Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:65]=[N:66][C:67]([C:70]#[N:71])=[CH:68][CH:69]=1>>[C:70]([C:67]1[N:66]=[CH:65][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[CH:69][CH:68]=1)#[N:71]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: N#Cc1ccc(N)cn1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)nc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Yield: 37.2 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.33 g, 0.57 mmol), was reacted with diisopropylethylamine (0.37 g, 2.9 mmol), diphenylphosphinic chloride (0.27 g, 1.1 mmol), then reacted with 3-amino-6-cyanopyridine (Aldrich) (0.1 g, 0.9 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (6-cyano-pyridin-3-yl)-amide as a yellow solid (Yield 0.12 g, 38%).
Reaction SMILES: C[OH:2].[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1O)=[CH2:4]>C1(C)C=CC=CC=1>[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:2])=[CH:7][CH:6]=1)=[CH2:4]
Reactant: C=Cc1ccccc1O
Reactant: CO
Solvent: Cc1ccccc1
Product: C=Cc1ccc(O)cc1

Procedure:
The procedure of Example 6 was repeated except that no methanol was added to the starting crude vinylphenol and the alkali aqueous solution. A toluene solution of p-vinylphenol having the same purity (99.1 wt%) as in Example 6 was obtained as a product. However, for 60 hours after the extraction operation a large amount of scale deposited on the inner wall of the extraction tower and line 8, and, as a result, it was impossible to further continue the operation.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[C:7]([Cl:10])[CH:6]=[CH:5][C:4]=1[Cl:11].[CH3:12][N:13]1[C:18](=[O:19])[CH:17]=[C:16]([CH3:20])[N:15]=[C:14]1[SH:21].C(N(CC)CC)C>C(O)C>[CH3:12][N:13]1[C:18](=[O:19])[CH:17]=[C:16]([CH3:20])[N:15]=[C:14]1[S:21][CH2:2][C:3]1[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([Cl:10])[C:8]=1[Cl:9]
Reactant: Cc1cc(=O)n(C)c(S)n1
Reactant: Clc1ccc(Cl)c(CBr)c1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(=O)n(C)c(SCc2c(Cl)ccc(Cl)c2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
A mixture of 2-(bromomethyl)-1,3,4-trichlorobenzene (576 mg, 2.1 mmol), 3,6-dimethyl-2-sulfanyl-3,4-dihydropyrimidin-4-one (300 mg, 1.9 mmol), and triethylamine (280 μl, 2.0 mmol) in absolute ethanol (10 mL) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. The solid product was suspended in water (30 mL). The solid material was recovered by filtration, washed with water (2×10 mL) and hexanes (2×20 mL), and dried in vacuo, affording the title compound (475 mg, 72% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.20 (s, 3H), 3.31 (s, 3H), 4.77 (s, 2H), 6.08 (s, 1H), 7.57 (d, 1H, J=8.8 Hz), 7.68 (d, 1H, J=8.8 Hz); M+350; HPLC purity: 95.8%.
Reaction SMILES: C([Mg]Cl)(C)C.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[C:9](I)[CH:8]=1.C[O:17][B:18](OC)[O:19]C.Cl>C1COCC1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[C:9]([B:18]([OH:19])[OH:17])[CH:8]=1
Reactant: CCc1ccc(Cl)cc1I
Reactant: COB(OC)OC
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CCc1ccc(Cl)cc1B(O)O
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
i-Propylmagnesium chloride (2M sol. in THF, 8.98 mL, 17.95 mmol) was added drop wise to a solution of 4-chloro-1-ethyl-2-iodobenzene (4.35 g, 16.3 mmol) in dry THF (40 mL) at −30° C. and the reaction mixture was stirred at the same temperature for 30 min, under argon. After this time, trimethylborate (3.63 mL, 32.6 mmol) was added drop wise and the reaction mixture was stirred at the same temperature for 1.5 h. HCl (1 M, 16 mL) was added and the reaction mixture extracted with EtOAc (3×50 mL). The combined organic layers were dried over sodium sulfate and, after removal of the solvent, a solid was obtained, which was triturated with hexane to obtain the title compound as a white solid (2.15 g, 72%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([NH:12][C:13]([C:15]1[C:20]([I:21])=[C:19]([NH:22][C:23](=[O:30])[CH:24]([Br:29])[CH2:25][CH2:26][CH2:27]Br)[C:18]([I:31])=[C:17]([C:32]([NH:34][CH:35]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[CH2:36][O:37][C:38](=[O:40])[CH3:39])=[O:33])[C:16]=1[I:46])=[O:14])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[C:9]([O:8][CH2:7][CH:6]([NH:12][C:13]([C:15]1[C:20]([I:21])=[C:19]([N:22]2[CH2:27][CH2:26][CH2:25][CH:24]([Br:29])[C:23]2=[O:30])[C:18]([I:31])=[C:17]([C:32]([NH:34][CH:35]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[CH2:36][O:37][C:38](=[O:40])[CH3:39])=[O:33])[C:16]=1[I:46])=[O:14])[CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:11])[CH3:10]
Reactant: CC(=O)OCC(COC(C)=O)NC(=O)c1c(I)c(NC(=O)C(Br)CCCBr)c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(=O)OCC(COC(C)=O)NC(=O)c1c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c(I)c(N2CCCC(Br)C2=O)c1I
Reaction time: 4 h
Yield: 98 %

Procedure:
To a solution of N,N'-bis[2-(acetyloxy)-1-[(acetyloxy)methyl]ethyl]-5-[(2,5-dibromo-1-oxopentyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamide of example 9a (32.5 g, 29.1 mmol) in dimethylacetamide (250 ml), was added powdered potassium carbonate (25.2 g, 116.5 mmol). After stirring for 4 hours, the mixture was filtered. The filtrate was freed of the solvent in vacuo at 45° C. and the resulting solid was redissolved in ethyl acetate (500 ml). The ethyl acetate solution was washed with water (2×50 ml) and saturated aqueous sodium chloride (1×100 ml), and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to obtain a white solid (29.5 g) which, upon crystallization from ethyl acetate (1.2 L), furnished analytically pure N,N'-bis[2-acetyloxy )-1-[(acetyloxy)-methyl]ethyl]-5-(3-bromo-2-oxo-1-piperidinyl)-2,4,6-triiodo-1,3-benzenedicarboxamide as a whine crystalline solid (23.95 g, 79.5% yield), m.p. 231°-3°.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:28]([CH3:29])=[CH:27][C:15]2[N:16]=[C:17]([C:19]3[C:24]([F:25])=[CH:23][N:22]=[C:21](Cl)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:37][N:38]1[C:46]2[C:41](=[CH:42][C:43](B(O)O)=[CH:44][CH:45]=2)[CH:40]=[N:39]1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=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>[C:1]([O:5][C@@H:6]([C:12]1[C:28]([CH3:29])=[CH:27][C:15]2[N:16]=[C:17]([C:19]3[C:24]([F:25])=[CH:23][N:22]=[C:21]([C:43]4[CH:42]=[C:41]5[C:46](=[CH:45][CH:44]=4)[N:38]([CH3:37])[N:39]=[CH:40]5)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cc(Cl)ncc3F)sc2c1-c1ccc(Cl)cc1
Reactant: Cn1ncc2cc(B(O)O)ccc21
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: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cc(-c4ccc5c(cnn5C)c4)ncc3F)sc2c1-c1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
A microwave vial containing (S)-ethyl 2-(tert-butoxy)-2-(2-(2-chloro-5-fluoropyridin-4-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)acetate (22 mg, 0.04 mmol) was charged with (1-methyl-1H-indazol-5-yl)boronic acid (19 mg, 0.11 mmol), then Pd(PPh3)4 (9 mg, 0.008 mmol). The vial was flushed with argon, diluted with dioxane (2.0 mL) and to this was added 2M aqueous K2CO3 (0.10 mL, 0.20 mmol). The vial was sealed, heated to 120° C. for 3 hours, and then allowed to cool to room temperature. The mixture was diluted with EtOAc, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (10-40% EtOAc/Hex gradient) to afford the desired product. LCMS-ESI+: calc'd for C35H33ClFN4O3S: 643.2 (M+H+); Found: 643.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:43])[N:10]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([F:25])[CH:19]=3)[CH2:16][N:15]([C:26]([CH:28]3[CH2:33][CH2:32][N:31]([C:34]4[CH:39]=[CH:38][C:37]([C:40](=[O:42])[CH3:41])=[CH:36][N:35]=4)[CH2:30][CH2:29]3)=[O:27])[CH2:14]2)[CH2:11][CH3:12])=[CH:4][CH:3]=1.[CH3:44][Mg]I>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:43])[N:10]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([F:25])[CH:19]=3)[CH2:16][N:15]([C:26]([CH:28]3[CH2:29][CH2:30][N:31]([C:34]4[CH:39]=[CH:38][C:37]([C:40]([OH:42])([CH3:44])[CH3:41])=[CH:36][N:35]=4)[CH2:32][CH2:33]3)=[O:27])[CH2:14]2)[CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: C[Mg]I
Reactant: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(c3ccc(C(C)=O)cn3)CC2)C[C@H]1c1ccc(Cl)c(F)c1
Product: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(c3ccc(C(C)(C)O)cn3)CC2)C[C@H]1c1ccc(Cl)c(F)c1
Reaction time: 1.5 h
Yield: 13.2 %

Procedure:
A mixture of 142 mg (0.23 mmol) [(3S,4R)-1-(5′-Acetyl-3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-4-carbonyl)-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester (example 59) and 0.097 mL (0.29 mmol) methylmagnesium iodide (3M) in 5 mL was stirred from 0° to 15° C. during 90 min and quenched at 0° C. with NH4Cl (aq.). The mixture was extracted with ethyl acetate and the combined organic layers were dried with Na2SO4 and evaporated. The residue was subjected to preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fractions were evaporated to yield 19 mg (13%) of the title compound as white solid. MS m/e: 627.2 [M+11]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9]Br)[C:5]([I:8])=[N:6][CH:7]=1.C([O-])([O-])=[O:12].[Ca+2]>O1CCOCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:12])[C:5]([I:8])=[N:6][CH:7]=1
Reactant: BrCc1cc(Br)cnc1I
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: C1COCCO1
Product: OCc1cc(Br)cnc1I
Temperature: 25 °C
Yield: 45.6 %

Procedure:
To a stirred solution of 5-bromo-3-bromomethyl-2-iodo-pyridine (25.0 g, crude, 66.313 mmol, 1 eq) in 1,4-dioxane (200 mL) was added suspension of CaCO3 (34.5 mL, 345 mmol, 5.2 eq) in water (200 mL) at room temperature. Resulting reaction mixture was refluxed for 10 hours. After complete consumption of starting material, reaction mixture was cooled to room temperature and filtered through celite bed over Buchner funnel, celite bed was washed with DCM (2×300 mL). Combined filtrate was washed with water (300 mL) and aqueous sodium bicarbonate (120 mL), dried over sodium sulfate and concentrated under reduced pressure to afford off white solid (15.3 g, crude). Crude compound was purified by washing with n-pentane (2×150 mL) to get desired compound as white solid (9.5 g, impure). Impure title compound was used as such for the next reaction. 1H NMR (400 MHz, CDCl3) δ: 2.14 (t, J=5.8 Hz, 1H), 4.62 (d, J=5.8, 2H), 7.86 (d, J=1.32 Hz, 1H), 8.33 (d, J=3.32, 1H). LC-MS (m/z): 313.9 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([C:22]3[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=3)[C:25]#[N:26])[C:9](=[O:21])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:11]([CH3:12])[C:5]2=[CH:4][N:3]=1.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CO>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([N:10]2[CH:11]([CH3:12])[C:5]3[C:6](=[N:7][C:2]([NH:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:3][CH:4]=3)[N:8]([C:22]3[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=3)[C:25]#[N:26])[C:9]2=[O:21])=[CH:18][CH:17]=1
Reactant: Nc1ccccc1
Reactant: COc1ccc(N2C(=O)N(c3cccc(C#N)c3)c3nc(Cl)ncc3C2C)cc1
Solvent: CO
Product: COc1ccc(N2C(=O)N(c3cccc(C#N)c3)c3nc(Nc4ccccc4)ncc3C2C)cc1
Temperature: 110 °C

Procedure:
A mixture of (±)-3-[7-chloro-3-(4-methoxy-phenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-benzonitrile (0.49 g; 1.21 mmol) (from Example 5a supra) and aniline (0.50 mL; 5.49 mmol) (Aldrich) was heated to 110° C. for one hour. Methanol was added to the hot mixture and the solution was then cooled. The solid that precipitated out of solution was collected and recrystallized from methanol to yield (±)-3-[3-(4-methoxy-phenyl)-4-methyl-2-oxo-7-phenylamino-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-benzonitrile as a white solid. (Yield 0.35 g; 62.2%). Melting Point: 224–228° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]([O:18]C)=O)=[CH:13][CH:12]=2)=[O:10])[CH:2]=1.O.[NH2:21][NH2:22]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]([NH:21][NH2:22])=[O:18])=[CH:13][CH:12]=2)=[O:10])[CH:2]=1
Reactant: COC(=O)c1ccc(C(=O)NCc2cccnc2)s1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc(C(=O)NCc2cccnc2)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
Methyl 5-(3-picolylcarbamoyl)thiophene-2-carboxylate (860 mg, 3.11 mmol) in ethanol (34 mL) was stirred with hydrazine monohydrate (1.57 m, 31.1 mmol) at 85° C. for 12 hours. The reaction solution was concentrated and stirred with diethyl ether at 0° C. for 1 hour. The precipitated solid was recovered by filtration and washed with a liquid mixture of diethyl ether and ethanol and dried to give the desired product, 5-hydrazinocarbonylthiophene-2-carboxylic acid 3-picolylamide (yield 92%).
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH:12](=O)[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[OH:15].CC(C)([O-])C.[K+].Cl>C(O)(C)(C)C>[OH:15][C:14]1[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=1[CH2:12][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]=1[OH:11]
Reactant: O=C1CCCc2ccccc21
Reactant: O=Cc1ccccc1O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: Oc1ccccc1Cc1ccc2ccccc2c1O
Temperature: 25 °C
Yield: 52.3 %

Procedure:
A solution of 1-tetralone (5.85 g, 0.040 mole) and salicylaldehyde (4.88 g, 0.040 mole) in t-butanol (400 mL) was treated with potassium t-butoxide (17.6 g, 0.160 mole) was heated at reflux for 16 hours. After cooling to room temperature, the solution was poured into stirred 1.0N hydrochloric acid. After isolation by extraction with ethyl acetate, the crude product was chromatographed with 4:1 petroleum ether/ether, to provide a tan solid. This was recrystallized (cyclohexane/chloroform) to give the titel compound as white needles (5.24 g, 52%), mp 124°-125°.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@H:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:25][C@@H:26]1[NH:31][CH2:30][CH2:29][NH:28][C:27]1=[O:32]>>[F:24][C:14]1[C:13]([C@@H:11]([C:8]2[N:6]3[N:7]=[C:2]([N:31]4[CH2:30][CH2:29][NH:28][C:27](=[O:32])[C@@H:26]4[CH3:25])[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:22]([F:23])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: C[C@@H]1NCCNC1=O
Reactant: C[C@@H](c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Product: C[C@@H](c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCNC(=O)[C@@H]3C)nn12

Procedure:
The title compound was prepared in analogy to Example 18, using enantiomerically pure 6-[(S)-1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (Intermediate B, 50 mg, 0.145 mmol) and (S)-3-methyl-piperazin-2-one (33.1 mg, 0.29 mmol) instead of the racemates and flash chromatography for the purification. 70:30 mixture of title compound with compound of Example 59 (tR 3.54 min (conditions 5), tR 8.63 and 10.13 min (conditions 3, 90% n-hexane and 10% isopropanol), MH+=423.1, 1H-NMR in DMSO-d6: 8.92 (m, 1H); 8.43 (d, 1H); 7.90 (s, 1H); 7.78 (d, 1H); 7.66-7.51 (m, 3H); 7.00 (d, 1H); 4.93 (m, 1H); 4.49 and 4.29 (q, 1H); 3.85 (m, 1H); 3.40-2.88 (m, 3H); 1.85 (m, 3H); 1.30 and 0.93 (d, 3H)).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C:10](=[O:14])[O:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>O1CCCC1>[OH:11][C:12]1[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][C:10]([N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14]
Reactant: O=C1CCc2ccc([N+](=O)[O-])cc2O1
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: O=C(CCc1ccc([N+](=O)[O-])cc1O)N1CCCC1
Reaction time: 1 h

Procedure:
The crude 7-nitro-chroman-2-one (1.1 g, approx. 4.2 mmol) was dissolved in tetrahydrofuran (15 ml). Pyrrolidine (0.35 ml) was added and the reaction mixture stirred for 1 hour. The solution was adsorbed onto silica and eluted using methanol in dichloromethane. 3-(2-hydroxy-4-nitrophenyl)-1-pyrrolidin-1-yl-propan-1-one was obtained as a brown solid (900 mg, 3.40 mmol);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH2:18][CH2:17][N:16]([C:19]([N:21]4[CH2:26]CN(C)CC4)=[O:20])[CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.CN1CCN([C:35](Cl)=[O:36])CC1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([O:12][N:11]=2)[CH2:18][CH2:17][N:16]([C:19]([N:21]([O:36][CH3:35])[CH3:26])=[O:20])[CH2:15]3)[CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCN(C(=O)N2CCC3(CC(C#Cc4cccc(Cl)c4)=NO3)C2)CC1
Reactant: CN1CCN(C(=O)Cl)CC1
Product: CON(C)C(=O)N1CCC2(CC(C#Cc3cccc(Cl)c3)=NO2)C1
Yield: 54.1 %

Procedure:
The title compound was synthesized using the method described for the compound of Example 104, replacing N-methoxy-N-methylcarbamoyl chloride for 4-methyl-1-piperazinecarbonyl chloride. After evaporation, the crude was purified by means of automated flash chromatography (SP01®TM-Biotage; gradient petroleum ether-EtOAc 8:2 to 4:6) to afford a pale yellow solid. Yield: 54.1%.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:16][C:17]1[N:22]=[CH:21][N:20]=[C:19]([C:23](Cl)=[O:24])[CH:18]=1.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([N:8]([CH2:9][C:10]([F:12])([F:11])[F:13])[C:23]([C:19]1[CH:18]=[C:17]([Cl:16])[N:22]=[CH:21][N:20]=1)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Reactant: FC(F)(F)CNCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(c1cc(Cl)ncn1)N(Cc1ccccc1)CC(F)(F)F
Reaction time: 2 h

Procedure:
1.04 g (5.50 mmol) benzyl-(2,2,2-trifluorethyl)-amine and 5.50 mL (5.50 mmol) of a 1M sodium hydroxide solution were added dropwise while cooling with a bath of ice/ethanol to 1.00 g (5.65 mmol) 6-chloropyrimidine-4-carboxylic acid chloride in 20 mL dichloromethane. The mixture was first stirred for 2 h while being cooled and then for a further 1 h at RT. 50 mL of a saturated sodium hydrogen carbonate solution were added and the mixture was stirred for 10 min. The organic phase was separated off, washed with water (1×30 mL) and 1M hydrochloric acid (1×50 mL), dried on sodium sulphate, filtered and evaporated down i. vac. The product was reacted further without any further purification.
Reaction SMILES: N#N.Br[C:4]1[S:8][C:7]([CH2:9][C:10]#[N:11])=[CH:6][CH:5]=1.CC1(C)C(C)(C)OB([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[NH2:26])O1>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:4]1[S:8][C:7]([CH2:9][C:10]#[N:11])=[CH:6][CH:5]=1
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
Reactant: N#CCc1ccc(Br)s1
Agent: [Pd]
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: N#CCc1ccc(-c2ccccc2N)s1
Temperature: 90 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
(The following reaction is done in an oxygenfree N2 atmosphere.) Dissolve tetrakis-(triphenylphosphine)-palladium(0) (29 mg, 2.5 mol %) and nitrile (83) (101 mg, 0.50 mmol) in DME (3.7 mL). The reaction mixture is degassed 5 times and flooded with N2 again. Add 2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenylamine (84) (120 mg, 0.55 mmol), rinse with DME (0.5 mL), add aqu. 1M NaHCO3, degas again (5 times) and stir the reaction solution 2 h at 90° C. (reflux). After cooling to rt partition the reaction mixture between EtOAc and brine (1+1) and extract the separated aqueous layer 3 times with EtOAc. Wash combined organic layer with brine and dry with Na2SO4. Remove solvent under reduced pressure and purify the crude product by preparative radial chromatography (silica gel 60PF, CyH/EtOAc 2+1) to obtain [5-(2-amino-phenyl)-thiophen-2-yl]-acetonitrile (85) as a brownish oil (84 mg, 78%). 1H NMR (400 MHz, CDCl3): 3.89 (br.s, 2H); 5.20-6.50 (br.s, 2H); 6.92 (t, 1H; J=7.6 Hz); 6.95-7.00 (m, 1H); 6.99 (d, 1H; J=3.8 Hz); 7.11 (d, 1H; J=3.8 Hz); 7.21 (dd, 1H; J1=7.6 Hz, J2=1.3 Hz); 7.27 (dd, 1H; J1=7.6 Hz, J2=1.3 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([NH:33]C(=O)OC(C)(C)C)[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][C:29]([NH:31][OH:32])=[O:30])=[CH:22][CH:21]=2)=[O:18])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:33][CH:16]([CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][N:13]=1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][C:29]([NH:31][OH:32])=[O:30])=[CH:22][CH:21]=1)=[O:18]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(OCc2ccccc2)cn1)C(=O)Nc1ccc(CCCC(=O)NO)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(Cc1ccc(OCc2ccccc2)cn1)C(=O)Nc1ccc(CCCC(=O)NO)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.8 %

Procedure:
t-Butyl 3-(5-(benzyloxy)pyridin-2-yl)-1-(4-(4-(hydroxyamino)-4-oxobutyl)-phenylamino)-1-oxopropan-2-ylcarbamate (0.1 g, 0.19 mmol) was dissolved in DCM/TFA (v/v=1:1) (30 mL), and stirred at room temperature for 4 h (monitored by TLC). The solution was evaporated in vacuo to give Compound 5 (0.062 g, 61%). mp>300° C.; NMR (400 MHz in CDCl3, Bruker AVANCE-400): δ 1.75 (m, 2H, CH2), 1.95 (t, 2H, CH2, J=7.37 Hz), 2.52 (t, 2H, CH2, J=7.55 Hz), 3.16 (m, 2H, CH2), 4.30 (m, 1H, CH), 5.16 (s, 2H, OBn), 7.13 (d, 2H, Ar—H, J=8.06 Hz), 7.24 (d, 1H, Ar—H, J=8.47 Hz), 7.33-8.46 (m, 9H, Ar—H), 8.22 (br, 2H, NH2), 8.30 (m, 1H, NH), 8.64 (br, 1H, NH), 10.33 (br, 1H, OH), 10.36 (br, 1H, TFA).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[OH:11])=O.C([O-])(=O)C.[Na+].Cl.[NH2:18][OH:19]>C(O)C>[OH:11][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:3]=1[CH:1]=[N:18][OH:19])[C:7]#[N:8]
Reactant: NO
Reactant: N#Cc1ccc(C=O)c(O)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc(C=NO)c(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
To a solution of 4-formyl-3-hydroxy-benzonitrile (CAS 84102-89-6) (6.90 g) in dry ethanol (165 ml) was added sodium acetate (4.23 g) and hydroxylamine hydrochloride (3.58 g). The mixture was stirred at rt for 1 h. The solvent was evaporated and the product was purified by flash chromatography (cyclohexane/EtOAc 8:2=>1:1) to give 3-hydroxy-4-(hydroxyimino-methyl)-benzonitrile (4.70 g). Light yellow solid. MS 162.0 ([M]+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[SH:12][C:13]1[S:14][C:15]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:16]=2[N:17]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[S:12][C:13]1[S:14][C:15]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:16]=2[N:17]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: FC(F)(F)c1ccc2sc(S)nc2c1
Product: O=[N+]([O-])c1ccc(Sc2nc3cc(C(F)(F)F)ccc3s2)c(Cl)c1

Procedure:
2-(2-Chloro-4-nitro-phenylsulfanyl)-5-trifluoromethyl-benzothiazole (252) was prepared (92%) from 2-chloro-1-fluoro-4-nitrobenzene, obtained from Aldrich, and 5-trifluoromethyl-benzothiazol-2-thiol (239) in a similar manner as described in example 251.