Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[CH:10](=O)/[CH:11]=[CH:12]/[CH3:13].[NH4+].[OH-]>Cl.C(OCC)(=O)C>[F:8][C:5]1[CH:6]=[C:7]2[C:2](=[C:3]([OH:9])[CH:4]=1)[N:1]=[C:12]([CH3:13])[CH:11]=[CH:10]2
Reactant: C/C=C/C=O
Reactant: Nc1ccc(F)cc1O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1ccc2cc(F)cc(O)c2n1
Reaction time: 0.5 h

Procedure:
2-Amino-5-fluorophenol (13.0 g, 102 mmol) was dissolved in 6N HCl (78 mL) and heated to reflux. The solution was treated with (E)-but-2-enal (8.8 ml, 107 mmol) in 1 mL portions over 1 hour. The reaction was heated at reflux for 13 hours. The reaction mixture was cooled and adjusted to pH 8 with concentrated NH4OH. The reaction was diluted with ethyl acetate, stirred for 30 minutes then filtered through a nylon membrane (0.45 μM). The filtrate was separated and the aqueous was washed with ethyl acetate. The combined organics were washed with saturated NaHCO3, saturated NaCl, dried over Na2SO4 and concentrated in vacuo to a thick dark oil (19 g). MS APCI (+) m/z 178.1 (M+1) detected.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].Br[CH:27]([CH3:30])[C:28]#[N:29]>CN(C=O)C>[C:28]([CH:27]([N:1]1[C:5]2=[N:6][C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:30])#[N:29]
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2n1
Reactant: CC(Br)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(C(C)C#N)c2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 43.4 %

Procedure:
To a solution of diethyl 1H-pyrrolo[2,3-b]pyridine-2,6-dicarboxylate (Intermediate D, 1.55 g, 5.91 mmol) in DMF (15 mL) is added potassium carbonate (2.45 g, 17.7 mmol), and the mixture is stirred at room temperature for 20 min. 2-bromopropionitrile (1.05 mL, 11.8 mmol) is added, the mixture is warmed to 80° C., and is stirred overnight. After being cooled to room temperature, the mixture is poured onto H2O, and the aqueous layer is extracted with EtOAc (3×100 mL). The combined organic extracts are dried (MgSO4), filtered, and concentrated. The crude material is purified via flash column chromatography using a gradient elution of 10-50% ethyl acetate/hexanes to afford the title compound as a bright yellow solid (809 mg, 43%).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[CH2:9][NH:10][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:35][OH:36]>C1COCC1>[C:1]1(/[CH:7]=[CH:8]/[CH2:9][NH:10][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:35][OH:36])=[O:18])=[CH:15][CH:14]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc(C(=O)NC/C=C/c2ccccc2)cc1
Reactant: NO
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(NO)c1ccc(C(=O)NC/C=C/c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
The compound of step A (0.7 g, 2.3 mmoles) was dissolved in 8 ml of anhydrous THF and added at 0° C. with CDI (0.46 g, 2.8 mmoles). The mixture was stirred at room temperature overnight, then hydroxylamine hydrochloride (0.2 g, 2.3 mmoles) was added thereto and stirring was continued at room temperature for a further 60 hours. The formed precipitate was filtered and suspended in 1N HCl, then stirred overnight. Upon filtration and drying under vacuum, 400 mg of the title compound were obtained (55.6% yield); m.p.=194-195° C.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.[C:18]([O:26][C:27]1[N:32]=[C:31]([OH:33])[C:30]([C:34]#[N:35])=[CH:29][CH:28]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCOCC1>[C:18]([O:26][C:27]1[N:32]=[C:31]([O:33][C:13](=[O:14])[C:12]2[CH:16]=[CH:17][C:9]([Br:8])=[CH:10][CH:11]=2)[C:30]([C:34]#[N:35])=[CH:29][CH:28]=1)(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: N#Cc1ccc(OC(=O)c2ccccc2)nc1O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: N#Cc1ccc(OC(=O)c2ccccc2)nc1OC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
Triethylamine (3.46 ml) and 1.82 g of 4-bromobenzoyl chloride were added to a solution of 2.00 g of 6-benzoyloxy-3-cyano-2-hydroxypyridine in 50 ml of dioxane. The mixture was stirred at room temperature for 1 hour. The salt thus produced was separated by filtration and the filtrate was concentrated. The concentrate was applied to silica gel column chromatography using, as an eluent, chloroform, giving 2.97 g of the title compound in a yield of 84%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:13][C:14]([OH:16])=O)([O-])=[O:2].Cl.O.O.[Sn](Cl)Cl>C(O)C.O>[OH:2][N:1]1[C:4]2[C:5](=[CH:6][CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=2)[CH2:13][C:14]1=[O:16]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: O=C1Cc2ccc([N+](=O)[O-])cc2N1O
Temperature: 60 °C
Reaction time: 4 h

Procedure:
2.0 g of 2,4-dinitrophenylacetic acid (prepared according to J: Chem. Soc. 1948, 1717) are dissolved in 40 ml ethanol and 6.0 ml of conc. hydrochloric acid and 4.1 g of tin-(II)-chloride-dihydrate are added in batches at ambient temperature. The mixture is stirred for 12 hours at ambient temperature and for 4 hours at 60° C. After cooling another 2.0 g of tin-(II)-chloride-dihydrate are added and the mixture is stirred for another 12 hours at ambient temperature. The reaction mixture is diluted with water, extracted with methylene chloride and the organic phase is dried over sodium sulphate. After elimination of the solvent the residue is triturated with ether and the precipitate is filtered off.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[N:11]=[C:12]=S)[CH3:2].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([NH:23][C:24]([C:26]3[CH:43]=[CH:42][C:29]4[N:30]=C(NC5N(C(C)C)C=CN=5)[NH:32][C:28]=4[CH:27]=3)=[O:25])[CH:21]=2)[CH:16]=[N:15]1>CN(C=O)C.C1COCC1>[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([NH:23][C:24]([C:26]3[CH:43]=[CH:42][C:29]4[N:30]=[C:12]([NH:11][C:4]5[C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=[CH:6][C:5]=5[CH2:9][CH3:10])[NH:32][C:28]=4[CH:27]=3)=[O:25])[CH:21]=2)[CH:16]=[N:15]1
Reactant: CC(C)n1ccnc1Nc1nc2ccc(C(=O)Nc3ccc4cn[nH]c4c3)cc2[nH]1
Reactant: CCc1cccc(CC)c1N=C=S
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCc1cccc(CC)c1Nc1nc2ccc(C(=O)Nc3ccc4cn[nH]c4c3)cc2[nH]1

Procedure:
A solution of 1,3-diethyl-2-isothiocyanatobenzene (0.5 mmol) in 1:1 DMF/THF (2 mL) was reacted with 3,4-diamino-N-(1H-indazol-6-yl)-benzamide (0.5 mmol; see Example 25) according to general procedure B to yield 2-(2,6-diethylphenylamino)-3H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide. MS: m/z 425 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](OC(=O)CC)(=O)[CH2:13][CH3:14]>>[CH2:13]([C:14]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:2]=2[N:1]=1)[CH3:12]
Reactant: CCC(=O)OC(=O)CC
Reactant: Nc1ccc(F)cc1C(=O)O
Product: CCc1nc2ccc(F)cc2c(=O)o1

Procedure:
A mixture of 2-amino-5-fluorobenzoic acid (23.3 g, 0.15 mol) and propionic acid anhydride (150 mL) was heated to reflux for 3 hr, then the propionic acid anhydride was removed in vacuo to afford 2-ethyl-6-fluoro-benzo[d][1,3]oxazin-4-one 2 as a gray solid, which was used directly in the next step.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[CH:11]([O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)([CH3:13])[CH3:12].Cl>C(O)CCC>[CH:11]([O:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]2[N:3]=[CH:4][C:5]3[CH:10]=[CH:9][NH:8][C:6]=3[N:7]=2)=[CH:17][CH:16]=1)([CH3:13])[CH3:12]
Reactant: Clc1ncc2cc[nH]c2n1
Reactant: CC(C)Oc1ccc(N)cc1
Agent: Cl
Solvent: CCCCO
Product: CC(C)Oc1ccc(Nc2ncc3cc[nH]c3n2)cc1
Temperature: 140 °C

Procedure:
To a suspension of 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (700 mg, 4.33 mmol) in BuOH (10 mL) is added 4-isopropoxyaniline (1.31 g, 8.66 mmol) and concentrated aqueous HCl (37%, 1.28 mL, 13.0 mmol). The reaction mixture is heated to 140° C. for 24 h, cooled to rt, and concentrated under reduce pressure. The residue is dissolved in EtOAc and the organic layer is washed with saturated aqueous Na2CO3 solution (2×). The organic layer is dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue solid residue is triturated with hexane to yield the title compound as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([CH3:9])[CH:3]=1.[F:10]OC(=O)C>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([CH3:9])[C:3]=1[F:10]
Reactant: Cc1cc(Cl)c(F)cn1
Reactant: CC(=O)OF
Product: Cc1ncc(F)c(Cl)c1F

Procedure:
4-Chloro-5-fluoro-2-picoline is treated with 1.1 equivalents of acetyl hypofluorite as described by O. Lerman, et al. J Org Chem, 49: 806-813 (1984) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:13]=[C:14]3[N:20]=[C:19]([C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[NH2:23])[S:18][C:15]3=[N:16][CH:17]=2)[CH2:7][CH2:6]1.[CH3:28][C:29]1[O:33][C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:31][C:30]=1[C:40](O)=[O:41]>>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:13]=[C:14]3[N:20]=[C:19]([C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[NH:23][C:40]([C:30]4[N:31]=[C:32]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[O:33][C:29]=4[CH3:28])=[O:41])[S:18][C:15]3=[N:16][CH:17]=2)[CH2:7][CH2:6]1
Reactant: Cc1oc(-c2ccccc2)nc1C(=O)O
Reactant: COCCN1CCN(Cc2cnc3sc(-c4ccccc4N)nc3c2)CC1
Product: COCCN1CCN(Cc2cnc3sc(-c4ccccc4NC(=O)c4nc(-c5ccccc5)oc4C)nc3c2)CC1

Procedure:
The title compound was prepared according to amide synthesis general method B, utilizing 2-(6-((4-(2-methoxyethyl)piperazin-1-yl)methyl)thiazolo[5,4-b]pyridin-2-yl)aniline and 5-methyl-2-phenyloxazole-4-carboxylic acid (1.5 eq). The product precipitated from the reaction mixture, and was filtered and chased with methanol. The product was purified by prep HPLC. MS Calcd for C31H32N6O3S: 568.23. Found (M+H)+ m/z=569.
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[CH2:4][C:3](=O)[CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28][NH2:29]>C1(C)C=CC=CC=1>[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28][NH:29][C:3]1[CH2:2][O:1][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[CH:4]=1
Reactant: O=C1COc2ccccc2C(=O)C1
Reactant: CN(C)CCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CN(C)CCNC1=CC(=O)c2ccccc2OC1
Temperature: 25 °C

Procedure:
A solution of 88 g (0.5 mole) 2,3,4,5-tetrahydro-1-benzoxepin-3,5-dione and a spatula tip of p-toluene sulfonic acid in 750 ml toluene are mixed while stirring with 44 g (0.5 mole) N,N-dimethylethylenediamine and subsequently stirred to the end of the reaction at room temperature. After concentration of the solution, a product is obtained by filtering off the solution under suction and subsequently recrystallizing from benzene/ligroin. 108 g (88% of the theoretical yield) of 3-(β-dimethylaminoethylamino)-1-benzoxepin-5(2H)-one are obtained. The melting point of this derivative is 100 to 101° C.
Reaction SMILES: [CH3:1][C:2]1([OH:6])[CH2:5][CH2:4][CH2:3]1.N1C=CC=CC=1.[C:13](Cl)([Cl:15])=[O:14]>C1C=CC=CC=1>[Cl:15][C:13]([O:6][C:2]1([CH3:1])[CH2:5][CH2:4][CH2:3]1)=[O:14]
Reactant: O=C(Cl)Cl
Reactant: CC1(O)CCC1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC1(OC(=O)Cl)CCC1
Reaction time: 0.5 h

Procedure:
A solution of 0.55 gm. (6.5 mM) of 1-methylcyclobutanol, and 0.44 ml. of pyridine in 10 ml. of benzene is added to a solution of phosgene in 10 ml. of benzene at 0°C. over a 30 minute period. The reaction is allowed to stir for 30 minutes and then filtered to remove pyridine hydrochloride formed during the reaction. Excess phosgene is removed by evaporation at reduced pressure and the volume of the benzene solution is reduced to 4-5 ml; the benzene solution of 1-methylcyclobutylchloroformate is employed in the following reaction.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1.[F:17][C:18]1[N:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1.[ClH:33].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:33].[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([NH:12][C:30](=[O:31])[C:27]4[CH:26]=[CH:25][C:24]([C:21]5[CH:22]=[N:23][C:18]([F:17])=[CH:19][CH:20]=5)=[CH:29][CH:28]=4)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(-c2ccc(F)nc2)cc1
Reactant: Cc1c(C2CC2)nc2ccc([N+](=O)[O-])cn12
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1c(C2CC2)nc2ccc(NC(=O)c3ccc(-c4ccc(F)nc4)cc3)cn12

Procedure:
Operations similar to those of Example 1 were conducted using 2-cyclopropyl-3-methyl-6-nitroimidazo[1,2-a]pyridine and 4-(6-fluoro-3-pyridyl)benzenecarboxylic acid. The resulting solid was dissolved in ethyl acetate, followed by addition of 4N hydrochloric acid-ethyl acetate solution and concentration under reduced pressure. The title compound was obtained as white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O=[C:23]1[C:31]2[C:26](=[N:27][C:28]([C:32]([OH:34])=[O:33])=[CH:29][CH:30]=2)[CH2:25][O:24]1.Cl>C1COCC1.CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:23]1[C:31]2[C:26](=[N:27][C:28]([C:32]([OH:34])=[O:33])=[CH:29][CH:30]=2)[CH2:25][O:24]1
Reactant: O=C(O)c1ccc2c(n1)COC2=O
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1Nc2ccc(F)cc2C1=C1OCc2nc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 29.3 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (177 mg, 1.17 mmol) in THF (2 mL) is treated with a solution of lithium bis(trimethylsilyl)amide (2.9 mL of a 1M solution in THF, 2.3 mmol) dropwise. The resulting solution is stirred at room temperature for 15 min. A solution 5-oxo-5,7-dihydro-furo[3,4-b]pyridine-2-carboxylic acid (105 mg, 0.59 mmol) in dimethylformamide (2 mL) is added dropwise to the reaction mixture. The resulting solution is stirred for 3 h and is then poured into a cold 10% aqueous HCl solution (30 mL). The reaction mixture is stirred at room temperature for 65 h. The solid which precipitated from solution is collected by filtration, washed with water and purified by chromatography (silica gel, MeOH/EtOAc). The product containing fractions are concentrated to give the title compound as a reddish solid (54 mg, 29%).
Reaction SMILES: C(O[C:9](=O)[N:10]([C@H:12]([C:14](=[O:43])[NH:15][C:16]1[C:17](=[O:42])[N:18]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:30]=2)[C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:20][CH:21]=1)[CH3:13])C)C1C=CC=CC=1.[H][H]>C(O)C>[C:22]1([C:19]2[N:18]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:30]=3)[C:17](=[O:42])[C:16]([NH:15][C:14](=[O:43])[C@@H:12]([NH:10][CH3:9])[CH3:13])=[CH:21][CH:20]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C[C@@H](C(=O)Nc1ccc(-c2ccccc2)n(Cc2cccc(Oc3ccccc3)c2)c1=O)N(C)C(=O)OCc1ccccc1
Reactant: [H][H]
Solvent: CCO
Product: CN[C@@H](C)C(=O)Nc1ccc(-c2ccccc2)n(Cc2cccc(Oc3ccccc3)c2)c1=O
Yield: 11.7 %

Procedure:
Compound 20D (55 mg, 0.094 mmol) in ethanol (2 mL) is hydrogenated under 10% palladium on carbon (10 mg) and hydrogen (balloon pressure). The reaction is monitored by LCMS. Upon completion the mixture is filtered and the filtrate is concentrated and purified by HPLC to afford the title compound (5 mg, 12%):
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([C:11]2[N:12]=[N:13][N:14]([CH2:16][CH2:17][OH:18])[CH:15]=2)([OH:10])[CH3:9])[CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[S:21][C:22]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([OH:37])([CH3:36])[CH3:35])=[CH:30][C:29]=2[F:38])=[CH:23][C:24]=1[C:25]([NH2:27])=[O:26]>>[F:38][C:29]1[CH:30]=[C:31]([C:34]([OH:37])([CH3:35])[CH3:36])[CH:32]=[CH:33][C:28]=1[C:22]1[S:21][C:20]([NH:19][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([C:8]([OH:10])([C:11]3[N:12]=[N:13][N:14]([CH2:16][CH2:17][OH:18])[CH:15]=3)[CH3:9])[N:7]=2)=[C:24]([C:25]([NH2:27])=[O:26])[CH:23]=1
Reactant: CC(O)(c1cn(CCO)nn1)c1cccc(Br)n1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(C(C)(O)c4cn(CCO)nn4)n3)s2)c(F)c1

Procedure:
The title compound was synthesized from 1-(6-bromopyridin-2-yl)-1-[1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl]ethanol (128 mg, 0.41 mmol) and 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (120 mg, 0.41 mmol) according to the general procedure in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15](=O)/[CH:16]=[CH:17]/[N:18](C)C)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29]N>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15]3[N:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[F:22])[N:18]=[CH:17][CH:16]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ccccc1F
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(Cl)c2)ccc1=O
Product: O=c1ccn(-c2cccc(Cl)c2)nc1-c1ccnn1-c1ccccc1F

Procedure:
The product was obtained starting from 1-(3-Chloro-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-23) and 2-fluoro-phenylhydrazine according to the method described for example 1. MS: M=367.0 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(OCC)(=O)C>CN(C=O)C>[CH2:17]([O:10][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=1[CH:7]=[O:8])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)ccc1OCc1ccccc1
Reaction time: 18 h

Procedure:
A mixture of 5-bromosalicylaldehyde (12 g), potassium carbonate (16.5 g) and benzyl bromide (7.8 ml) in DMF (50 ml) was stirred for 18 hours, poured into ethyl acetate (100 ml), washed with 0.05M HCl (100 ml), sodium bicarbonate (100 ml) and brine (100 ml), dried (sodium sulphate), filtered and evaporated. The residue was triturated with hexane/diethyl ether to give 2-benzyloxy-5-bromo-benzaldehyde (15.8 g) mp.70°-72° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30](=[O:33])[CH:31]=[CH2:32])[CH:24]=3)[S:10][C:11]=2[C:12]2[N:16]=[CH:15][N:14](C3CCCCO3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:34][O:35][CH2:36][C@@H:37]1[CH2:41][CH2:40][CH2:39][NH:38]1>O1CCCC1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH3:34][O:35][CH2:36][C@@H:37]1[CH2:41][CH2:40][CH2:39][N:38]1[CH2:32][CH2:31][C:30]([NH:29][C:25]1[CH:24]=[C:23]([C:9]2[S:10][C:11]([C:12]3[NH:16][CH:15]=[N:14][N:13]=3)=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[CH:28]=[CH:27][N:26]=1)=[O:33]
Reactant: COC[C@@H]1CCCN1
Reactant: C=CC(=O)Nc1cc(-c2nc(-c3ccccc3)c(-c3ncn(C4CCCCO4)n3)s2)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC[C@@H]1CCCN1CCC(=O)Nc1cc(-c2nc(-c3ccccc3)c(-c3nnc[nH]3)s2)ccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.3 %

Procedure:
To a solution of N-(4-(4-phenyl-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl)pyridin-2-yl)prop-2-enamide (92 mg, 0.2 mmol) prepared in Example 4-B (iii) in tetrahydrofuran (2.0 mL) was added (2S)-2-(methoxymethyl)pyrrolidine (120 mg, 1.0 mmol), and the mixture was heated under reflux for 14 hr. The reaction solution was cooled to room temperature, and diluted with ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate solution (30 mL). The aqueous layer was separated, extracted with ethyl acetate (40 mL), and the combined organic layer was dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated. The obtained residue was dissolved in trifluoroacetic acid (4.0 mL), and the mixture was stirred at room temperature for 3 hr. Trifluoroacetic acid was evaporated under reduced pressure, and the residue was diluted with ethyl acetate (30 mL), and washed with saturated aqueous sodium bicarbonate solution (30 mL). The aqueous layer was separated and extracted with ethyl acetate (30 mL), and the combined organic layer was dried over anhydrous magnesium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (methanol/ethyl acetate=0/100→50/50) to give the title compound (60 mg, 62%) as a pale-yellow solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:10]([F:13])([F:12])[F:11].[OH-].[K+].[CH2:16]([OH:18])[CH3:17]>>[F:9][C:4]1[CH:5]=[C:6]([Br:8])[CH:7]=[C:2]([O:18][CH2:16][CH3:17])[C:3]=1[C:10]([F:13])([F:12])[F:11]
Reactant: CCO
Reactant: Fc1cc(Br)cc(F)c1C(F)(F)F
Agent: [K+]
Agent: [OH-]
Product: CCOc1cc(Br)cc(F)c1C(F)(F)F
Reaction time: 4 h

Procedure:
To a 500 ml three neck flask provided with a stirrer, thermometer, and cooling tube were added 20.0 g (76.7 mmol) of 2,6-difluoro-4-bromobenzotrifluoride, 12.9 g (222.9 mmol) of potassium hydroxide, and 100 ml of ethanol, and heated to reflux while being stirred for 4 hours. After unreacted ethanol was distilled off under a reduced pressure from the reaction mixture, 200 ml of water was added thereto and extracted with 200 ml of diethyl ether. The extract was washed with water (150 ml) thrice and then dried over anhydrous magnesium sulfate. The colorless oily product in an amount of 20.5 g which was obtained by distilling off the solvent was purified by silica gel column chromatography (eluent: heptane) to obtain 18.7 g of colorless oily 2-fluoro-4-bromo-6-ethoxybenzotrifluoride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH2:33][CH3:34])[CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:19][CH:18]=1.C1C(=O)N([Cl:42])C(=O)C1>CN(C=O)C>[Cl:42][C:11]1[C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]([CH2:33][CH3:34])[CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[CH:19][CH:18]=2)=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: CCC(CNC(=O)OC(C)(C)C)c1ccc(-c2c(OC)ccc3[nH]c(=O)c4sccc4c23)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CCC(CNC(=O)OC(C)(C)C)c1ccc(-c2c(OC)cc(Cl)c3[nH]c(=O)c4sccc4c23)cc1
Yield: 60.3 %

Procedure:
Following General Procedure H, tert-butyl 2-(4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)butylcarbamate (100 mg, 0.21 mmol) in (DMF) was reacted with NCS (34 mg, 0.25 mmol) to afford the desired product (65 mg, 61%) as a yellow solid: ESI MS m/z 513 [C27H29ClN2O4S+H]+.