Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[S:6][C:5]=1[C:15]([O:17]C)=[O:16])[CH3:2].C[O-].[Na+].CO.Cl>O>[CH2:1]([NH:3][C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[S:6][C:5]=1[C:15]([OH:17])=[O:16])[CH3:2]
Reactant: CCNc1cc(-c2ccncc2)sc1C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCNc1cc(-c2ccncc2)sc1C(=O)O
Yield: 69.1 %

Procedure:
A mixture of methyl 3-(ethylamino)-5-(pyridin-4-yl)thiophene-2-carboxylate (0.636 g, 2.42 mmol), sodium methoxide (0.393 g, 7.27 mmol), methanol (10 mL) and water (2.5 mL) was refluxed overnight. The mixture was cooled in an ice-bath and conc. HCl (0.600 mL, 7.27 mmol) was added to adjust the pH to 4. The resultant yellow precipitate was collected by filtration and washed with water and methanol to afford the title compound (0.415 g, 69%) as an orange solid:
Reaction SMILES: CC1C=CC(S([O:11][C@H:12]2[CH2:15][C@@H:14]([C:16]([N:18]3[CH2:24][CH2:23][CH2:22][N:21]([CH:25]4[CH2:28][CH2:27][CH2:26]4)[CH2:20][CH2:19]3)=[O:17])[CH2:13]2)(=O)=O)=CC=1.[C:29]([O-])(=[O:31])[CH3:30].[K+]>CN(C=O)C.C(Cl)Cl>[C:29]([O:11][C@H:12]1[CH2:13][C@H:14]([C:16]([N:18]2[CH2:24][CH2:23][CH2:22][N:21]([CH:25]3[CH2:26][CH2:27][CH2:28]3)[CH2:20][CH2:19]2)=[O:17])[CH2:15]1)(=[O:31])[CH3:30]
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2C[C@@H](C(=O)N3CCCN(C4CCC4)CC3)C2)cc1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)O[C@H]1C[C@H](C(=O)N2CCCN(C3CCC3)CC2)C1
Temperature: 110 °C

Procedure:
To a stirred solution cis-3-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]cyclobutyl 4-methylbenzenesulfonate (73 mg, 0.18 mmol) in DMF (3 ml) at RT was added potassium acetate (108 mg, 1.1 mmol). The mixture was heated at 110° C. overnight and then cooled to RT and diluted with DCM. The resulting mixture was washed with 1:1 H2O/brine and the organic phase dried (Na2SO4), filtered and concentrated at reduced pressure to yield the title compound (50 mg, 94%), which was used without further purification.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:23])([CH3:22])[C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([CH3:23])([CH3:22])[C:18]([O:20][CH3:21])=[O:19])=[CH:15][C:16]=1[N+:1]([O-:4])=[O:2]
Reactant: COC(=O)C(C)(C)c1ccc(Cl)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)(C)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
After dropwise addition of 40.0 g of concentrated nitric acid to 90.7 g of concentrated sulfuric acid under ice cooling, 62.3 g of methyl 2-(4-chlorophenyl)-2-methylpropionate was added dropwise. The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into ice water, followed by extraction with ethyl acetate. The organic layer was washed successively with water and brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure, whereby 75.5 g of the title compound was obtained.
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[N:15][C:14]=1[CH3:21])=[O:12].[C:22]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:23]([C:28](O)=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=1>>[C:22]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:23]([C:28]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[N:20]3[C:16]([S:17][CH:18]=[CH:19]3)=[N:15][C:14]=2[CH3:21])=[O:12])=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CCC[C@@H]21
Reactant: O=C(O)c1ccccc1-c1ccccc1
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1[C@H]2CCC[C@H]2CN1C(=O)c1ccccc1-c1ccccc1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with commercially available biphenyl-2-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH2:7][C:8]1[S:9][C:10]([C:13]2[CH:18]=[C:17]([NH:19][C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=3)[CH:16]=[C:15]([CH3:30])[CH:14]=2)=[CH:11][N:12]=1)[C:3]([O:5]C)=[O:4].C1COCC1.[OH-].[K+]>CO>[CH3:1][C:2]([CH3:31])([CH2:7][C:8]1[S:9][C:10]([C:13]2[CH:18]=[C:17]([NH:19][C:20]3[N:25]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:23]=[CH:22][N:21]=3)[CH:16]=[C:15]([CH3:30])[CH:14]=2)=[CH:11][N:12]=1)[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)(C)Cc1ncc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)s1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(CC(C)(C)C(=O)O)s2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Methyl 2,2-dimethyl-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]propanoate (278 mg, 0.617 mmol) was taken up in MeOH (4 mL)/THF (4 mL), and 1 M KOH (648 μL, 0.648 mmol) was added. The reaction was stirred at room temperature overnight. LC/MS analysis showed only ˜40% conversion, so additional 1 M KOH (123 μL, 0.123 mmol) was added, and the reaction was stirred at 50° C. overnight. The reaction was subsequently evaporated to dryness, providing 2,2-dimethyl-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]propanoic acid (potassium salt) as a yellow solid that was used without purification in subsequent reactions (337 mg, 87% pure, 100% yield). A small portion (40 mg) was purified by reverse phase HPLC (50-100% MeCN/water w/0.025% TFA). Product fractions were combined and evaporated to provide a clean sample of 2,2-dimethyl-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3-thiazol-2-yl]propanoic acid (TFA salt) as an off-white foam (28 mg). MS ESI: [M+H]+ m/z 437.0. 1H NMR (600 MHz, DMSO-d6) δ 12.41 (s, 1H), 10.23 (s, 1H), 8.80 (d, J=4.9, 1H), 7.98-7.86 (m, 2H), 7.44 (s, 1H), 7.26 (d, J=4.9, 1H), 7.11 (s, 1H), 3.16 (s, 2H), 2.29 (s, 3H), 1.16 (s, 6H). rhSYK activity=+++
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.[CH:18]1([C:21]2[CH:22]=[C:23]([CH3:33])[C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH2:20][CH2:19]1>>[CH:18]1([C:21]2[CH:22]=[C:23]([CH3:33])[C:24]([N:27]3[CH2:28][CH2:29][N:30]([C:12]([C:11]4[CH:10]=[CH:9][C:8]([CH2:7][N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:17])=[CH:16][CH:15]=4)=[O:14])[CH2:31][CH2:32]3)=[N:25][CH:26]=2)[CH2:20][CH2:19]1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: O=C(O)c1ccc(CN2CCCS2(=O)=O)cc1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(CN3CCCS3(=O)=O)cc2)CC1
Yield: 54.7 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-ylmethyl)benzoic acid (153 mg) described in Preparation Example 18 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (196 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Example 87, the title compound (149 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]#[C:13][C:14]([OH:16])=O.[NH2:17][C:18]1[CH:33]=[CH:32][C:21]([O:22][CH2:23][CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][C@H:26]2[CH2:30][OH:31])=[C:20]([O:34][CH3:35])[CH:19]=1>ClCCl.CO>[OH:31][CH2:30][C@@H:26]1[CH2:27][CH2:28][CH2:29][N:25]1[CH2:24][CH2:23][O:22][C:21]1[CH:32]=[CH:33][C:18]([NH:17][C:14](=[O:16])[C:13]#[C:12][C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[Cl:1])=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1cc(N)ccc1OCCN1CCC[C@H]1CO
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Solvent: CO
Solvent: ClCCl
Product: COc1cc(NC(=O)C#Cc2ccc(C(F)(F)F)cc2Cl)ccc1OCCN1CCC[C@H]1CO

Procedure:
Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethylphenyl)propynoic acid and {(S)-1-[2-(4-amino-2-methoxyphenoxy)ethyl]pyrrolidin-2-yl}methanol. Yield: 140 mg (58.9% of theory); melting point: decomposition at 300° C.; C24H24ClF3N2O4 (M=496.91); calc.: molecular ion peak (M+H)+: 497/499; found: molecular ion peak (M+H)+: 497/499; Rf value: 0.2 (silica gel, dichloromethane/methanol (9:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([OH:36])=O)=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:50][N:51]([CH3:56])[CH2:52][CH2:53][NH:54][CH3:55]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([N:54]([CH2:53][CH2:52][N:51]([CH3:56])[CH3:50])[CH3:55])=[O:36])=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:48][CH:49]=1
Reactant: CNCCN(C)C
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N(C)CCN(C)C)cc3)cn2)cc1
Yield: 56.6 %

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid (46.5 mg, 0.0705 mmol) obtained in Step A in Example 1-D-19 and N,N,N′-trimethyl ethylenediamine (36.7 μl, 0.282 mmol) instead of 3-(aminomethyl)pyridine, in the same manner as Step B in Example 1-D-19, amidation was carried out, to obtain a crude product of 4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-N-(2-dimethylamino-ethyl)-N-methyl-benzamide as a yellow liquid (29.7 mg), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-84) as a colorless powder (14.0 mg, 39%).
Reaction SMILES: CO[C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=3)[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.O.[NH2:33][NH2:34]>CO>[CH2:16]([N:13]1[CH2:12][CH2:11][C:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]([NH:33][NH2:34])=[O:31])=[CH:9][CH:8]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[CH2:15][CH2:14]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NN
Reactant: COC(=O)c1ccc(C2(c3cccc(OC)c3)CCN(Cc3ccccc3)CC2)cc1
Solvent: O
Solvent: CO
Product: COc1cccc(C2(c3ccc(C(=O)NN)cc3)CCN(Cc3ccccc3)CC2)c1
Temperature: 25 °C

Procedure:
To a solution of 4-[1-benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-benzoic acid methyl ester (9.5 g, 22.9 mmol) in methanol (60 mL) was added hydrazine hydrate (8 mL). The reaction mixture was heated to reflux for 36 hours. The mixture was cooled to room temperature and concentrated. The residue was dissolved in toluene (50 mL) and concentrated under vacuum, and 4-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-benzoic acid hydrazide was obtained in quantitative yield. The residue was used in the subsequent steps without purification. 1HNMR (400 MHz, CD3OD) δ 7.82 (d, 1H), 7.67 (d, 1H), 7.39-7.05 (comp, 8H), 6.86 (d, 1H), 6.80 (s, 1H), 6.67 (d, 1H), 3.69 (s, 3H), 3.38 (s, 2H), 2.62-2.37 (comp, 8H); MS (M+1) 416.3.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:6][C:7](=[O:11])[C:8]=1OC)=[O:5])#[N:2].O.[NH2:13][NH2:14]>C(O)(C)C>[C:1]([C:3]1[C:4]([NH:6][C:7](=[O:11])[C:8]=1[NH:13][NH2:14])=[O:5])#[N:2]
Reactant: COC1=C(C#N)C(=O)NC1=O
Reactant: NN
Solvent: O
Solvent: CC(C)O
Product: N#CC1=C(NN)C(=O)NC1=O
Temperature: 25 °C
Yield: 94 %

Procedure:
50 parts of 2-cyano-3-methoxymaleimide are introduced into a solution of 16.5 parts of hydrazine hydrate in 300 parts by volume of isopropanol, while cooling with ice, the reaction mixture is then stirred at room temperature for half an hour, and the red precipitate is filtered off under suction, washed with isopropanol and dried. 47 PG,6 parts (94% of theory) of 2-cyano-3-hydrazinomaleimide of melting point >350° C. are obtained. IR (KBr): 3120, 2200, 1670 cm-1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:12])=[C:4](Cl)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[CH2:13]([O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)[CH3:14].C(N(CC)CC)C>CCO>[Cl:1][C:2]1[C:3]([Cl:12])=[C:4]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][CH2:13][CH3:14])=[CH:17][CH:18]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1
Reactant: CCOc1ccc(N)cc1
Reactant: Clc1nn2ccnc2c(Cl)c1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOc1ccc(Nc2c(Cl)c(Cl)nn3ccnc23)cc1
Temperature: 90 °C
Yield: 86 %

Procedure:
A mixture of 6,7,8-trichloroimidazo[1,2-b]pyridazine (0.04 g, 0.18 mmol) from 1d, p-ethoxyaniline (0.025 g, 0.18 mmol) and triethylamine (0.055 mL, 0.4 mmol) were suspended in EtOH (1.0 mL) and heated to 90° C. for 2.5 hours. The reaction mixture was then cooled to room temperature and concentrated in vacuo to provide crude 6,7-dichloro-N-(4-ethoxyphenyl)imidazo[1,2-b]pyridazin-8-amine (0.05 g, 86%).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[N:11][C:6]=2[S:5][C:4]([NH:12][C:13]2[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=2)=[N:3]1.[H-].[Li+].[CH3:26]I>>[CH3:26][N:3]1[C:2](=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[N:11][C:6]=2[S:5][C:4]1=[N:12][C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1ccc(Nc2nc(=O)c3cccnc3s2)cc1
Reactant: CI
Agent: [H-]
Agent: [Li+]
Product: CCOC(=O)c1ccc(N=c2sc3ncccc3c(=O)n2C)cc1

Procedure:
The reaction procedure of Example 11 was followed except that 1.31 g of ethyl 4-[(4-oxo-4H-pyrido[3,2-e]-1,3-thiazin-2-yl)amino]benzoate, 36 mg of lithium hydride and 0.25 ml of methyl iodide were used. As a result, 656 mg of ethyl 4-[(3-methyl-4-oxo-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-2-ylidene)amino]benzoate was obtained.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[C:11]1[C:10]([OH:17])=[CH:9][C:8]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:7][C:6]=1[O:5]2.[N:24]1[CH:29]=[CH:28][C:27]([CH2:30][OH:31])=[CH:26][CH:25]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>CS(C)=O>[OH:17][C:10]1[C:11]2[C:12](=[O:16])[C:13]3[C:4](=[CH:3][C:2]([O:31][CH2:30][C:27]4[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=4)=[CH:15][CH:14]=3)[O:5][C:6]=2[CH:7]=[C:8]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:9]=1
Reactant: OCc1ccncc1
Reactant: O=c1c2ccc(F)cc2oc2cc(N3CCOCC3)cc(O)c12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1c2ccc(OCc3ccncc3)cc2oc2cc(N3CCOCC3)cc(O)c12
Temperature: 80 °C

Procedure:
6-Fluoro-1-hydroxy-3-morpholin-4-yl-xanthen-9-one (16 mg, 0.05 mmol) and 4-pyridylmethanol (8 mg, 0.07 mmol) were dissolved in DMSO (0.25 mL) and KHMDS (0.5 M in toluene, 0.24 mL) was added. The reaction mixture was heated at 80° C. for 16 hours. The reaction mixture wad quenched with sat. NH4Cl/water (1:1, 2 mL) and the solids were filtered. The solid was purified via flash chromatography eluting with CH2Cl2/MeOH (98:2) to produce 3.9 mg (20%). 1H NMR (CDCl3, 400 MHz) δ: 12.80 (s, 1H), 8.66 (s, 2H), 8.16 (d, 1H), 7.38 (d, 2H), 7.00 (d, 1H), 6.80 (s, 1H), 6.27 (dd, 1H), 6.25 (s, 1H), 5.21 (s, 2H), 3.86-3.83 (m, 4H), 3.37-3.35 (m, 4H). LRMS (APCI, positive): Da/e 405.1 (m+1).
Reaction SMILES: [Cl:1][C:2]([Cl:12])=[CH:3][C@@H:4]1[C:6]([CH3:8])([CH3:7])[C@H:5]1[C:9]([OH:11])=[O:10].[Br:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:15]=1[CH2:16]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[Cl:1][C:2]([Cl:12])=[CH:3][C@@H:4]1[C:6]([CH3:8])([CH3:7])[C@H:5]1[C:9]([O:11][CH2:16][C:15]1[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:14]=1[Br:13])=[O:10]
Reactant: CC1(C)[C@@H](C=C(Cl)Cl)[C@@H]1C(=O)O
Reactant: Clc1cccc(Br)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC1(C)[C@@H](C=C(Cl)Cl)[C@@H]1C(=O)OCc1c(Cl)cccc1Br
Yield: 98 %

Procedure:
1 cis/trans 2-(2,2-dichlorovinyl)-3,3-dimethylcyclopropane carboxylic acid (2.3 g), 2-bromo-6-chlorobenzylbromide (2.85 g) and potassium carbonate (1.6 g) were stirred together in acetone (30 ml) under reflux for 6 hours. The reaction mixture was cooled, diluted with water, and extracted three times with 50 ml portions of diethyl ether. The combined ether extracts were washed with water and with aqueous sodium bicarbonate solution (three times), dried over magnesium sulphate and evaporated to give the orange title product (4. g, 98%) m.p. 61°-67° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[N:2]=1.[F:8][C:9]([F:34])([F:33])[C:10]1[CH:32]=[CH:31][CH:30]=[CH:29][C:11]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:25]=[N:24][C:23]([C:26](Cl)=[O:27])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[O:13]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:26]([C:23]2[N:24]=[N:25][C:20]([N:17]3[CH2:16][CH2:15][N:14]([C:12](=[O:13])[C:11]4[CH:29]=[CH:30][CH:31]=[CH:32][C:10]=4[C:9]([F:34])([F:33])[F:8])[CH2:19][CH2:18]3)=[CH:21][CH:22]=2)=[O:27])[N:2]=1
Reactant: O=C(Cl)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: Nc1cccnn1
Product: O=C(Nc1cccnn1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 28, making variations only as required to use pyridazin-3-ylamine in place of 2-aminopyridine to react with 6-[4-(2-trifluoromethylbenzoyl)-piperazin-1-yl]pyridazine-3-carbonyl chloride, the title compound was obtained as a white powder (17.3% yield). 1H NMR (300 MHz, CDCl3) δ 10.81, 9.05, 8.70, 8.13, 7.87-7.57, 7.39, 6.95, 4.16-3.80, 3.40. 13C NMR (300 MHz, CDCl3) δ 167.7, 162.3, 160.1, 148.6, 144.1, 132.4, 129.6, 128.1, 127.2, 126.9, 118.3, 112.1, 43.4, 44.6, 44.3, 41.3. MS (ES+) m/z 458.3 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:16][CH2:15][C:10]3(OCC[O:11]3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.Cl.[OH-].[Na+]>>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:16][CH2:15][C:10](=[O:11])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1
Reactant: c1cc(N2CCC3(CC2)OCCO3)ccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1CCN(c2ccncc2)CC1
Reaction time: 0.17 h

Procedure:
8-(Pyridin-4-yl)-1,4-dioxa-8-azaspiro[4.5]decane was dissolved at 0° C. in ice-cooled concentrated HCl (6 ml) and stirred for 10 min. After monitoring by thin-layer chromatography, the reaction mixture was adjusted to pH 10-12 with 2 M NaOH and extracted with chloroform (3×100 ml). The combined organic phases were washed with sat. NaCl solution (in each case 50 ml), dried over sodium sulfate and concentrated under reduced pressure. The product so obtained was used in the next stage without being purified further.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.Cl[CH2:22][C:23]([O:25][CH3:26])=[O:24].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][CH:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1CC(O)C(F)(F)F
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O
Temperature: 25 °C

Procedure:
3.04 g (9.9 mmol) of the compound from Example 4A were dissolved in 100 ml of acetonitrile, and 1.07 g (9.9 mmol) of methyl chloroacetate, 2.73 g (19.8 mmol) of potassium carbonate and a small spatula tip of potassium iodide were added. The reaction mixture was heated under reflux for 1 h and then allowed to cool to RT and filtered. The filtrate was freed from the volatile components on a rotary evaporator and the residue was dried under high vacuum. This gave 3.70 g of the title compound in a purity of about 90%, (89% of theory).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[F:9][C:10]1[CH:11]=[C:12]([CH2:16][CH2:17][C:18]2[O:22][C:21]([C:23]3[CH:24]=[CH:25][C:26]([N+:38]([O-])=O)=[C:27]([CH:37]=3)[NH:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)=[N:20][N:19]=2)[CH:13]=[CH:14][CH:15]=1.O1CCCC1.C(=O)([O-])O.[Na+]>C(O)C>[F:9][C:10]1[CH:11]=[C:12]([CH2:16][CH2:17][C:18]2[O:22][C:21]([C:23]3[CH:37]=[C:27]([NH:28][C:29]4[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=4)[C:26]([NH2:38])=[CH:25][CH:24]=3)=[N:20][N:19]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: COc1ccc(Nc2cc(-c3nnc(CCc4cccc(F)c4)o3)ccc2[N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(Nc2cc(-c3nnc(CCc4cccc(F)c4)o3)ccc2N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
To an aqueous solution (5.1 mL) of sodium hydrosulfite (1.15 g, 6.61 mmol) was added a mixed solution of 5-[5-[2-(3-fluorophenyl)ethyl]-1,3,4-oxadiazol-2-yl]-N-(4-methoxyphenyl)-2-nitroaniline (0.20 g, 0.41 mmol), tetrahydrofuran (4.1 mL) and ethanol (2.1 mL) at 0° C., and the resulting mixture was stirred at room temperature for 30 min. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=1/2) to give the title compound (0.12 g, yield 71%) as a yellow oil.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][O:6][C@@H:5]([CH3:8])[O:4][C@H:3]1[CH2:9][OH:10].[C:11]([Si:15]([CH3:18])([CH3:17])Cl)([CH3:14])([CH3:13])[CH3:12].N1C=CN=C1>CN(C)C=O.C(OCC)(=O)C>[O:10]([CH2:9][C@H:3]1[C@H:2]([OH:1])[CH2:7][O:6][C@@H:5]([CH3:8])[O:4]1)[Si:15]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@H]1OC[C@@H](O)[C@H](CO)O1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H]1OC[C@@H](O)[C@H](CO[Si](C)(C)C(C)(C)C)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.1 %

Procedure:
A mixture of (2R,4S,5R)-5-hydroxy-4-hydroxymethyl-2-methyl-1,3-dioxane (13.0 g), t-butyldimethylchlorosilane (14.5 g) and imidazol (13.1 g) in N,N-dimethylformamide (130 ml) was stirred at room temperature for 2 hours and the mixture was diluted with ethyl acetate (500 ml). The solution was washed successively with water, diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to give (2R,4S,5R)-4-t-butyldimethylsiloxymethyl-5-hydroxy-2-methyl-1,3-dioxane (24.2 g) as a colorless oil.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([F:15])([F:14])[F:13])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:16]Br.OS(O)(=O)=O>C(O)(=O)C>[Br:16][C:9]1[CH:10]=[CH:11][C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[C:7]([C:12]([F:13])([F:14])[F:15])[CH:8]=1
Reactant: BrBr
Reactant: FC(F)(F)c1ccccc1C1CCCC1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(Br)ccc1C1CCCC1
Temperature: 0 °C
Yield: 36.5 %

Procedure:
To a solution of 1-cyclopentyl-2-(trifluoromethyl)benzene (0.5 g, 2.334 mmol) in acetic acid (2.5 mL) was added bromine (1.202 mL, 23.34 mmol). The mixture was stirred well, added concentrated H2SO4 (2.5 mL), and stirred at 40° C. for 1.5 h. The reaction mixture was poured into ice-water and extracted with CH2Cl2. The CH2Cl2 layer was washed with water, followed by a solution of sodium thiosulfate, then with water. The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (250 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.52-1.75 (m, 4H), 1.78-1.88 (m, 2H), 1.95-2.04 (m, 2H), 3.16-3.26 (m, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.76 (d, J=2 Hz, 1H), 7.81 (dd, J=8.4 Hz, 2 Hz, 1H).