Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C2C[CH2:27][C:26]3C(=CC=[C:24]([O:29]C)[CH:25]=3)C2)=C(NCCC2C=CC(O)=CC=2)C=1.[Si:31]([O:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][NH:47][C:48]2[CH:53]=[C:52]([O:54][CH3:55])[CH:51]=[CH:50][C:49]=2[CH:56]2[CH2:65][CH2:64][C:63]3[C:58](=[CH:59][CH:60]=[C:61]([O:66][CH3:67])[CH:62]=3)[CH2:57]2)=[CH:41][CH:40]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].C(N(CC)CC)C.C1(C(Cl)=O)CC1>O1CCCC1>[Si:31]([O:38][C:39]1[CH:40]=[CH:41][C:42]([CH2:45][CH2:46][N:47]([C:48]2[CH:53]=[C:52]([O:54][CH3:55])[CH:51]=[CH:50][C:49]=2[CH:56]2[CH2:65][CH2:64][C:63]3[C:58](=[CH:59][CH:60]=[C:61]([O:66][CH3:67])[CH:62]=3)[CH2:57]2)[C:24]([CH:25]2[CH2:26][CH2:27]2)=[O:29])=[CH:43][CH:44]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCCc1ccc(O)cc1)C2
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCCc1ccc(O[Si](C)(C)C(C)(C)C)cc1)C2
Agent: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1N(CCc1ccc(O[Si](C)(C)C(C)(C)C)cc1)C(=O)C1CC1)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Synthesized from 4-{2-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamino]ethyl}phenol according to an analogous synthetic method to Example 201, to a solution of the resulting {2-[4-(tert-butyldimethylsilyloxy)phenyl]ethyl}[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (2.3 g) in tetrahydrofuran (50 ml) was added triethylamine (895 mg), cyclopropanecarbonyl chloride (693 mg) was added dropwise thereto on an ice bath followed by stirring for 30 minutes at room temperature. The solution was extracted with ethyl acetate, then sequentially washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (2.3 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[ClH:11]>[OH-].[Pd+2].[OH-].C(O)C>[ClH:11].[NH2:5][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:2]=1[F:1]
Reactant: N#Cc1ccc(O)cc1F
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: NCc1ccc(O)cc1F

Procedure:
A mixture of 2-fluoro-4-hydroxy-benzonitrile (6 g, 43.8 mmol), palladium hydroxide (600 mg), ethanol (60 ml) and 2N hydrochloric acid (6 ml) was hydrogenated (60 psi) for 18 hours. The mixture was filtered through Arbocel® and the filter cake was washed with methanol and the filtrates were evaporated in-vacuo. The residue was triturated with diethylether to give 4-aminomethyl-3-fluoro phenol hydrochloride (4.71 g).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=2)[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:3]=1.[CH2:22]([O:24][C:25](=[O:39])[C:26]1[CH:31]=[C:30]([Cl:32])[C:29]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[N:28][CH:27]=1)[CH3:23].CC([O-])(C)C.[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:22]([O:24][C:25](=[O:39])[C:26]1[CH:31]=[C:30]([Cl:32])[C:29]([N:33]2[CH2:38][CH2:37][N:36]([C:2]3[CH:3]=[C:4]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[N:5]=[C:6]([C:8]4[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=4)[CH:7]=3)[CH2:35][CH2:34]2)=[N:28][CH:27]=1)[CH3:23]
Reactant: Fc1ccc(-c2cc(Br)cc(N3CCOCC3)n2)cc1Cl
Reactant: CCOC(=O)c1cnc(N2CCNCC2)c(Cl)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnc(N2CCN(c3cc(-c4ccc(F)c(Cl)c4)nc(N4CCOCC4)c3)CC2)c(Cl)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a de-gassed mixture of 4-{4-bromo-6-(3-chloro-4-fluoro-phenyl)-pyridin-2yl}-morpholine (50 mg, 0.135 mmol), 5-chloro-6-piperazin-1-yl-nicotinic acid ethyl ester (0.162 mmol), and 1M (THF) t-BuOK (0.162 mmol), in toluene (3 mL) under nitrogen add Pd2(dba)3 (0.0054 mmol) and BINAP (0.0067 mmol). Stir the mixture at 80° C. for 16 h, concentrate, extract with EtOAc. Dry over Na2SO4, concentrate under vacuum, and purify by preparative TLC (3:1 hexanes/EtOAc) to give the title compound.
Reaction SMILES: C(O)(=O)[C@H]([C@@H](C(O)=O)O)O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][C@H:19]1[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)(O)[O-].[Na+].Cl[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36].[Cl-].[Na+]>O1CCCC1.O.C(OCC)(=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])[CH2:20][C@H:19]1[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCOC(=O)[C@@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1CN(C(=O)OCc2ccccc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (2S)-2-ethoxycarbonylpiperazine-1-carboxylic acid 1-tert-butyl ester D-tartarate (9.56 g) in tetrahydrofuran (90 ml) and water (90 ml) was added sodium bicarbonate (7.87 g) under ice-cooling. Benzyl chloroformate (4.01 ml) was added dropwise to the solution over 2 minutes at the same temperature, and stirred at room temperature for 15 minutes. Ethyl acetate (60 ml) and sodium chloride (5 g) was added to the mixture. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated under reduced pressure to give (2S)-2-ethoxycarbonylpiperazine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester (10.4 g) as a colorless oil.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH:19]=[C:18]([I:20])[CH:17]=[N:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:21]1COCC1.C([N-]C(C)C)(C)C.[Li+].C1CCCCC1.CI.[NH4+].[Cl-]>>[Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:19]([CH3:21])=[C:18]([I:20])[CH:17]=[N:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2cc(I)cn2)CC1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: CI
Product: Cc1c(I)cnn1[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Reaction time: 0.08 h

Procedure:
A solution of 1-(trans-4-{[tert-Butyl(dimethyl)silyl]oxy}cyclohexyl)-4-iodo-1H-pyrazole (2.00 g, 4.92 mmol) in THF (20 mL, 200 mmol) was cooled to −78° C., and 1.5 M of Lithium Diisopropylamide in Cyclohexane (4.26 mL, 6.40 mmol) was added. After stirring for 5 min, Methyl iodide (2 mL, 20 mmol) was added slowly, and the mixture was stirred at −78° C. for 30 min. Sat. NH4Cl was added to quench, and the organic solvent was removed in vacuo. The material was extracted with DCM and water, and the organic layer was dry-loaded onto silica gel for column chromatography, eluting with 1% EtOAc/heptane. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a clear oil. 1H NMR (400 MHz, methanol-d4): δ=0.11 (s, 6H), 0.93 (s, 9H), 1.48-1.60 (m, 2H), 1.85-2.05 (m, 6H), 2.34 (s, 3H), 3.70-3.81 (m, 1H), 4.16-4.26 (m, 1H), 7.43 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[C:15]([Cl:22])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:13][CH3:14])=[C:9]([CH:12]=1)[CH:10]=[O:11].CC(=CC)C.Cl([O-])=[O:29].[Na+].Cl>C1COCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)(C)(C)C>[Cl:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[C:15]([Cl:22])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:13][CH3:14])=[C:9]([CH:12]=1)[C:10]([OH:29])=[O:11]
Reactant: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1C=O
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.4 %

Procedure:
To a solution of 5-(2,6-dichloro-4-nitro-phenoxy)-2-methoxy-benzaldehyde (3.0 g, 8.8 mmol) in a mixture of THF (50 ml), tert-butyl alcohol (50 ml) and 2-methyl-2-butene (11 ml, 132 mmol) was added dropwise a solution of sodium chlorite (7.1 g, 79 mmol) in potassium phosphate buffer (100 ml of a 0.6 M solution, 60 mmol). The resulting mixture was stirred vigorously for 16 h at RT then acidified with 1 M HCl (200 ml). The resulting mixture was extracted with EtOAC (3×150 ml). The combined EtOAc extracts were washed with 1 M HCl (2×250 ml), water (250 ml), 10% NaHSO3, and brine (250 ml). The extracts were dried (Na2SO4), filtered, and concentrated to give the title compound of Step B (3.1 g) as a yellow solid. The title product of Step B was used in the next step without further purification. MS (ES−) Calc.: 357.0, Found: 356.0 (M−1).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:9][CH:10]=3)[C@:5]3([CH2:25][O:24][C:23]([NH2:26])=[N:22]3)[C:4]=2[CH:3]=1.CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[NH:65]1[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1>C1COCC1.[Cl-].[NH4+].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:19][C:18]([CH3:21])([CH3:20])[CH2:17][O:16][C:8]1[CH:9]=[CH:10][C:11]2[O:12][C:13]3[C:4](=[CH:3][C:2]([N:65]4[CH2:70][CH2:69][O:68][CH2:67][CH2:66]4)=[CH:15][CH:14]=3)[C@@:5]3([CH2:25][O:24][C:23]([NH2:26])=[N:22]3)[C:6]=2[CH:7]=1
Reactant: C1COCCN1
Reactant: CC(C)(C)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(Br)ccc1O2
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(N3CCOCC3)ccc1O2
Temperature: 65 °C

Procedure:
A vial was charged with (4R)-2′-bromo-7′-(2,2-dimethylpropoxy)spiro[1,3-oxazole-4,9′-xanthen]-2-amine (80.0 mg, 192 μmol), DavePhos (9.05 mg, 23.0 μmol), tris(dibenzylideneacetone)dipalladium(0) (8.78 mg, 9.59 μmol), lithium bis(trimethylsilyl)amide (767 μl of a 1.0 M solution in THF, 767 μmol), and morpholine (50.1 μl, 575 μmol). The vial was sealed and heated in a 65° C. oil bath for 15 h. The reaction mixture was diluted with a saturated aqueous ammonium chloride solution (10 mL) and extracted with DCM (3×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on a 12-g Redi-Sep column, eluting with 0-8% MeOH/DCM. The first fraction containing product was mixed and was discarded. The remaining fractions were combined and evaporated to yield (4S)-2′-(2,2-dimethylpropoxy)-7′-(4-morpholinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine as a pale yellow solid. MS m/z=424.2 [M+H]+. Calc'd for C24H30N3O4: 424.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.[F:13][C:14]1[C:19](B(O)O)=[CH:18][CH:17]=[C:16]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:25][CH:24]=2)[N:15]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O.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:13][C:14]1[C:19]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=2)=[CH:18][CH:17]=[C:16]([C:23]2[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:27][CH:28]=2)[N:15]=1
Reactant: CCCCCCCCCc1ccc(-c2ccc(B(O)O)c(F)n2)cc1
Reactant: CCCCCc1ccc(Br)cc1
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: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCCCCCCc1ccc(-c2ccc(-c3ccc(CCCCC)cc3)c(F)n2)cc1

Procedure:
A solution of 40 mmol of 1 -bromo-4-pentylbenzene in 90 ml of toluene is admixed with 44 mmol of 2-fluoro-6-(4-nonylphenyl)pyridine-3-boronic acid, 45 ml of ethanol, a solution of 80 mmol of sodium carbonate in 45 ml of water and 0.4 mmol of tetrakis(triphenylphosphine)palladium(0) at room temperature. The mixture is heated at the boil for 5 h. After cooling, the phases are separated, the aqueous phase is extracted with tert-butyl methyl ether and the combined organic phases are washed with water and saturated sodium chloride solution and dried with magnesium sulfate. The solvents are then removed under reduced pressure and the raw product is purified by column chromatography over silica gel 60 using n-heptane/dichloromethane 1:1 as eluent and recrystallization from acetonitrile/acetone 1:1, giving 2-fluoro-6-(4-nonylphenyl)-3-(4-pentylphenyl)pyridine.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:13][C@@H:12]3[C@@H:14]([NH:17]C(=O)OC(C)(C)C)[CH2:15][CH2:16][C@@H:11]3[CH2:10]2)=[N:7][CH:8]=1.Cl.O1CCOCC1>>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:13][C@@H:12]3[C@@H:14]([NH2:17])[CH2:15][CH2:16][C@@H:11]3[CH2:10]2)=[N:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cn3)C[C@@H]21
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cn3)C[C@@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-butyl(3aR,4S,6aS)-2-(5-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-ylcarbamate (282 mg, 0.759 mmol) from Step A was combined with 4 N HCl in 1,4-dioxane (2.5 mL, 9.87 mmol). The reaction was stirred at room temperature overnight and then the volatiles were removed in vacuo. The compound was purified using a 12 g silica gel cartridge eluting with a gradient of 0-7.5% methanol (2 N ammonia)/dichloromethane over 20 minutes to give (3aR,4S,6aS)-2-(5-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.64 (s, 1H), 7.69 (dd, J=8.9, 2.5, 1H), 6.38 (d, J=8.9, 1H), 4.95 (s, 2H), 3.56 (dd, J=23.7, 14.1, 3H), 3.25 (d, J=6.2, 1H), 3.11 (q, J=6.0, 1H), 2.83-2.68 (m, 1H), 2.35 (ddd, J=13.1, 7.9, 5.3, 1H), 2.02 (dtd, J=13.5, 8.3, 5.5, 1H), 1.92 (ddd, J=18.3, 7.4, 5.6, 1H), 1.46-1.30 (m, 2H); MS (ESI+) m/z 272 (M+H)+.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:23](=[O:24])[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[NH:16][C:15]3=[O:25])[CH2:10][CH2:9]2)C=CC=CC=1>[Pd]>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:25])[CH2:12][CH2:13]1
Reactant: O=c1[nH]c2ccccc2c(=O)n1C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Product: O=c1[nH]c2ccccc2c(=O)n1C1CCNCC1
Yield: 70 %

Procedure:
Prepared analogously to Example A3f) from 3-[1-(phenylmethyl)-4-piperidinyl]-2,4(1H,3H)-quinazolindione by hydrogenolysis in the presence of palladium/charcoal in a yield of 70% of theory.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[N:16][C:17]([C:21]([F:24])([F:23])[F:22])=[C:18](I)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25]1([CH3:34])[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[N:16][C:17]([C:21]([F:24])([F:23])[F:22])=[C:18]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH3:34])[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(I)c(C(F)(F)F)nn2)CC1
Reactant: Cc1ccccc1B(O)O
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccccc1-c1cc(N2CCN(C(=O)OC(C)(C)C)CC2)nnc1C(F)(F)F
Reaction time: 48 h
Yield: 48.3 %

Procedure:
A mixture of 4-(5-iodo-6-trifluoromethyl-pyridazin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (D10) (0.20 g, 0.436 mmol), o-tolylboronic acid (0.071 g, 0.523 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II).dichloride, dichloromethane (0.022 g, 0.026 mmol), 1,1′-bis(diphenylphosphino)ferrocene (0.015 g, 0.026 mmol) and potassium phosphate (0.138 g, 0.654 mmol) in dioxane (8.5 ml) was stirred at 80° C. for 16 h. and then at 110° C. for 2 days. The mixture was then filtered through a pad of diatomaceous earth and the solvent was evaporated in vacuo. The residue was purified by column chromatography (silica gel; dichloromethane/methanol 70/30) to yield D11 (0.089 g, 48%) as a yellow solid. C21H25F3N4O2 requires 422; Found 423 (MH+).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]=[C:8]([NH2:10])[N:7]([C:11]([NH:13][CH3:14])=[S:12])[N:6]=1)(=[O:3])[CH3:2].[C:15](OC(OCC)OCC)(=O)C>>[C:1]([NH:4][C:5]1[N:9]=[C:8]2[N:10]=[CH:14][N:13]([CH3:15])[C:11](=[S:12])[N:7]2[N:6]=1)(=[O:3])[CH3:2]
Reactant: CCOC(OCC)OC(C)=O
Reactant: CNC(=S)n1nc(NC(C)=O)nc1N
Product: CC(=O)Nc1nc2ncn(C)c(=S)n2n1
Yield: 87 %

Procedure:
The synthesis method of Example 55 was applied. The compound (1.02 g) obtained in Example 32 and diethoxymethyl acetate (10 ml) were used as reagents. The mixture was reacted at 100° C. for 5.5 hours to give 925 mg of white crystals (yield 87%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)[CH:5]=[CH:6][C:7]=1[C:8]([NH:10][C@H:11]([C:15]([O:17][CH3:18])=[O:16])[CH:12]([CH3:14])[CH3:13])=[O:9].Cl>C(O)C.[Fe]>[NH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:4]2[CH:5]=[CH:6][C:7]([C:8]([NH:10][C@H:11]([C:15]([O:17][CH3:18])=[O:16])[CH:12]([CH3:14])[CH3:13])=[O:9])=[C:2]([CH3:1])[CH:3]=2)=[CH:24][CH:23]=1
Reactant: COC(=O)[C@@H](NC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1C)C(C)C
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: COC(=O)[C@@H](NC(=O)c1ccc(-c2ccc(N)cc2)cc1C)C(C)C
Temperature: 25 °C

Procedure:
Iron powder (0.79 g, 14 mmol) was added to a solution of methyl N-[(3-methyl-4′-nitrobiphenyl-4-yl)carbonyl]-L-valinate (0.65 g, 1.4 mmol) in ethanol (20 mL). Concentrated HCl (0.71 mL, 1.4 mmol) was added, and the mixture was heated at reflux for 1 h. Upon cooling to rt, the mixture was filtered through a pad of Celite®, and the filtrate was concentrated in vacuo. The material was purified by column chromatography (33% EtOAc in hexanes), yielding 0.50 g (quantitative) of the title compound. LC/MS m/z 341.1 (MH+), retention time 2.19 min. 1H NMR (400 MHz, CD2Cl2) δ 1.06 (dd, 6H), 2.32-2.39 (m, 1H), 2.50 (s, 3H), 3.78 (s, 3H), 4.71-4.78 (m, 1H), 6.33 (d, 1H), 6.78 (d, 2H), 7.38-7.44 (m, 5H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[F:28][C:29]([F:49])([F:48])[C:30]([NH:32][CH2:33][CH2:34][CH2:35][N:36]([S:44]([CH3:47])(=[O:46])=[O:45])[C:37]1[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=1)=[O:31]>>[F:49][C:29]([F:28])([F:48])[C:30]([NH:32][CH2:33][CH2:34][CH2:35][N:36]([C:37]1[CH:38]=[CH:39][C:40]([NH:43]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:41][CH:42]=1)[S:44]([CH3:47])(=[O:45])=[O:46])=[O:31]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CS(=O)(=O)N(CCCNC(=O)C(F)(F)F)c1ccc(N)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(CCCNC(=O)C(F)(F)F)S(C)(=O)=O)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-(3-trifluoroacetylamino-propyl)-N-methylsulphonyl-p-phenylenediamine Rf value: 0.5 (aluminium oxide, methylene chloride/methanol=20:1) C29H27F3N4O6S
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4](=O)[CH2:5]Br.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH:26][C:27]([NH2:29])=[S:28])[CH:17]=[CH:18][C:19]=1[N:20]1[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]1>>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]1[N:29]=[C:27]([NH:26][C:16]2[CH:17]=[CH:18][C:19]([N:20]3[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]3)=[C:14]([O:13][CH3:12])[CH:15]=2)[S:28][CH:5]=1
Reactant: O=C(CBr)c1ccccc1F
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2nc(-c3ccccc3F)cs2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 106 %

Procedure:
The title compound was prepared in analogy to example 1 step e) from 72 mg (0.33 mmol) 2-fluorophenacylbromide and 79 mg (0.3 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea. The crude product was purified through stirring with methylene chloride at room temperature yielding 121 mg (99%) [4-(2-fluoro-phenyl)-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine as a light green solid. MS ISP (m/e): 381.3 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.77 (s, 1H), 9.29 (s, 1H), 8.12 (t, 1H), 8.02 (s, 1H), 7.69 (s, 1H), 7.53 (d, 1H), 7.38-7.29 (m, 5H), 3.92 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: [C:1]([NH:8][C@H:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:10]([NH:12][N:13]1[CH2:16][CH:15]([OH:17])[CH2:14]1)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(Cl)(=O)C(Cl)=O.CS(C)=O>C(Cl)Cl>[C:1]([NH:8][C@H:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[C:10]([NH:12][N:13]1[CH2:14][C:15](=[O:17])[CH2:16]1)=[O:11])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)NN1CC(O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)NN1CC(=O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.3 %

Procedure:
(2R)-2-(BOC)Amino-N-(3-hydroxyazetidine-1-yl)-3-(4-chlorophenyl)propionamide (3.54 g, 10 mmol) was placed in a round-bottomed flask, filled with nitrogen, and DCM (30 mL) and oxalyl chloride (872 μl, 10 mmol) were added. The mixture was cooled to −78-C, and DMSO (709 μl, 10 mmol) was added. The reaction solution was stirred for 3 h keeping the temperature below −50° C. The reaction mixture was quenched by addition of TEA and warmed to rt. The reaction solution was diluted with a saturated aqueous NH4Cl solution, and the organic material was extracted with EtOAc. The extracts was dried over MgSO4 and concentrated in vacuo, and the residue was purified by column chomatography (eluent: EtOAc/Hex=1/3) to give the title compound (2.88 g, 84%).
Reaction SMILES: [CH:1]1([N:4]2[C:9]3[N:10]=[C:11]([S:15](=[S:18])([OH:17])=[O:16])[C:12]([F:14])=[CH:13][C:8]=3[C:7](=[O:19])[NH:6][C:5]2=[O:20])[CH2:3][CH2:2]1.[H-].[Na+].[N+:23](C1C=C([N+]([O-])=O)C=CC=1NO)([O-])=O>CN(C)C=O.O1CCOCC1>[NH2:23][N:6]1[C:7](=[O:19])[C:8]2[CH:13]=[C:12]([F:14])[C:11]([S:15](=[S:18])([OH:17])=[O:16])=[N:10][C:9]=2[N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]1=[O:20]
Reactant: O=c1[nH]c(=O)n(C2CC2)c2nc(S(=O)(O)=S)c(F)cc12
Reactant: O=[N+]([O-])c1ccc(NO)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Nn1c(=O)c2cc(F)c(S(=O)(O)=S)nc2n(C2CC2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
A solution of 0.47 g (1.57 mmol) of 1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidine-7-thiosulfonic acid (Example 35) in 20 mL of dimethylformamide/dioxane (1:1) is treated portionwise with 0.08 g (2.0 mmol) of 60% sodium hydride/mineral oil. The reaction is stirred at room temperature for 1 hour and 0.32 g (1.6 mmol) of 2,4-dinitrophenylhydroxylamine is added all at once. After stirring at room temperature overnight, the dioxane is removed in vacuo and the residue is diluted to 100 mL with ice and water and stirred at 5° C. for 1 hour. The aqueous solution is extracted with ethyl acetate (3×50 mL) with the combined organic layers being washed with water, dried (MgSO4), filtered and evaporated in vacuo to give 0.4 g of the title compound, mp 167–169° C.