Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1.[K].[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12>CN(C)C=O>[CH3:12][O:11][C:9]([C:8]1[CH:13]=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:20]2[C:19](=[O:21])[C:18]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]3[C:16]2=[O:26])=[CH:6][CH:7]=1)=[O:10]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COC(=O)c1ccc(OCCBr)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
Methyl 4-(2-Bromoethoxy)benzoate (126.52 g) and 99.5 g of potassium salt of phthalimide were dissolved in 600 ml of N,N-dimethylformamide and the solution was stirred at 78°-80° C. for 2 hours. The reaction solution was poured over ice water and extracted with chloroform. The chloroform layer was washed with water twice, dried with anhydrous magnesium sulphate, and concentrated in vacuo whereupon the residue was crystallised. Ether was added to the residue and filtered to give crystals in 149.23 g (yield: 94%). M.p. 129°-130.5° C.
Reaction SMILES: FC1C(O[C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=C(F)C(F)=C(F)C=1F.[CH2:29]([C:31]1[CH2:35][CH:34]([CH2:36][O:37][NH2:38])[O:33][N:32]=1)[CH3:30]>>[CH2:29]([C:31]1[CH2:35][CH:34]([CH2:36][O:37][NH:38][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)[O:33][N:32]=1)[CH3:30]
Reactant: CCC1=NOC(CON)C1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccccc1NCc1ccncc1
Product: CCC1=NOC(CONC(=O)c2ccccc2NCc2ccncc2)C1

Procedure:
Prepared by a similar method as described for example 415. Starting materials: 2-[(Pyridin-4-ylmethyl)-amino]-benzoic acid pentafluorophenyl ester (preparation 7C) and O-(3-ethyl-4,5-dihydro-isoxazol-5-ylmethyl)-hydroxylamine (see preparation 90).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:12][N:11]([CH3:13])[CH2:10]2)=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1.[F:17][C:18]1[CH:19]=[CH:20][C:21]2=[C:22]([CH:43]=1)[O:23][CH2:24][C:25]1[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:26]=1/[C:27]/2=[CH:28]\B1OC(C)(C)C(C)(C)O1.O1CCCC1.C[O-].[Na+]>CO.C(OCC)(=O)C.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>[F:17][C:18]1[CH:19]=[CH:20][C:21]2=[C:22]([CH:43]=1)[O:23][CH2:24][C:25]1[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:26]=1/[C:27]/2=[CH:28]\[C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:12][N:11]([CH3:13])[CH2:10]2)=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1
Reactant: CN1CC(Nc2ccc(Br)cc2[N+](=O)[O-])C1
Reactant: CC1(C)OB(/C=C2/c3ccc(F)cc3OCc3c(F)cccc32)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CN1CC(Nc2ccc(/C=C3/c4ccc(F)cc4OCc4c(F)cccc43)cc2[N+](=O)[O-])C1
Yield: 118.3 %

Procedure:
Purge with nitrogen for five min a mixture of (4-bromo-2-nitro-phenyl)-(1-methyl-azetidin-3-yl)-amine (709 μmol, 203 mg), (E)-3,7-difluoro-11-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-ylmethylene)-6,11-dihydro-dibenzo[b,e]oxepine (723 μmol, 268 mg) in methanol (1.0 mL)/tetrahydrofuran (3.0 mL) (1:3 solvent ratio) in a sealed tube. Add sodium methoxide (1.42 mmol, 77 mg), tetrakis(triphenylphosphine)palladium (35 μmol, 41 mg) and heat at 70° C. overnight. Dilute with ethyl acetate, wash with 10% sodium bicarbonate twice, dry over anhydrous sodium sulfate, filter, and concentrate in vacuo to obtain 377 mg of an orange oil residue. Purify on a 12 g silica gel column eluting with 5% methanol in dichloromethane to obtain the title compound (199 mg, 62%). LC-MS m/z 450.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([F:9])[C:3]=1[OH:10].[C:11]([C:16]1[CH:17]=[N:18][C:19]2[C:24]([C:25]=1Cl)=[CH:23][CH:22]=[CH:21][C:20]=2[O:27][CH3:28])(=[O:15])[CH2:12][CH2:13][CH3:14]>O1CCOCC1>[C:11]([C:16]1[CH:17]=[N:18][C:19]2[C:24]([C:25]=1[NH:8][C:6]1[CH:7]=[C:2]([F:1])[C:3]([OH:10])=[C:4]([F:9])[CH:5]=1)=[CH:23][CH:22]=[CH:21][C:20]=2[O:27][CH3:28])(=[O:15])[CH2:12][CH2:13][CH3:14]
Reactant: Nc1cc(F)c(O)c(F)c1
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(OC)cccc2c1Nc1cc(F)c(O)c(F)c1
Yield: 27.6 %

Procedure:
2,6-Difluoro-4-aminophenol (1.49 g, 5.65 mmol) and 3-butyryl-4-chloro-8-methoxyquinoline (1.23 g, 8.48 mmol) in dioxan (50 ml) were refluxed under nitrogen for 2.5 hours. The solvent was evaporated and the product was converted to the free base, purified by flash chromatography (silica, methanol-ammonia/chloroform), triturated with methanol, filtered, washed and dried to give the title compound (0.58 g), m.p. 274°-5° (dec).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:38]([S:40]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)(=[O:42])=[O:41])[CH3:39]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:46]3[CH2:45][CH2:44][N:43]([S:40]([CH2:38][CH3:39])(=[O:41])=[O:42])[CH2:48][CH2:47]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CCS(=O)(=O)N1CCNCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(S(=O)(=O)CC)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 1-ethanesulfonyl-piperazine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C35H44Cl2N5O4S [(M+H)+] 700.2486, observed 700.2486.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)(O)[C:10]3[N:11]=[C:12]([CH3:14])[O:13][C:9]=3[CH2:8][CH2:7][C:6]=2[CH:26]=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:10]3[N:11]=[C:12]([CH3:14])[O:13][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:26]=1
Reactant: Cc1nc2c(o1)CCc1cc(Cl)ccc1C2(O)c1cn(C)c(=O)[nH]c1=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2c(o1)C=Cc1cc(Cl)ccc1C2c1cn(C)c(=O)[nH]c1=O

Procedure:
A solution of the product from step (viii) (0.85 g) in trifluoroacetic acid (20 ml) was heated at reflux for 8 days. The solvent was evaporated and the residue triturated with ethyl acetate/isohexane to give a solid.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].Cl[C:13]1([C:25]2[C:26]([O:31][CH2:32][CH3:33])=[N:27][CH:28]=[CH:29][CH:30]=2)[C:21]2[C:16](=[CH:17][C:18]([F:23])=[C:19]([Cl:22])[CH:20]=2)[NH:15][C:14]1=[O:24].Cl>CN(C)C=O.ClCCl.CCCCCCC.C(OCC)(=O)C>[Cl:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[F:23])[NH:15][C:14](=[O:24])[C:13]2([CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])[C:25]1[C:26]([O:31][CH2:32][CH3:33])=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCOc1ncccc1C1(Cl)C(=O)Nc2cc(F)c(Cl)cc21
Reactant: COC(=O)CC(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCOc1ncccc1C1(C(C(=O)OC)C(=O)OC)C(=O)Nc2cc(F)c(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.4 %

Procedure:
7.26 ml (63.5 mmol) of dimethyl malonate were slowly added dropwise to a suspension, cooled to 10° C., of 2.311 g (57.8 mmol, 60% w/w) of sodium hydride in 150 ml of dimethylformamide. The reaction mixture was then stirred at room temperature for 30 minutes and subsequently 6.57 g (19.26 mmol) of 3,5-dichloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-1,3-dihydroindol-2-one (prepared using 5-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-3-hydroxy-1,3-dihydroindol-2-one in analogy to example 1.1) was added in portions undiluted. The reaction mixture was then stirred for a further 15 minutes at room temperature. The progress of the reaction was monitored by thin-layer chromatography (silica gel, heptane/ethyl acetate 1:1). The mixture was worked up by stirring into cold 1N HCl and adding dichloromethane. The phases were separated, and the aqueous phase was extracted with dichloromethane (1×). The combined organic phase was washed initially with water (1×) and then with saturated sodium chloride solution (1×), dried over magnesium sulfate and filtered, and the solvent was removed in vacuo. The residue was again partly dissolved in a little dichloromethane, and pentane was added. Several fractions of crystals were obtained. In total, 3.23 g of the title compound were obtained as a white solid and 1.62 g as a beige-colored solid.
Reaction SMILES: C([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([S:16][CH2:17][CH3:18])[N:13]([CH3:15])[CH:14]=2)=[CH:6][CH:5]=1)C.Br.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:17]([S:16][C:12]1[N:13]([CH3:15])[CH:14]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([OH:3])=[CH:5][CH:6]=2)[N:11]=1)[CH3:18]
Reactant: CCOc1ccc(-c2cn(C)c(SCC)n2)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCSc1nc(-c2ccc(O)cc2)cn1C

Procedure:
A mixture of 20 parts of 4-(4-ethoxyphenyl)-2-(ethylthio)-1-methyl-1H-imidazole and 37.5 parts of hydrobromic acid solution 48% in glacial acetic acid is stirred and refluxed for 3 hours. The reaction mixture is cooled and neutralized with sodium hydrogen carbonate. The precipitated product is filtered off and crystallized from 4-methyl-2-pentanone, yielding 5 parts of 4-[2-(ethylthio)-1-methyl-1H-imidazol-4-yl]phenol; mp. 209.9° C.
Reaction SMILES: [Br:1][C:2]1[N:6]([C@H:7]2[C@H:12]([O:13]C(=O)C)[C@H:11]([O:17]C(=O)C)[C@@H:10]([CH2:21][O:22]C(=O)C)[O:9][CH2:8]2)[C:5]2[CH:26]=[C:27]([Cl:31])[C:28]([Cl:30])=[CH:29][C:4]=2[N:3]=1.CO.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].CO.C(Cl)(Cl)Cl>O.C(O)(=O)C>[Br:1][C:2]1[N:6]([C@H:7]2[C@H:12]([OH:13])[C@H:11]([OH:17])[C@@H:10]([CH2:21][OH:22])[O:9][CH2:8]2)[C:5]2[CH:26]=[C:27]([Cl:31])[C:28]([Cl:30])=[CH:29][C:4]=2[N:3]=1
Reactant: CC(=O)OC[C@H]1OC[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: OC[C@H]1OC[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Reaction time: 0.5 h
Yield: 81 %

Procedure:
(3R,4S,5S,6R)-2-Bromo-5,6-dichloro-1-(4,5-diacetoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-3-yl)-1H-benzimidazole (part e of this example, 0.810 g, 1.53 mmol) was dissolved in 1:1 methanol-ethanol (100 ML) and treated with a solution of sodium carbonate (0.163 g, 1.53 mmol) in water (10 ML). After 0.5 h at room temperature, TLC analysis indicated a single new spot (silica gel, 10% methanol-chloroform). The pH was then adjusted to 5 with glacial acetic acid and the solvents evaporated in vacuo. The residual solid was slurried in water until the solids were free-flowing, then suction-filtered and dried overnight in vacuo affording the title compound as a white solid (0.510 g, 81%); m.p. 207-209° C.; [α]20D−162° (c 0.26, EtOH); 1H-NMR (DMSO-d6, 200 MHz) δ: 8.30, 8.28 (s, each 1H), 5.26 (d, J=5.5 Hz, 1H), 5.13 (d, J=4.2 Hz, 1H), 5.05 (t, J=4.7 Hz, 1H), 5.04 (m, 1H), 4.78 (m, 1H), 4.33-4.00 (m, 3H), 3.84-3.68 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([N:8]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24](=[O:32])[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>>[C:35]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24](=[O:32])[C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH2:20][CH2:19]2)[C:9]2[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[O:7])=[CH:33][CH:34]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(N)cc2)cc1
Product: CC(=O)Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2ccc(C)cc2)cc1
Yield: 95.4 %

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(4-methylphenyl)benzamide (452.7 mg, 0.99 mmol) and acetic anhydride (0.122 ml, 1.19 mmol), the procedure of Inventive Example 94 was repeated to obtain 473.6 mg (95.4%) of the title compound in a light brown amorphous form.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]([C:21]3[C:22]([O:27]C)=[N:23][CH:24]=[CH:25][CH:26]=3)=[O:20])=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].C([O-])(O)=O.[Na+]>Br.CC(O)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]([C:21]3[C:22]([OH:27])=[N:23][CH:24]=[CH:25][CH:26]=3)=[O:20])=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:29]([F:32])([F:30])[F:31]
Reactant: COc1ncccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(c1cccnc1O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 61.7 %

Procedure:
A mixture of 4-chloro-N-[5-chloro-2-(2-methoxy-pyridine-3-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzene sulfonamide (10 mg, mmol) in 30% HBr in AcOH (1 mL) was stirred at 50° C. for 2 h. The reaction mixture was cooled to room temperature, diluted with water (1 mL) and treated with saturated aqueous NaHCO3 solution slowly till pH 5-6. The mixture was extracted with EtOAc (2×25 mL), dried (anhydrous Na2SO4) and concentrated. The obtained residue was column purified (SiO2, 10% MeOH in CH2Cl2) to afford 4-chloro-N-[5-chloro-2-(2-hydroxy-pyridine-3-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (6 mg) in 61.8% yield. 1H NMR (400 MHz, CDCl3) δ 8.24 (d, 1H), 8.17 (d, 1H), 8.15 (d, 1H), 7.97 (dd, 1H), 7.72 (dd, 1H), 7.63 (d, 1H), 7.43 (dd, 1H), 6.37 (t, 1H); ESMS m/z (relative intensity): 491.9 (M+H)+ (100).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].B1([O-])OO1.[OH2:14].[OH2:15].O.O.[Na+].O>C(O)(=O)C>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[N+:4]([O-:15])=[O:14]
Reactant: O
Reactant: Nc1c(F)cccc1F
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(F)cccc1F
Temperature: 85 °C
Yield: 51.8 %

Procedure:
2,6-Difluoroaniline (11.0 g, 85 mmol) in glacial acetic acid (50 mL) was added slowly to a stirred suspension of sodium perborate tetrahydrate (65 g, 422 mmol) in glacial acetic acid (250 mL) at 80° C. The temperature was maintained between 80-90° C. for 1 hour. The cooled reaction mixture was poured into water and extracted twice with diethyl ether, the combined organic layers were washed with a dilute solution of sodium bicarbonate, dried (MgSO4) and evaporated. The residue was purified by silica gel column chromatography (Hexane:THF, 9:1) and the product washed with hexane to afford 2,6-difluoronitrobenzene (7.0 g) which was used without further examination.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[C:10]([C:17]([F:20])([F:19])[F:18])[CH:9]=1.CN.C1COCC1.[CH2:28]([N:30](CC)CC)C>CN(C=O)C.ClCCl>[F:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH:30][CH3:28])=[O:13])=[C:10]([C:17]([F:20])([F:19])[F:18])[CH:9]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc(F)cc1C(F)(F)F
Agent: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
DMF (3 drops) and oxalyl chloride (2.55 ml) were added to a mixture of 4-fluoro-2-(trifluoromethyl)benzoic acid (5.50 g) and dichloromethane (50 ml), followed by stirring at room temperature for 3 hours. The reaction solution was added dropwise to a 2M methylamine-THF solution (17.3 ml) and a solution of triethylamine (5.55 ml) in dichloromethane (50 ml) under ice cooling, followed by stirring for 30 minutes and concentration under reduced pressure, addition of water and extraction with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate solution and then saturated brine in this order, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with diisopropylether to obtain 4-fluoro-N-methyl-2-(trifluoromethyl)benzamide (4.37 g) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:24][C:25]1[CH:33]=[C:32]([C:34]#[C:35][CH2:36][CH2:37][O:38][CH3:39])[C:28]2[O:29][CH2:30][O:31][C:27]=2[C:26]=1[NH2:40].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[F:24][C:25]1[CH:33]=[C:32]([C:34]#[C:35][CH2:36][CH2:37][O:38][CH3:39])[C:28]2[O:29][CH2:30][O:31][C:27]=2[C:26]=1[NH:40][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COCCC#Cc1cc(F)c(N)c2c1OCO2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCC#Cc1cc(F)c(Nc2ncnc3cc(OCCCN4CCOCC4)c(OC)cc23)c2c1OCO2
Yield: 57.6 %

Procedure:
This was prepared using the method described in example 4 using 4-chloro-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazoline (200 mg, 0.59 mmol), 5-fluoro-7-(4-methoxybut-1-yn-1-yl)-1,3-benzodioxol-4-amine (154 mg, 0.65 mmol) and a solution of sodium bis(trimethylsilyl)amide (1.0M in THF, 1.25 ml) in DMF (3 ml). The crude product was purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent. There was thus obtained the title compound (183 mg, 57%) as a pale brown solid; NMR Spectrum:(DMSOd6) 1.96 (quintet, 2H), 2.39 (m, 4H), 2.46 (t, 2H), 2.72 (t, 2H), 3.33 (s, 3H), 3.52 (t, 2H), 3.60 (m, 4H), 3.93 (s, 3H), 4.19 (t, 2H), 6.14 (s, 2H), 6.84 (d, 1H), 7.19 (s, 1H), 7.81 (s, 1H), 8.36 (s, 1H), 9.51 (s, 1H); Mass Spectrum: M+H+ 539.
Reaction SMILES: [CH2:1]([S:8][CH2:9][C@H:10]([C:26](O)=[O:27])[NH:11][C:12](=[O:25])[C:13]([CH3:24])([CH3:23])[CH2:14][S:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:30]([O:32][C:33](=[O:36])[CH2:34][NH2:35])[CH3:31].ON1C2C=CC=CC=2N=N1.Cl>CN(C)C=O.CN1CCOCC1>[CH2:30]([O:32][C:33](=[O:36])[CH2:34][NH:35][C:26](=[O:27])[C@@H:10]([CH2:9][S:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[NH:11][C:12](=[O:25])[C:13]([CH3:23])([CH3:24])[CH2:14][S:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:31]
Reactant: CCOC(=O)CN
Reactant: CC(C)(CSCc1ccccc1)C(=O)N[C@H](CSCc1ccccc1)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)CNC(=O)[C@@H](CSCc1ccccc1)NC(=O)C(C)(C)CSCc1ccccc1
Reaction time: 2 h
Yield: 90.9 %

Procedure:
To a stirred solution of S-benzyl-N-(3-benzylthio-2,2-dimethyl-propionyl)-D-cysteine (0.32 g) and glycine ethyl ester hydro-chloride (0.12 g) in N,N-dimethylformamide (DMF, 3 ml), N-methylmorpholine (NMM, 0.19 ml), 1-hydroxybenzotriazole (HOBt, 0.17 g) and then a solution of N,N,-dicyclohexylcarbodiimide (DCC, 0.18 g) in DMF (2 ml) were added under ice cooling. The mixture was stirred for 2 hr. at 0° C. and for 2 hr. at room temperature, and stood overnight. 1 N hydrochloric acid (30 ml) was added into the reaction mixture and the mixture was extracted with ether. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 0.35 g (91%) of the titled compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:8]=O)[CH:5]=[N:6][CH:7]=1.[CH2:11]([S:13]([NH2:16])(=[O:15])=[O:14])[CH3:12].[BH4-].[Na+]>CO>[Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH2:8][NH:16][S:13]([CH2:11][CH3:12])(=[O:15])=[O:14])[CH:5]=[N:6][CH:7]=1
Reactant: Cc1c(Br)cncc1C=O
Reactant: CCS(N)(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCS(=O)(=O)NCc1cncc(Br)c1C

Procedure:
In analogy to the procedure described for the preparation of intermediate A-11, 5-bromo-4-methyl-pyridine-3-carbaldehyde has been reacted first with ethanesulfonamide, followed by reduction of the thus formed imine with NaBH4 in MeOH to give the title compound as an off-white solid. MS: 293.1 and 295.3 (M+H+).
Reaction SMILES: [C:1](=[N:9][OH:10])([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:2].C([Li])CCC.CON(C)[C:19]([CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1)=[O:20]>O1CCCC1>[OH:20][C:19]1([CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[O:10][N:9]=[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:2]1
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(=NO)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C2(O)CC(c3ccccc3)=NO2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
Acetophenone oxime (180 mg, 1.3 mmol) was dissolved in tetrahydrofuran (15 mL). Mixture was cooled to 0° C. 2.0M Butyllithium in pentanes (1.35 mL, 2.7 mmol) was added to the mixture drop-wise. Reaction stirred at 0° C. for 1 hour. A solution of tert-Butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (360 mg, 1.3 mmol) in tetrahydrofuran (5 mL) was added to the reaction mixture drop-wise. Reaction stirred at 0° C. for 1 hour. Reaction was quenched with aqueous ammonium chloride. Mixture was extracted 2× ethyl acetate. Combined extracts were dried (magnesium sulfate), filtered and concentrated in vacuo. Silica gel chromatography afforded the title compound as clear colorless oil in 71% yield. MS m/e (M−H)−=345.1.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1)=[O:5])C.O1CCCC1.CO.[H-].[OH-].[Li+]>O>[C:11]1([C:9]2[N:10]=[C:6]([C:4]([OH:5])=[O:3])[S:7][CH:8]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1nc(-c2ccccc2)cs1
Agent: [H-]
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1nc(-c2ccccc2)cs1
Yield: 54 %

Procedure:
4-Phenyl-thiazole-2-carboxylic acid ethyl ester, commercially available from Pharma Core, (1.0 g, 4.28 mmol) in a mixture solution of tetrahydrofuran, methanol and water (3:1:1, 10 mL) was treated with lithium hydroxide monohydride (514 mg, 12.8 mmol) at room temperature for three hours. After the reaction was complete, solvent was evaporated. To the residue, water was added, and pH of the resulting solution was adjusted to ˜1-2 by addition of dilute hydrochloride acid (1N). The white precipitation was collected by centrifugation and further washed with water to give 4-phenyl-thiazole-2-carboxylic acid (473 mg, 54%). LCMS calcd for C10H7NO2S (m/e) 205, obsd 206 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([P:16]([O:20][CH3:21])([O:18][CH3:19])=[O:17])[NH:5]C(OCC1C=CC=CC=1)=O>[Pd].CO>[CH3:1][O:2][C:3](=[O:22])[CH:4]([P:16]([O:18][CH3:19])([O:20][CH3:21])=[O:17])[NH2:5]
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(N)P(=O)(OC)OC
Reaction time: 1 h
Yield: 96.1 %

Procedure:
A mixture of rac.-N-(benzyloxycarbonyl)-2-(dimethoxyphosphinyl)glycine methyl ester (3.5 g, 10.56 mmol) and 10% palladium on carbon (0.5 g) in methanol (75 mL) was hydrogenated at 50 psi for 1 h. The solution was filtered through Celite® and the filtrate was concentrated and then dried under high vacuum to furnish rac.-2-(dimethoxy-phosphinyl)glycine methyl ester as an clear oil (2.0 g, 96% yield). The amine prepared in this manner was used per se in subsequent reactions.