:13]([C:24]([O-:26])=[O:25])=[C:14]([CH2:17][N+:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[C:2]#[CH:3]
Reactant: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
A mixture of 7-[2-(2-propynyloxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (11.2 g) and conc. hydrochloric acid (2.3 g) in methanol (80 ml) was stirred for 3 hours at ambient temperature. The reaction mixture was poured into water (120 ml) and adjusted to pH 3.5 with 10% aqueous solution of sodium hydroxide and washed with ethyl acetate. The aqueous layer was adjusted to pH 5.0 with 10% aqueous solution of sodium hydroxide. After removing the solvent under reduced pressure, the aqueous solution was adjusted to pH 4.0 with 10% aqueous hydrochloric acid under ice-cooling. The solution was subjected to column chlomatography on macroporous non-ionic adsorption resin "Diaion HP-20:" (Trademark: prepared by Mitsubishi Chemical Industries) and eluted with 10% aqueous solution of isopropyl alcohol. The fractions containing the objected compound were concentrated and lyphylized to give 7-[2-(2-propynyloxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-(1-pyridiniomethyl)- 3-cephem-4-carboxylate (syn isomer) (5.3 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[C:21]([O:23][CH2:24][CH2:25][C:26]2[S:30][CH:29]=[N:28][C:27]=2[CH3:31])[CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18]C)=[O:17])=[CH:12][N:11]=1)=[O:8])([O-])=O.C(O)C.[H][H]>[Pd].C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:20]=[C:21]([O:23][CH2:24][CH2:25][C:26]2[S:30][CH:29]=[N:28][C:27]=2[CH3:31])[CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][N:11]=1)=[O:8]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(OCCc3scnc3C)cc([N+](=O)[O-])c2)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ncsc1CCOc1cc(N)cc(C(=O)Nc2ccc(C(=O)O)cn2)c1
Reaction time: 18 h
Yield: 45.5 %

Procedure:
10% Palladium on carbon (0.20 g) was added under an argon atmosphere to a solution of methyl 2-[3-nitro-5-(4-methyl-thiazol-5-yl) ethoxy benzoyl]amino-5-pyridine carboxylate (1.05 g, 1.7 mM) in ethyl acetate (50 ml)/ethanol (50 ml). Hydrogen gas was introduced and the reaction mixture stirred vigorously for 18 hrs before filtering through diatomaceous earth, concentration in vacuo and replacement of the catalyst (80 mg). After stirring under hydrogen gas for a further 18 hrs a final catalyst change was carried out, after which the crude aniline was purified on silica gel (1% to 4% MeOH/DCM) to give the title compound as a colourless solid (0.43 g, 60%); 1H NMR δ (d6-DMSO): 2.36 (s, 3H), 3.18 (dd, 2H), 3.88 (s, 3H), 4.12 (dd, 2H), 5.32 (bs, 2H), 6.33 (m, 1H), 6.79 (m, 2H), 8.30 (m, 2H), 8.81 (s, 1H), 8.88 (m, 1H), 10.90 (bs, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH3:23][S:24][CH2:25][CH2:26][O:27][C:28]([NH:30][C:31]1[N:39]=[CH:38][N:37]=[C:36]2[C:32]=1[N:33]=[CH:34][N:35]2[CH2:40][C:41](O)=[O:42])=[O:29]>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[C:41](=[O:42])[CH2:40][N:35]1[CH:34]=[N:33][C:32]2[C:36]1=[N:37][CH:38]=[N:39][C:31]=2[NH:30][C:28]([O:27][CH2:26][CH2:25][S:24][CH3:23])=[O:29])[CH3:2]
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nc2ccccc2s1
Reactant: CSCCOC(=O)Nc1ncnc2c1ncn2CC(=O)O
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nc2ccccc2s1)C(=O)Cn1cnc2c(NC(=O)OCCSC)ncnc21
Yield: 87 %

Procedure:
The title compound (2.77 g, 85%) was synthesized by the reaction of N-[2-(benzothiazole-2-sulfonylamino)-ethyl]-glycine ethyl ester (1.72 g, 5 mmol) and [6-N-(2-methylthioethoxycarbonyl)-adenin-9-yl]-acetic acid (1.56 g, 5 mmol) as per the procedure of Example 20. 1H NMR (500 MHz; DMSO-d6) δ 10.59 (s, 1H), 8.97 (brs, 0.6H), 8.76 (brs, 0.4H), 8.57 (s, 0.4H), 8.52 (s, 0.6H), 8.28 (d, 1H), 8.17 (d, 1H), 7.65 (m, 2H), 5.35 (s, 1.2H), 5.14 (s, 0.8H), 4.46 (s, 0.8H), 4.17 (q, 0.8H), 4.06 (s, 1.2H), 4.02 (q, 1.2H), 3.70 (t, 1.2H), 3.47 (t, 1.2H), 3.42 (t, 0.8H), 3.21 (t, 0.8H), 2.12 (s, 3H), 1.23 (t, 1.2H), 1.12 (t, 1.8H).
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]4[CH3:28])[N:17]=3)=[CH:12][CH:11]=2)C=CC=CC=1.C(N(CC)CC)C.[CH2:37]([CH2:39][NH2:40])[OH:38]>CN(C=O)C>[OH:38][CH2:37][CH2:39][NH:40][C:8]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[N:17]=2)=[CH:14][CH:15]=1)=[O:29]
Reactant: NCCO
Reactant: C[C@H]1COCCN1c1nccc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H]1COCCN1c1nccc(-c2ccc(NC(=O)NCCO)cc2)n1

Procedure:
(S)-phenyl(4-(2-(3-methylmorpholino)pyrimidin-4-yl)phenyl)carbamate (intermediate 29) (100 mg, 0.26 mmol) was stirred with triethylamine (85 mg, 0.82 mmol) and ethanolamine (78 mg, 1.28 mmol) in DMF (1 ml) for 2 hours at room temperature. The crude residue was purified by flash chromatography (0-10% EtOH:MeOH) to yield the title compound. (34 mg, 8%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]([NH:14][C:15](=[O:27])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[CH:23]=[C:24]([CH3:26])[CH3:25])([C:11]([OH:13])=[O:12])[CH2:5]2>C(O)(=O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]([NH:14][C:15](=[O:27])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[CH2:23][CH:24]([CH3:25])[CH3:26])([C:11]([OH:13])=[O:12])[CH2:5]2
Reactant: CC(C)=Cc1c(C)cccc1C(=O)NC1(C(=O)O)Cc2ccc(F)cc2C1
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1cccc(C(=O)NC2(C(=O)O)Cc3ccc(F)cc3C2)c1CC(C)C
Yield: 85.9 %

Procedure:
To a solution of 2-[3-methyl-2-(2-methyl-propenyl)-benzoylamino]-indan-2-carboxylic acid (149) (230 mg, 0.63 mmol) in acetic acid (10 mL) is added the catalyst, Pd—C (5 wt. % Pd, 134 mg, 6.3% mmol) under argon. The resulting reaction mixture is moved to the Paar apparatus to run hydrogenation: 55 psi, 95° C., overnight. The catalyst is removed by filtration through a pre-column (10 g silica gel) and washed with EtOH. The combined organic solution is concentrated in vacuo. The residue is purified by HPLC to give a pure product (150) as white solid (200 mg, 86%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:13][C:12]([F:21])=[CH:11][C:10]=2[F:22])[C:5]([Cl:23])=[CH:4][N:3]=1.[CH3:24][O:25][CH2:26][CH2:27][N:28]1[CH2:34][CH2:33][C:32]2[CH:35]=[C:36]([NH2:39])[CH:37]=[CH:38][C:31]=2[CH2:30][CH2:29]1>>[Cl:23][C:5]1[C:6]([NH:8][C:9]2[C:14]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:13][C:12]([F:21])=[CH:11][C:10]=2[F:22])=[N:7][C:2]([NH:39][C:36]2[CH:37]=[CH:38][C:31]3[CH2:30][CH2:29][N:28]([CH2:27][CH2:26][O:25][CH3:24])[CH2:34][CH2:33][C:32]=3[CH:35]=2)=[N:3][CH:4]=1
Reactant: Fc1cc(F)c(Nc2nc(Cl)ncc2Cl)c(N2CCOCC2)c1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4c(F)cc(F)cc4N4CCOCC4)n3)cc2CC1

Procedure:
Title compound was prepared from (2,5-Dichloro-pyrimidin-4-yl)-(2,4-difluoro-6-morpholin-4-yl-phenyl)-amine and 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine in an analogous manner to Example 1221d. Title compound was isolated as a white solid (80 mg, 48%), HPLC 99% purity, LCMS 547.26 (M+H), 1H-NMR (DMSO-d6, 400 MHz) δ 9.69 (s, 1H), 9.37 (s, 1H), 8.52 (s, 1H), 8.13 (s, 1H), 7.28 (s, 1H), 7.17 (d, J=7.9 Hz, 1H), 7.02 (dd, J=6.9 Hz, 1H), 6.88 (d, J=8.2 Hz, 1H), 6.83 (10.9 Hz, 1H), 3.70-3.68 (m, 2H), 3.62-3.58 (m, 2H), 3.55-3.50 (m, 4H), 3.37-3.35 (m, 2H), 3.33 (s, 3H), 3.15-2.87 (m, 10H).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:23])[N:4]2[C:8](=[C:9]([C:20]([OH:22])=O)[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[F:19])[CH2:7][CH2:6][CH2:5]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[C:55]([O:59][CH2:60][CH2:61][O:62][NH2:63])([CH3:58])([CH3:57])[CH3:56]>CN(C=O)C>[C:55]([O:59][CH2:60][CH2:61][O:62][NH:63][C:20]([C:9]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[C:2]([F:1])[C:3](=[O:23])[N:4]2[C:8]=1[CH2:7][CH2:6][CH2:5]2)=[O:22])([CH3:58])([CH3:57])[CH3:56]
Reactant: CC(C)(C)OCCON
Reactant: O=C(O)c1c(Nc2ccc(I)cc2F)c(F)c(=O)n2c1CCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OCCONC(=O)c1c(Nc2ccc(I)cc2F)c(F)c(=O)n2c1CCC2
Temperature: 70 °C
Reaction time: 16 h
Yield: 87.7 %

Procedure:
Example 1 (656 mg, 1.52 mmol), HATU (870 mg, 2.28 mmol) and N-Methylmorpholine (835 μL, 7.59 mmol) were stirred in DMF (7.6 mL) at r.t. for 10 min. O-(2-tert-Butoxy-ethyl)-hydroxylamine (303 mg, 2.28 mmol) was added, and the reaction stirred at 70° C. for 16 h. Purification by prep-HPLC gave 730 mg (73%) of compound 4a as a beige solid. MS (ES) [m+H] calc'd for C21H24F2IN3O4, 548. found 548.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.C(N(CC)CC)C.[CH2:19]([NH2:23])[CH:20]([CH3:22])[CH3:21]>>[CH3:21][CH:20]([CH3:22])[CH2:19][NH:23][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1
Reactant: FC(F)(F)c1nccc(Cl)n1
Reactant: CC(C)CN
Solvent: CCN(CC)CC
Product: CC(C)CNc1ccnc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-chloro-2-(trifluoromethyl)pyrimidine (548 mg, 3 mmol) and triethylamine (0.460 mL, 3.30 mmol) in isobutylamine (1.5 mL) was stirred at room temperature for 11 hours and 30 minutes (Care: exotherm). The mixture was evaporated, then dichloromethane (DCM) (5 mL) and water (5 mL) added. The organic layer was separated and purified by silica (Si) chromatography (0-100% ethyl acetate-cyclohexane gradient). The relevant fractions were combined and concentrated to yield the title compound, 548 mg. LCMS (2 min, formic) Rt 1.08 min, m/z (ES+) 220 (M+H).
Reaction SMILES: [F:1][C:2]1[C:10]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])=[CH:9][CH:8]=[C:7]([F:18])[C:3]=1[C:4]([OH:6])=O.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.[N:41]1([C:46]2[C:54]3[C:49](=[N:50][CH:51]=[C:52]([NH2:55])[CH:53]=3)[NH:48][N:47]=2)[CH:45]=[CH:44][N:43]=[CH:42]1>CN(C=O)C>[N:41]1([C:46]2[C:54]3[C:49](=[N:50][CH:51]=[C:52]([NH:55][C:4](=[O:6])[C:3]4[C:7]([F:18])=[CH:8][CH:9]=[C:10]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])[C:2]=4[F:1])[CH:53]=3)[NH:48][N:47]=2)[CH:45]=[CH:44][N:43]=[CH:42]1
Reactant: Nc1cnc2[nH]nc(-n3ccnc3)c2c1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc(-n4ccnc4)c3c2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.8 %

Procedure:
2,6-Difluoro-3-(propylsulfonamido)benzoic acid (140 mg, 0.495 mmol), HOBt.H2O (89 mg, 0.584 mmol), and EDCI (120 mg, 0.674 mmol) was added to 3-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-5-amine (90 mg, 0.450 mmol) in DMF (10 mL). The mixture was stirred at ambient temperature overnight. The reaction mixture was evaporated, and the residue partitioned between ethyl acetate and water. The ethyl acetate was washed with brine, dried over magnesium sulfate, filtered, and concentrated to an oil. The crude product was purified by column chromatography (10:1 DCM:MeOH), which was followed by trituration with DCM to afford N-(3-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (57.7 mg, 28% yield) as a solid. 1H NMR (400 MHz, CD3OD) δ 8.80 (d, 1H), 8.74 (d, 1H), 8.36 (s, 1H), 7.80 (s, 1H), 7.70-7.64 (m, 1H), 7.27 (s, 1H), 7.17-7.12 (m, 1H), 3.14-3.09 (m, 2H), 1.92-1.82 (m, 2H), 1.06 (t, 3H); m/z (ESI-pos) M+1 462.2.
Reaction SMILES: [CH:1]1([CH:7]2[S:11][C:10]3[C:12]([Cl:19])=[C:13]([Cl:18])[C:14]([O:16][CH3:17])=[CH:15][C:9]=3[CH:8]2O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(F)(F)F.CCOCC.[OH-].[Na+]>C(O)(=O)C>[Cl:18][C:13]1[C:14]([O:16][CH3:17])=[CH:15][C:9]2[CH:8]=[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[S:11][C:10]=2[C:12]=1[Cl:19]
Reactant: COc1cc2c(c(Cl)c1Cl)SC(C1CCCCC1)C2O
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: COc1cc2cc(C3CCCCC3)sc2c(Cl)c1Cl
Reaction time: 1 h
Yield: 64.7 %

Procedure:
A mixture of 14.7 g of 2-cyclohexyl-6,7-dichloro-2,3-dihydro-3-hydroxy-5-methoxybenzo[b]thiophene, 90 ml of glacial acetic acid and 21 ml of boron trifluoride etherate is warmed on a steam bath until it becomes homogeneous and then stirred for one hour. To the reaction mixture is added 100 ml of cold 10% sodium hydroxide solution. The mixture is further basified with 50% sodium hydroxide solution and extracted with three 230 ml-portions of ether. The organic extracts are dried over anhydrous magnesium sulfate, filtered and evaporated. Recrystallization of the residue from ether-hexane gives 9.0 g of 6,7-dichloro-2-cyclohexyl-5-methoxybenzo[b]thiophene as off-white crystals, mp 60°.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:11]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[C:10]([Cl:17])[N:9]=[C:8]2[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:4][CH:3]=1.[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[CH2:24]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[C:10]([Cl:17])[N:9]=[C:8]2[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:22][CH:23]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=Cc1ccccc1
Reactant: CCCCc1nc(Cl)c(CC(=O)OC)n1Cc1ccc(N)cc1
Solvent: C1CCOC1
Product: CCCCc1nc(Cl)c(CC(=O)OC)n1Cc1ccc(NCc2ccccc2)cc1
Reaction time: 8 h
Yield: 57.9 %

Procedure:
A mixture of methyl 1-(4-aminobenzyl)-2-butyl-4-chloroimidazole-5-acetate (1.00 g, 3.0 mmol, 1 eq), benzaldehyde (0.30 mL, 3.0 mmol, 1 eq), 4 Å powdered molecular sieves (enough to make a slurry) and 40 mL THF was stirred overnight. The next day, more benzaldehyde (0.2 mL) and acidic Al2O3 (activity 1, 1 g) were added and the slurry stirred another 24 hours. The solids were filtered and the solvent from the filtrate removed in vacuo. The residue was dissolved in methanol (10 mL) and sodium cyanoborohydride was added (0.19 g, 3.0 mmol, 1 eq). The mixture was stirred for 24 hours, after which the solvent was removed in vacuo to yield a green oil which was flash chromatographed over silica gel in 70:30 hexane/ethyl acetate to give 740 mg of product as an oil. NMR (200 MHz, CDCl3) δ7.42-7.24 (m, 5H); 6.74 (d, 2H, J=7 Hz); 6.56 (d, 2H, J=7 Hz); 4.98 (s, 2H); 4.31 (s, 2H); 3.61 (s, 3H); 3.48 (s, 2H); 2.60 (t, 2H, J=7 Hz); 1.67 (t of t, 2H, J=7,7 Hz); 1.35 (t of q, 2H, J=7,7 Hz); 0.89 (t, 3H, J=7 Hz). Mass Calcd. for C24H28ClN3O2 : 425.1868. Found: 425.1853.
Reaction SMILES: O[C:2]1[C:7]([CH3:8])=[N:6][CH:5]=[C:4]([CH3:9])[N:3]=1.P(Cl)(Cl)([Cl:12])=O>>[Cl:12][C:2]1[C:7]([CH3:8])=[N:6][CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cnc(C)c(O)n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cnc(C)c(Cl)n1

Procedure:
The 2-hydroxy-3,6-dimethylpyrazine disclosed by Baxter et al can be reacted with phosphorus oxychloride by the method described in Preparation 13, Step B, to provide 2-chloro-3,6-dimethylpyrazine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[N:9]2[CH2:12][CH:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)[N:9]2[CH2:10][CH:11]([N:13]([CH3:33])[S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:12]2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: O=S(=O)(NC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CN(C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)S(=O)(=O)c1ccccc1

Procedure:
By carrying out the operation according to the procedure of Example 24, but starting with 0.21 g of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-phenylsulfonamide, 17 mg of 80% sodium hydride and introducing iodomethane in two portions at an interval of 3 hours. 80 mg of N-{1-[bis(4-chlorophenyl)-methyl]azetidin-3-yl}-N-methylphenylsulfonamide are thus obtained in the form of a white lacquer [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): 2.70 (s: 3H); 3.03 (broad t, J=7.5 Hz: 2H); 3.37 (broad t, J=7.5 Hz: 2H); 3.94 (mt: 1H); 4.28 (s: 1H); from 7.20 to 7.35 (mt: 8H); from 7.45 to 7.65 (mt: 3H); 7.74 (broad d, J=8 Hz: 2H)].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([OH:12])=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:3]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19].[OH-].[Na+]>C(Cl)(Cl)Cl>[C:13]([C:4]1[CH:3]=[C:2]([NH:1][S:18]([CH3:17])(=[O:20])=[O:19])[CH:7]=[C:6]([C:8]([CH3:9])([CH3:10])[CH3:11])[C:5]=1[OH:12])([CH3:16])([CH3:15])[CH3:14]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc(NS(C)(=O)=O)cc(C(C)(C)C)c1O
Temperature: 35 °C
Yield: 18 %

Procedure:
To a solution of 11.05 grams (0.05 mole) of 4-amino-2,6-di-tert-butylphenol in 60 ml of chloroform was added with stirring 5.75 grams (0.05 mole) of methanesulfonyl chloride over a 5-minute period. The reaction mixture was heated to 35° C for 15 minutes followed by the dropwise addition of 8.0 grams (0.05 mole) of a 25% aqueous sodium hydroxide solution and finally heating at 47° C for 30 minutes. After cooling to room temperature, the chloroform layer was separated, washed with water and dried over 4A Molecular Sieves and filtered. The solvent was removed in vacuo, and the residue was washed with hexane leaving 5.8 grams of a crude pink product. Recrystallization from toluene and again from ethylene dichloride gave 2.7 grams of colorless crystals melting at 149°-151° C. (Compound 2)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:29])[CH2:9][CH2:10][C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:13][C:12]=2[CH:26]([CH3:28])[CH3:27])=[CH:4][CH:3]=1.[CH:30]1[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[C:33]([S:39](Cl)(=[O:41])=[O:40])=[CH:32][CH:31]=1.O>N1C=CC=CC=1>[CH:26]([C:12]1[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[S:15][C:11]=1[CH2:10][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:39]([C:33]2[CH:32]=[CH:31][CH:30]=[CH:35][C:34]=2[N+:36]([O-:38])=[O:37])(=[O:40])=[O:41])=[CH:3][CH:4]=1)=[O:29])([CH3:27])[CH3:28]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CC(C)c1nc(-c2ccc(C(F)(F)F)cc2)sc1CCC(=O)c1ccc(N)cc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)c1nc(-c2ccc(C(F)(F)F)cc2)sc1CCC(=O)c1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
The obtained 1-(4-aminophenyl)-3-[4-isopropyl-2-[4-(trifluoromethyl)phenyl]thiazol-5-yl]-propan-1-one (250 mg, 0.597 mmol) was dissolved in anhydrous pyridine (5 mL). O-nitrophenylsulfonyl chloride (146 mg, 0.659 mmol) was added to the solution. The mixture was stirred at room temperature for 1 hour. The outer temperature was heated to 80° C., and the mixture was further stirred for 16 hours. The mixture was cooled to room temperature. Water was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated brine, and dried with anhydrous sodium sulfate to remove the solvent. The obtained residue was purified by silica gel column chromatography with hexane/ethyl acetate (8:2, v/v) to give the desired compound (265 mg) as yellow crystalline product (yield 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)=[CH:11][C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][OH:34]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:32][CH2:33][OH:34])[CH:14]=3)=[CH:11][C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cccc(O)c2)n(-c2cccc(Cl)c2)n1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(-c2cccc(OCCO)c2)n(-c2cccc(Cl)c2)n1

Procedure:
100 mg (0.29 mmol) of the compound of Example 44A are provided in 2 ml of dry acetone, 44.4 mg (0.32 mmol) of potassium carbonate and 36.5 mg (0.29 mmol) of 2-bromoethanol are added, and the mixture is heated under reflux overnight. The reaction mixture is subsequently purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with the addition of 0.1% formic acid) and 13.1 mg of the title compound are obtained.
Reaction SMILES: [C:1]1([C:7]2[CH:20]=[CH:19][C:18]3[C:9](=[CH:10][C:11]4[C:16]([CH:17]=3)=[CH:15][C:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:13][CH:12]=4)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:27]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:27][C:17]1[C:18]2[C:9]([CH:10]=[C:11]3[C:16]=1[CH:15]=[C:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:13]=[CH:12]3)=[CH:8][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH:20][CH:19]=2
Reactant: c1ccc(-c2ccc3cc4cc(-c5ccccc5)ccc4cc3c2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Brc1c2ccc(-c3ccccc3)cc2cc2ccc(-c3ccccc3)cc12
Temperature: 60 °C
Reaction time: 6 h
Yield: 81.9 %

Procedure:
First, 33.0 g of 2,6-diphenylanthracene were dissolved in 200 mL of N,N-dimethylformamide under heat, and then a solution of 18.0 g of N-bromosuccinimide in 20 mL of N,N-dimethylformamide was added to the solution. The mixture was stirred at 60° C. for 6 hours under heat. After having been cooled to room temperature, the reaction solution was poured into 1 L of water. The resultant solid was sequentially washed with methanol, water, and methanol. After that, the solid was repeatedly recrystallized with toluene and hexane and washed. Thus, 33.5 g of 9-bromo-2,6-diphenylanthracene were obtained (in 82% yield).