Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N+:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:13]([OH:15])=O)([O-:9])=[O:8].ClCCl.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1.CN(C)C=O>[CH3:19][C:18]1[CH:17]=[CH:16][C:12]([C:13]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:15])=[CH:11][C:10]=1[N+:7]([O-:9])=[O:8]
Reactant: Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: Nc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
Oxalyl chloride (3 mL, 35 mmol) was added dropwise to a stirred solution of 3-nitro-4-methylbenzoic acid (5.0 g, 28 mmol) in a mixture of tetrahydrofuran or dichloromethane (125 mL) and dimethylformamide (1/2 mL) under N2 at ice bath temperature. The mixture was allowed to warm to room temperature. After 1 hour, the solvent was removed by rotary evaporator under reduced pressure. The residue was redissolved in fresh tetrahydrofuran (100 mL) and recooled to ice bath temperature under N2, while a solution of aniline (5.2 g, 56 mmol) in tetrahydrofuran (25 mL) was added dropwise. After 16 hours of stirring at room temperature, the mixture was concentrated to half-volume by rotary evaporator and the residue stirred in water (200 mL). After several hours, the precipitate was filtered off, rinsed three times with water, and dried to afford the product (6.8 g); m.p. 147-148° C.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]#[C:15][CH3:16])=[CH:8][CH:7]=1)(=[O:5])=[O:4].Br[CH:18]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:19]([O:21][CH3:22])=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([S:3]([N:2]([CH3:1])[CH:18]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:19]([O:21][CH3:22])=[O:20])(=[O:5])=[O:4])=[CH:7][CH:8]=1)[C:14]#[C:15][CH3:16]
Reactant: COC(=O)C(Br)c1ccc(Cl)cc1
Reactant: CC#CCOc1ccc(S(=O)(=O)NC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)OC)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a similar manner as described in Example 211,a mixture of 2.39 g N-methyl-[4-(2-butynyloxy)phenyl]sulfonamide], methyl alpha-bromo(4-chlorophenyl)acetate, and powdered potassium carbonate in DMF was stirred at room temperature for 18 hours. The mixture was combined with water and the precipitate was collected and purified by chromatography on silica gel using hexane-ethyl acetate, 4:1 to give methyl 2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-2-(4-chlorophenyl)acetate as a yellow oil which was then used in the subsequent step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([NH2:12])=[C:5]([N+:13]([O-])=O)[CH:4]=1.[CH:16]([CH:18]=O)=O.Cl.CCOC(C)=O>CCO.O.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]2[C:6]([N:12]=[CH:16][CH:18]=[N:9]2)=[C:5]([NH2:13])[CH:4]=1
Reactant: COc1cc([N+](=O)[O-])c(N)c([N+](=O)[O-])c1
Reactant: O=CC=O
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: COc1cc(N)c2nccnc2c1

Procedure:
A solution of 4-methoxy-2,6-dinitro-phenylamine (5 g, 23.5 mmol) in EtOH (200 mL) was hydrogenated over 10% Pd/C (2 g) at 40 psi for 1 hour. After H2 uptake had ceased, the reaction was filtered through a pad of celite and washed with EtOAc (50 mL) and concentrated. Glyoxal (8 ml, 704 mmol) and EtOH (50 mL) were immediately added and the reaction was heated at reflux for 2 hours. The cooled reaction was diluted with H2O (50 mL) and extracted into CH2Cl2 (3×100 mL). The organic phases were combined, dried over Na2SO4, filtered and concentrated. The resulting oil was purified by column chromatography (10% MeOH/CH2Cl2) affording 430 mg (10%) as a red oil. An analytical sample was prepared as the HCl salt from EtOAc affording a red solid.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[CH2:46]([O:48][C:49](=[O:58])[CH2:50][C:51]1[N:52]=[C:53]([NH2:57])[S:54][C:55]=1[CH3:56])[CH3:47].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[CH2:46]([O:48][C:49](=[O:58])[CH2:50][C:51]1[N:52]=[C:53]([NH:57][C:8](=[O:10])[CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[S:54][C:55]=1[CH3:56])[CH3:47]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Reactant: CCOC(=O)Cc1nc(N)sc1C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1nc(NC(=O)C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)sc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid (200 mg, 0.67 mmol) in a mixture of dry methylene chloride (5 mL) and dry DMF (1 mL) were added HOBT (20 mg) and DCC (155 mg, 0.75 mmol), and the mixture was stirred at room temperature for 2 h. A solution of (2-amino-5-methyl-thiazol-4-yl)-acetic acid ethyl ester (220 mg, 0.78 mmol) and DIPEA (135 μl, 102 mg, 0.79 mmol) in dry DMF (1 mL) was added to the reaction mixture and stirring was continued for 18 h at room temperature. The mixture was evaporated in vacuo and the residue purified on a silica gel column (heptan:ethyl acetate (7:3)) to give {2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-5-methyl-thiazol-4-yl}-acetic acid ethyl ester. Yield: 120 mg (37%). 1H-NMR (CDCl3): δ 8.86 (broad s, 1H), 7.91 (d, 2H), 7.52 (d, 2H), 4.14 (q, 2H), 3.66 (t, 1H), 3.57 (s, 2H), 3.07 (s, 3H), 2.32 (s, 3H), 2.25-2.18 (m, 1H), 1.93-1.86 (m, 1H), 1.81-1.43 (m, 7H), 1.24 (t, 3H), 1.16-1.06 (m, 2H); HPLC-MS: m/z=480 (M+1); Rt=4.09 min.
Reaction SMILES: [O:1]([CH2:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.[NH2:15][C:16]1[CH:28]=[C:27]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:25][C:17]=1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(N(CC)CC)C>[O:29]([C:27]1[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])=[C:16]([NH:15][C:9](=[O:10])[CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:28]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1N
Reactant: O=C(Cl)COc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1NC(=O)COc1ccccc1
Reaction time: 2 h

Procedure:
0.029 mL of 2-phenoxyacetyl chloride was added to 2.5 mL of methylene chloride solution containing 40 mg of tert-butyl 2-amino-4-phenoxybenzoate and 0.039 mL of triethylamine at room temperature and stirred at the same temperature for 2 hours. 0.25 g of aminomethylated polystyrene was added to the reaction mixture and after stirred at the same temperature overnight, 5 mL of 10% citric acid aqueous solution was added. The organic layer was separated and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate: acetic acid=20:5:1] to obtain tert-butyl 4-phenoxy-2-(2-phenoxyacetamido)benzoate.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:12])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.Cl[C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15].C1(C)C=CC=CC=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:12])[CH2:8][N:9]2[C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])=[CH:4][CH:3]=1
Reactant: O=c1cnc2cc(Br)ccc2[nH]1
Reactant: CC(C)OC(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)OC(=O)N1CC(=O)Nc2ccc(Br)cc21
Yield: 97 %

Procedure:
To a solution of 7-bromo-3-oxo-3,4-dihydroquinoxaline (6.8 g, 30 mmol) in pyridine (50 ml) was added a solution of isopropyl chloroformate in toluene (35 ml, 1M, 35 mmol) over 30 minutes. The mixture was triturated with water/chloroform, the organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated to obtain crude isopropyl 7-bromo-3-oxo-3,4-dihydroquinoxaline-1(2H)-carboxylate(9.3 g, 97%). A sample was recrystallized from ethanol: m.p. 159-161° C. 1H-NMR (DMSO-d6) δ 1.25 (d, J=6.2 Hz, 6H), 4.25 (s, 2H), 4.90 (Sep, J=6.2 Hz, 1H), 6.89 (d, J=8.6 Hz, 1H), 7.27 (dd, J=9.1, 2.1 Hz, 1H), 7.74 (s, 1H), 12.51 (s, 1H), MS (ESI) m/z 330/332 (M+NH4)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])[CH:5]=[CH:6][C:7]([OH:9])=[O:8].[CH:14]12CC(C=C1)CC2CO.C1(C)C(C)=CC=CC=1>[OH-].C([O-])(=O)C.[Zr+4].C(OCC)(=O)C>[CH:12]12[CH2:5][CH:4]([CH:3]=[CH:2]1)[CH2:10][CH2:11]2.[CH3:14][C:3]1[C:2]([F:1])=[C:12]([F:13])[CH:11]=[CH:10][C:4]=1[CH:5]=[CH:6][C:7]([O-:9])=[O:8]
Reactant: O=C(O)C=Cc1ccc(F)c(F)c1
Reactant: OCC1CC2C=CC1C2
Agent: [Zr+4]
Agent: CC(=O)[O-]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: C1=CC2CCC1C2
Product: Cc1c(C=CC(=O)[O-])ccc(F)c1F
Temperature: 145 °C
Yield: 63 %

Procedure:
5 g (27.2 mmol) of 3,4-di-fluoro-cinnamic acid, 3.38 g (1 eq.) of 5-norbornene-2-methanol, and 0.13 g (0.02 eq.) of zirconium(IV) acetate hydroxide were added to 50 ml of xylene and stirred. The mixture was heated to 145° C. under N2 atmosphere and azeotropically refluxed for 24 hours. After the reaction, the mixture cooled down to room temperature and was added with 100 volume % of ethyl acetate. The resulting product was extracted by 1M HCl and washed again with water. The organic layer was dried with Na2SO4 and the solvent was evaporated out to give a highly viscous material. (Yield: 63%, Purity (GC): 80%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][C:15](O)=O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C1CCC(N=C=NC2CCCCC2)CC1.[N:33]1[C:37]2[CH:38]=[CH:39][C:40]([C:42]([NH:44][NH2:45])=O)=[CH:41][C:36]=2[NH:35][CH:34]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:55])=CC=1>>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10])[CH2:13][CH2:14][C:15]1[S:55][C:42]([C:40]2[CH:39]=[CH:38][C:37]3[NH:33][CH:34]=[N:35][C:36]=3[CH:41]=2)=[N:44][N:45]=1
Reactant: COc1cc(CCC(=O)O)cc(OC)c1OC
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: COc1cc(CCc2nnc(-c3ccc4[nH]cnc4c3)s2)cc(OC)c1OC

Procedure:
The compound was synthesized starting from 3-(3,4,5-trimethoxyphenyl)propionic acid (241 mg; 1 mmol), DCC (206 mg; 1 mmol), benzimidazol-5-carbohydrazide (176 mg; 1 mmol) and Lawesson's reagent (606 mg; 1.5 mmol) as described in method 2; yield: 0.033 g (8.3%); MS m/z: 397.3 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 3.04 (t, 2H, 3J=7.9 Hz); 3.47 (t, 2H, 3J=7.9 Hz); 3.62 (s, 3H); 3.74 (s, 6H); 6.62 (s, 2H); 7.83 (d, 1H, 3J=8.7 Hz); 7.93 (dd, 1H, 4J=1.7 Hz, 3J=8.7 Hz); 8.22 (d, 1H, 4J=1.7 Hz); 8.91 (s, 1H); HPLC (METHOD [A]): rt 11.54 min (98.2%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=3)[N:17]=2)[N:10]([C:25](=[O:35])[CH:26]([NH:30][C:31]([O:33][CH3:34])=[O:32])[CH:27]([CH3:29])[CH3:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:36][O:37][C:38](=[O:71])[NH:39][CH:40]([C:44]([N:46]1[CH2:50][CH2:49][CH2:48][CH:47]1[C:51]1[NH:52][CH:53]=[C:54]([C:56]2[CH:61]=[CH:60][C:59](B3OC(C)(C)C(C)(C)O3)=[CH:58][CH:57]=2)[N:55]=1)=[O:45])[CH:41]([CH3:43])[CH3:42].C(=O)([O-])[O-].[K+].[K+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]2[NH:17][C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:59]4[CH:60]=[CH:61][C:56]([C:54]5[NH:55][C:51]([CH:47]6[CH2:48][CH2:49][CH2:50][N:46]6[C:44](=[O:45])[CH:40]([NH:39][C:38]([O:37][CH3:36])=[O:71])[CH:41]([CH3:43])[CH3:42])=[N:52][CH:53]=5)=[CH:57][CH:58]=4)=[CH:20][CH:19]=3)=[CH:15][N:14]=2)[N:10]([C:25](=[O:35])[CH:26]([NH:30][C:31]([O:33][CH3:34])=[O:32])[CH:27]([CH3:29])[CH3:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CN(C(=O)OC(C)(C)C)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CN(C(=O)OC(C)(C)C)CN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Temperature: 120 °C
Yield: 48.1 %

Procedure:
4-(4-Bromo-phenyl)-3′-(2-methoxycarbonylamino-3-methyl-butyryl)-2′,3′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-1′-carboxylic acid tert-butyl ester (75 mg, 0.136 mmol) was combined with [2-Methyl-1-(2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (67.6 mg, 0.136 mmol) under an argon atmosphere. Potassium carbonate (37.5 mg, 0.272 mmol) and Pd(PPh3)4 (15.7 mg, 0.014 mmol) were added, followed by DME (3 mL) and water (0.6 mL). The mixture was heated under microwave conditions for 20 minutes at 120° C. All volatiles were removed in vacuo and the crude material was dissolved in DMF and purified via RP-HPLC (eluent: water/MeCN w 0.1% TFA) to yield the product (55 mg): LCMS-ESI+: calc'd for C44H57N9O8: 839.9 (M+). Found: 840.5 (M+H+); 1H-NMR: 300 MHz, (MeOH-d4) δ: 7.90-7.81 (m, 10H), 5.58 (m, 1H), 5.43 (m, 1H), 5.25-5.20 (m, 2H), 4.24 (d, J=7.5 Hz, 1H), 4.11 (m, 1H), 3.99 (m, 1H), 3.86 (m, 2H), 3.67 (s, 3H), 3.66 (s, 3H), 3.46 (d, J=7.2 Hz, 1H), 2.59 (m, 1H), 2.22-2.10 (m, 5H), 1.53 & 1.44 (s, 9H) 1.04-0.89 (m, 12H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]([CH2:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:21](=O)[CH3:22].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:14]([CH2:21][CH3:22])[CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]([CH2:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCc1c(NC2CCOCC2)cc(Cl)cc1C(=O)OC
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCc1c(C(=O)OC)cc(Cl)cc1N(CC)C1CCOCC1
Yield: 82.4 %

Procedure:
To a solution of methyl 5-chloro-2-ethyl-3-[(oxan-4-yl)amino]benzoate (350 mg, 1.18 mmol) in 1,2-dichloroethane (10 ml) at room temperature under nitrogen was added acetaldehyde (0.66 ml, 11.8 mmol) followed by acetic acid (0.4 ml, 7.05 mmol). This solution was stirred for 5 minutes before the addition of sodium triacetoxyborohydride (2.49 g, 11.8 mmol) at room temperature. After stirring for 23 hours acetaldehyde (0.66 ml, 11.8 mmol) was added to the dark reaction mixture and this was stirred for 10 minutes before the addition of sodium triacetoxyborohydride (2.49 g, 11.8 mmol). After stirring for 3 hours deionized water (15 ml) was added and the mixture was neutralized with solid NaHCO3. The phases were separated and the aqueous layer was extracted with EtOAc (2×15 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (10 g silica, Isolute cartridge, gradient of eluents; 99:1 Heptane:EtOAc to 85:15 Heptane:EtOAc) to give 317 mg of the title compound as a colorless oil. The product contains ˜25% ether ester. The material was taken through the next step without further purification. LC-MS 55%, 2 m/z=326.0/328.0, 1H NMR (500 MHz, Chloroform-d) δ ppm 7.52 (d, J=2.2 Hz, 1H), 7.23 (d, J=2.2 Hz, 1H), 3.97 (d, J=11.1 Hz, 2H), 3.90 (s, 3H), 3.32 (td, J=11.6, 2.5 Hz, 2H), 3.04 (q, J=7.1 Hz, 4H), 2.93 (ddd, J=15.1, 10.8, 4.3 Hz, 1H), 1.76-1.62 (m, 4H), 1.08 (t, J=7.4 Hz, 3H), 0.88 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[OH-].[K+].[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br.[Br-]>CS(C)=O.O>[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][NH:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: Clc1ccccc1CBr
Reactant: Nc1c2c(nc3ccccc13)CCCC2=O
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C1CCCc2nc3ccccc3c(NCc3ccccc3Cl)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.2 %

Procedure:
To a suspension of 9-amino-3,4-dihydroacridin-1(2H)-one (8.0 g) in 75 ml of dimethyl sulfoxide was added pulverized potassium hydroxide (6.2 g). This was stirred for 0.5 hour at ambient temperature. To this solution was added 2-chlorobenzyl bromide (9.4 g). After 1 hour, an additional 1 ml of the bromide was added. This was stirred for an additional hour. At this time, 200 ml of water was added, and the precipitate was filtered and washed with water. The solid was taken up in dichloromethane and dried over anhydrous magnesium sulfate. The compound was purified via flash chromatography to yield 6.75 g of solid, mp 150°-161° C. A portion of this was recrystallized from methanol to give analytically pure needles, mp 162°-165° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[C:4]([C:3]1[CH:8]=[C:9]([O:12][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([Cl:13])[CH:15]=2)[CH:10]=[CH:11][C:2]=1[OH:1])([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(O)ccc1O
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OCc2cccc(Cl)c2)ccc1O
Yield: 68.2 %

Procedure:
Eight grams (47.62 mmoles) of the above ester was treated with 6.3 ml (47.62 mmoles) of 3-chlorobenzyl bromide and 8 grams potassium carbonate in 70 ml acetonitrile under reflux for 4 hours. The mixture was diluted with 100 ml ethyl acetate, filtered, and stripped in vacuo. The residue was recrystallized from ethanol to give 9.5 g of 2-Carbomethoxy-4-(m-chlorophenylmethyloxy)-phenol (62% yield from 2,5-dihydroxybenzoic acid).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([S:18]([NH2:21])(=[O:20])=[O:19])[CH2:14][CH2:13]1)=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:31]([N:34]=[C:35]=[S:36])([CH3:33])[CH3:32]>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([S:18]([NH:21][C:35]([NH:34][CH:31]([CH3:33])[CH3:32])=[S:36])(=[O:20])=[O:19])[CH2:14][CH2:13]1)=[O:8]
Reactant: CC(C)N=C=S
Reactant: COc1ccc(Cl)cc1C(=O)NCCC1CCN(S(N)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COc1ccc(Cl)cc1C(=O)NCCC1CCN(S(=O)(=O)NC(=S)NC(C)C)CC1
Yield: 59.5 %

Procedure:
188 mg (0.5 mmol) of 4-(2-(5-chloro-2-methoxybenzamido)ethyl)piperidine-1-sulfonamide and 326 mg (1 mmol) of cesium carbonate were heated in 5 ml of N-methyl-2-pyrrolidone with 0.1 ml (0.9 mmol) of isopropyl isothiocyanate at 80° C. for 10 minutes. The reaction mixture was poured onto ice/2 M hydrochloric acid and extracted three times with 10 ml of dichloromethane each time. The combined organic phases were dried over sodium sulfate and filtered after addition of activated carbon. The crude product obtained after removal of the solvent was recrystallized from methanol. 142 mg (60%) of the title compound were obtained as a colorless solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:11](Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>CS(C)=O.O>[CH2:11]([O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: Oc1ccc(I)cc1
Reactant: CCCCCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCCCOc1ccc(I)cc1
Yield: 88.3 %

Procedure:
To 34.0 g of p-iodo-phenol dissolved in 350 ml of DMSO, were added 7.4 g of sodium hydroxide dissolved in 50 ml of water and stirred to obtain a homogeneous solution. Then, 32.4 g of n-decyl bromide were added and stirred at room temperature for 3 days. The resulting solution was introduced into 1 l of iced water, and extracted three times with hexane. The hexane phase was washed with water, followed by distilling off the hexane to obtain 46.6 g of oily p-n-decyloxy-iodobenzene.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[F:11].C(Cl)(=O)C(Cl)=O.Cl.[CH3:19][NH:20][O:21][CH3:22].C(N(CC)CC)C>ClCCl.CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:20]([O:21][CH3:22])[CH3:19])=[O:7])=[CH:4][C:3]=1[F:11]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.9 %

Procedure:
To a suspension of 4-bromo-3-fluorobenzoic acid (1, 967.9 g, 4.4 mol) in dichloromethane (5.9 L) and DMF (21 mL) was slowly added a solution of oxalyl chloride ((COCl)2, 560 mL, 6.4 mol, 1.45 equiv) in dichloromethane (520 mL) at room temperature. The resulting reaction mixture was stirred at room temperature for 20 h and then cooled to 0° C. by ice-water bath. N,O-dimethyl hydroxylamine hydrochloride (826 g, 8.4 mol, 1.9 equiv) was added followed by slow addition of triethylamine (TEA, 2.5 L, 17.7 mol, 4.0 equiv) at 0° C. The reaction mixture was then gradually warmed to room temperature and stirred at room temperature overnight. Once the coupling reaction was complete, the reaction mixture was washed with saturated aqueous sodium bicarbonate solution (NaHCO3, 2 L). The aqueous phase was back extracted with dichloromethane (1 L). The combined organic phases were washed with water (1 L), brine (1 L), and concentrated under reduced pressure. The resulting solid residue was dissolved into methyl tert-butyl ether (MTBE, 5 L), washed sequentially with water (5×1 L), brine (1 L), and dried over anhydrous sodium sulfate (Na2SO4). The filtrated solution was concentrated under reduced pressure and the resulting solid was dried in a vacuum oven at 45° C. to afford 4-bromo-3-fluoro-N-methoxy-N-methylbenzamide (3, 1106 g, 1153 g theoretical, 95.9% yield) which was used for the subsequent reaction without further purification. For 3: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.78 (t, 1H, J=7.47 Hz), 7.56 (dd, 1H, J=9.3, 1.6 Hz), 7.18 (d, 1H, J=8.1 Hz), 3.53 (s, 3H), 3.25(s, 3H); C9H9BrFNO2 (MW 262.08), LCMS (EI) m/e 262.0/264.0 (M++H).
Reaction SMILES: [CH2:1]([N:5]1[CH:14]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[C:13]2[C:12](=[O:23])[CH2:11][CH2:10][CH2:9][C:8]=2[N:7]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:6]1=[O:34])[CH2:2]CC.BrC[CH2:37][O:38]C>>[F:32][C:30]([F:33])([F:31])[C:26]1[CH:25]=[C:24]([N:7]2[C:8]3[CH2:9][CH2:10][CH2:11][C:12](=[O:23])[C:13]=3[CH:14]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)[N:5]([CH2:1][CH2:2][O:38][CH3:37])[C:6]2=[O:34])[CH:29]=[CH:28][CH:27]=1
Reactant: COCCBr
Reactant: CCCCN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1
Product: COCCN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1

Procedure:
The title compound is prepared in analogy to 4-(3-butyl-1-(3-(trifluoromethyl)phenyl)-2,5-dioxo-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)benzonitrile (example 21), using 1-bromo-2-methoxyethane as alkylating agent. Yield: 15 mg; ESI mass spectrum [M+H]+=470; Retention time HPLC: 1.33 min (V001—006).