Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:17]([NH2:18])=[N:16][C:10]2[N:11]=[C:12]([NH2:15])[N:13]=[CH:14][C:9]=2[CH:8]=1.[C:20]([N:24]=[C:25]=[O:26])([CH3:23])([CH3:22])[CH3:21].N>C>[NH2:15][C:12]1[N:13]=[CH:14][C:9]2[CH:8]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:19])[C:17]([NH:18][C:25]([NH:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])=[N:16][C:10]=2[N:11]=1
Reactant: CC(C)(C)N=C=O
Reactant: Cc1ccccc1-c1cc2cnc(N)nc2nc1N
Agent: C
Agent: N
Product: Cc1ccccc1-c1cc2cnc(N)nc2nc1NC(=O)NC(C)(C)C

Procedure:
The title compound was prepared from 6-o-tolyl-pyrido[2,3-d]pyrimidine-2,7-diamine from Example 90 and tert-butyl isocyanate according to Example 2. The product was purified by MPLC eluting with CHCl3 :EtOAc (1:1) afford the pure product; mp 195°-197° C., CIMS (1% ammonia in methane): m/z (relative intensity) 351 (MH+ +1, 55), 352 (MH+ +2, 12), 84 (100).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[OH2:11]>C1COCC1>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:11][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:3]=1)=[O:5]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: O
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
A solution (10 mL) of 2-methylbenzoyl chloride (4.16 mL) in THF was added dropwise to the reaction mixture, followed by stirring overnight at room temperature. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=9:1) to afford phenyl 2-methylbenzoate (2.88 g, 64%).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[CH2:12][CH:13]([NH:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])[CH2:14][C:6]=3[C:5]=2[CH:4]=1)#[N:2].[F:21][C:22]1[N:27]=[C:26]([CH2:28]Br)[CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:28][C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([F:21])[N:27]=3)[C:7]3[CH2:12][CH:13]([NH:15][C:16](=[O:20])[CH:17]([CH3:18])[CH3:19])[CH2:14][C:6]=3[C:5]=2[CH:4]=1)#[N:2]
Reactant: Fc1cccc(CBr)n1
Reactant: CC(C)C(=O)NC1Cc2[nH]c3ccc(C#N)cc3c2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)C(=O)NC1Cc2c(n(Cc3cccc(F)n3)c3ccc(C#N)cc23)C1
Yield: 56.5 %

Procedure:
Mix (±)-N-(7-cyano-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-isobutyramide (6.28 g, 18.8 mmol), 6-fluoro-2-bromomethylpyridine (3.93 g, 20.7 mmol), and Cs2CO3 (12.25 g, 37.6 mmol) in DMF (25 mL). Heat the reaction at 50° C. for 18 h. Cool, dilute with EtOAc, and wash with water (3×200 mL). Dry the organic layer (MgSO4) and concentrate to give 7.1 g crude material. Purify by silica gel chromatography (5-20% EtOAc/CH2Cl2). Obtain 4.0 g (56%) yellow-tan solid. MS (m/z): 377 (M+1), 375 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH:28]=[N:27][N:26]=[N:25]4)=[CH:20][CH:19]=3)=O)[C:9]=2[F:29])[CH:5]=[CH:6][CH:7]=1.C([SiH](CC)CC)C.[OH-].[NH4+]>C(O)(C(F)(F)F)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH:28]=[N:27][N:26]=[N:25]4)=[CH:20][CH:19]=3)[C:9]=2[F:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)c2ccc(-n3cnnn3)cc2)c(F)c1-c1cccc(Cl)c1
Agent: CC[SiH](CC)CC
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc(Cc2ccc(-n3cnnn3)cc2)c(F)c1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 81 %

Procedure:
To (3′-chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-(4-tetrazol-1-yl-phenyl)-methanone synthesized above (0.1 g, 0.24 mmol) in TFA (1.5 mL) was added triethylsilane (0.28 g, 2.4 mmol). The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was cooled to 0° C., diluted with water (3 mL), basified with ammonium hydroxide solution (28%), filtered, washed with water dried to afford 0.08 g (81%) of 1-[4-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-1H-tetrazole (P-404) as off-white solid. 1H NMR (DMSO-d6, 400 MHz): 7.2-7.4 (m, 6H), 7.04-7.12 (s, 3 H), 6.7 (d, J=8.4 Hz, 1H), 3.95 (s, 2H), 3.77 (s, 3H) ppm; MS (APCI+): 365.1 (M−28), LC-MS: 95.9%.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]=[CH:10][C:9]([CH:12]([OH:16])[CH:13]([CH3:15])[CH3:14])=[CH:8][CH:7]=2)=[CH:2]1.[CH:17]1[N:21]=[CH:20][N:19]([C:22](N2C=NC=C2)=[O:23])[CH:18]=1>C(#N)C>[N:19]1([C:22]([O:16][CH:12]([C:9]2[CH:10]=[N:11][C:6]([C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)=[CH:7][CH:8]=2)[CH:13]([CH3:14])[CH3:15])=[O:23])[CH:18]=[CH:17][N:21]=[CH:20]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)C(O)c1ccc(-c2ccoc2)nc1
Solvent: CC#N
Product: CC(C)C(OC(=O)n1ccnc1)c1ccc(-c2ccoc2)nc1

Procedure:
Synthesized using compound 49a (73.0 mg, 0.36 mmol), CDI (291 mg, 1.80 mmol) and acetonitrile (4 mL) according to Method E. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (1:1) as eluent. Green oil. Yield: 62 mg, 67%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=0.92 (d, J=6.9 Hz, 3H), 1.11 (d, J=6.3 Hz, 3H), 2.25-2.44 (m, 1H), 5.63 (d, J=7.9 Hz, 1H), 6.88 (s, 1H), 7.08 (s, 1H), 7.41-7.58 (m, 3H), 7.66 (dd, J=7.9, 1.9 Hz, 1H), 8.03 (s, 1H), 8.16 (s, 1H), 8.60 (s, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=18.6, 18.8, 33.5, 83.8, 108.7, 117.2, 120.0, 126.8, 131.1, 131.4, 135.4, 137.2, 141.7, 144.2, 148.2, 148.8, 152.5; MS (ESI): m/z=312.32 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)=[O:3].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+].C(O)(=O)C>CO>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])/[CH:1]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(/C=C/c1ccccc1)c1ccc(Br)cc1
Reaction time: 3 h
Yield: 70.2 %

Procedure:
In a 500 mL flask, 99.4 g (0.50 mol) of 4-bromoacetophenone and 53.0 g (0.5 mol) of benzaldehyde were initially charged and dissolved in 50 g of methanol. The mixture was admixed with 6.7 g (0.025 mol) of 15% strength aqueous sodium hydroxide solution carefully added dropwise at 20-25° C. and subsequently stirred for 3 h. The reaction mixture was neutralized with glacial acetic acid and filtered and the solid was dried in vacuo to obtain 107 g (351 mmol) of (2E)-1-(4-bromophenyl)-3-phenylprop-2-en-1-one.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](I)[CH:8]=2)[N:3]=1.[OH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[CH2:25][OH:24])[CH:8]=2)[N:3]=1
Reactant: OCc1ccccc1B(O)O
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(I)ccc2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3CO)ccc2n1
Temperature: 130 °C

Procedure:
100 mg of (2-amino-6-iodoquinazolin-4-yl)-(1,3-dihydroisoindol-2-yl)methanone are dissolved in 2 ml of ethylene glycol dimethyl ether. 48 mg of 2-hydroxymethylphenylboronic acid, 66 mg of potassium carbonate, 14 mg of [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride and 50 μl of water are added to this solution, and the mixture is heated at 130° C. under argon for 30 min. The hot mixture is filtered off through Celite, and the solution is evaporated to dryness under reduced pressure. The reddish residue obtained is triturated with acetonitrile, during which a beige solid precipitates out. This is filtered, washed with acetonitrile and dried overnight at 40° C. in a drying cabinet.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([OH:28])[C:19]2[N:20]=[C:21]([C:24]([F:27])([F:26])[F:25])[S:22][CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].[F:29][C:30]([F:41])([F:40])[C:31]1[S:32][CH:33]=[C:34]([C:36](=[O:39])[CH2:37]Br)[N:35]=1.C(=O)([O-])O.[K+]>CC(C)=O>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:17][CH:18]([C:19]3[N:20]=[C:21]([C:24]([F:26])([F:27])[F:25])[S:22][CH:23]=3)[O:28][C:36]([OH:39])([C:34]3[N:35]=[C:31]([C:30]([F:41])([F:40])[F:29])[S:32][CH:33]=3)[CH2:37]2)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)COc1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1
Reactant: O=C(CBr)c1csc(C(F)(F)F)n1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(CC(C)N2CC(c3csc(C(F)(F)F)n3)OC(O)(c3csc(C(F)(F)F)n3)C2)cc1

Procedure:
from N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine (pair of diastereomers A) with 2-trifluoromethyl-4-bromoacetyl-thiazole and potassium hydrogen carbonate in acetone.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([NH:19][C:20]3([C:24](OCC)=[O:25])[CH2:23][CH2:22][CH2:21]3)[S:17][CH:18]=2)=[CH:10][CH:9]=1.O.[OH-].[Na+]>O1CCCC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:15]=[C:16]([NH:19][C:20]3([CH2:24][OH:25])[CH2:23][CH2:22][CH2:21]3)[S:17][CH:18]=2)=[CH:12][CH:13]=1
Reactant: CCOC(=O)C1(Nc2nc(-c3ccc(Br)cc3)cs2)CCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCC1(Nc2nc(-c3ccc(Br)cc3)cs2)CCC1
Reaction time: 3 h
Yield: 54.8 %

Procedure:
Lithium aluminum hydride (290 mg, 7.6 mmol) was added under nitrogen in portions to a solution of ethyl 1-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}cyclobutane carboxylate (990 mg, 2.6 mmol), prepared in the previous step, in 15 mL of tetrahydrofuran at ice bath temperature. After the addition, the reaction was stirred at ice bath temperature for 3 h. Water (290 μL) was added dropwise, followed by the addition of 290 μL of 15% NaOH and then 870 μL of water. After the addition, the reaction was stirred for 40 min. The reaction was filtered through the Celite™ reagent and the Celite™ reagent washed with ethyl acetate. The filtrate was partitioned with water. The organic layer was separated, washed one time with water, one time with saturated sodium chloride, dried (MgSO4), filtered and the solvent removed under reduced pressure. Purification of the residue on a Horizon™ Flash Collector (the Biotage FLASH 40+™ cartridge) using a linear gradient of ethyl acetate in methylene chloride gave (1-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}cyclobutyl)methanol (483 mg, 55%) as a light yellow solid, MS (ESI) m/z 339 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[Br:11][C:12]1[CH:13]=[C:14]([C:19]2[N:20]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=3[Cl:31])[CH:21]=[CH:22][N:23]=2)[C:15](Cl)=[N:16][CH:17]=1>O1CCOCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:15]2[C:14]([C:19]3[N:20]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=4[Cl:31])[CH:21]=[CH:22][N:23]=3)=[CH:13][C:12]([Br:11])=[CH:17][N:16]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CN)cc1
Reactant: Clc1cccc(-n2ccnc2-c2cc(Br)cnc2Cl)c1Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(CNc2ncc(Br)cc2-c2nccn2-c2cccc(Cl)c2Cl)cc1
Temperature: 100 °C

Procedure:
To a solution of excess (4-methoxyphenyl)methanamine (0.2 mL) in dioxane (2 mL)was added 5-bromo-2-chloro-3-(1-(2,3-dichlorophenyl)-1H-imidazol-2-yl)pyridine (0.089 g, 0.222 mmol). The mixture was heated at 100° C. for 16 hours in a sealed reaction vessel. The mixture was then cooled, diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, and the combined organics dried over sodium sulfate. After filtration and concentration, the residue was purified by flash chromatography (20% hexanes/methylene chloride to 25% ethyl acetate/methylene chloride to provide 0.065 g of N-(4-methoxybenzyl)-5-bromo-3-(1-(2,3-dichlorophenyl)-1H-imidazol-2-yl)pyridin-2-amine [LC-MS m/e=505.0 (M+H)]. Using the same procedure, N-(4-methoxybenzyl)-5-bromo-3-(1-(2,3-difluorophenyl)-1H-imidazol-2-yl)pyridin-2-amine and N-(4-methoxybenzyl)-5-bromo-3-(1-(3-chloro-2-fluorophenyl)-1H-imidazol-2-yl)pyridin-2-amine can be produced from 5-bromo-2-chloro-3-(1-(2,3-difluorophenyl)-1H-imidazol-2-yl)pyridine and 5-bromo-2-chloro-3-(1-(3-chloro-2-fluorophenyl)-1H-imidazol-2-yl)pyridine, respectively
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([CH2:23][C@H:24]([CH:29]([CH3:31])C)[C:25]([NH:27][OH:28])=[O:26])(=[O:22])=[O:21])[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.FC1C=CC(C2C=NC(N3CCN(S(CC4(C(O)=O)CC[O:58][CH2:57][CH2:56]4)(=O)=O)CC3)=NC=2)=CC=1>>[OH:28][NH:27][C:25]([C:24]1([CH2:23][S:20]([N:17]2[CH2:16][CH2:15][N:14]([C:11]3[N:12]=[CH:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[CH:9][N:10]=3)[CH2:19][CH2:18]2)(=[O:21])=[O:22])[CH2:29][CH2:31][O:58][CH2:57][CH2:56]1)=[O:26]
Reactant: O=C(O)C1(CS(=O)(=O)N2CCN(c3ncc(-c4ccc(F)cc4)cn3)CC2)CCOCC1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)NO
Product: O=C(NO)C1(CS(=O)(=O)N2CCN(c3ncc(-c4ccc(F)cc4)cn3)CC2)CCOCC1
Yield: 92 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-N-hydroxy-3-methyl-butyramide, from 4-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonyl-methyl}tetrahydropyran-4-carboxylic acid (0.29 g), to provide the title compound as a white solid (0.27 g, 92%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[C:4]([CH3:9])[C:3]=1[CH3:10].[SH:11][CH2:12][CH2:13][C:14]1[S:18][CH:17]=[N:16][C:15]=1[CH3:19].[H-].[Na+]>>[CH3:9][C:4]1[C:3]([CH3:10])=[C:2]([S:11][CH2:12][CH2:13][C:14]2[S:18][CH:17]=[N:16][C:15]=2[CH3:19])[CH:7]=[CH:6][N+:5]=1[O-:8]
Reactant: Cc1ncsc1CCS
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Agent: [H-]
Agent: [Na+]
Product: Cc1ncsc1CCSc1cc[n+]([O-])c(C)c1C
Yield: 79 %

Procedure:
Following the procedure described in Example Aa), the reaction of 4-chloro-2,3-dimethylpyridine N-oxide with 5-(2-mercaptoethyl)-4-methylthiazole in the presence of sodium hydride gives 2,3-dimethyl-4-[2-(4-methyl-5-thiazolyl)-ethylthio]pyridine N-oxide; m.p.: 135°-137° C (yield: 79%).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[C:5]([CH3:11])[C:4]=1[CH3:12])=[O:2].[CH2:13]([C:15]1[CH:30]=[C:29]([C:31](=[NH:34])[NH:32]O)[CH:28]=[C:27]([CH3:35])[C:16]=1[O:17][CH2:18][C@@H:19]([OH:26])[CH2:20][NH:21][C:22](=[O:25])[CH2:23][OH:24])[CH3:14]>>[CH2:13]([C:15]1[CH:30]=[C:29]([C:31]2[N:34]=[C:8]([C:6]3[S:7][C:3]([CH:1]=[O:2])=[C:4]([CH3:12])[C:5]=3[CH3:11])[O:10][N:32]=2)[CH:28]=[C:27]([CH3:35])[C:16]=1[O:17][CH2:18][C@@H:19]([OH:26])[CH2:20][NH:21][C:22](=[O:25])[CH2:23][OH:24])[CH3:14]
Reactant: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H](O)CNC(=O)CO
Reactant: Cc1c(C=O)sc(C(=O)O)c1C
Product: CCc1cc(-c2noc(-c3sc(C=O)c(C)c3C)n2)cc(C)c1OC[C@@H](O)CNC(=O)CO

Procedure:
The title compound is prepared according to Method A starting from 5-formyl-3,4-dimethyl-thiophene-2-carboxylic acid and N—((S)-3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenoxy]-2-hydroxy-propyl)-2-hydroxy-acetamide; LC-MS: tR=0.95 min; [M+H]+=474.07; 1H NMR (D6-DMSO): δ 1.22 (t, J=7.5 Hz, 3H), 2.35 (s, 3H), 2.57 (s, 3H), 2.63 (s, 3H), 2.73 (q, J=7.8 Hz, 2H), 3.20-3.28 (m, 1H), 3.39-3.48 (m, 1H), 3.70-3.81 (m, 2H), 3.84 (d, J=5.5 Hz, 2H), 3.92-4.01 (m, 1H), 5.31 (d, J=4.8 Hz, 1H), 5.55 (t, J=5.5 Hz, 1H), 7.70 (t, J=5.3 Hz, 1H), 7.77 (s, 2H), 10.22 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:17][C:18]1[N:48]=[C:21]2[CH:22]=[CH:23][C:24]([O:26][C:27]3[CH:28]=[C:29]([NH:34][C:35](=[O:47])[C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([C:45]#[N:46])([CH3:44])[CH3:43])[CH:37]=4)[CH:30]=[CH:31][C:32]=3[CH3:33])=[CH:25][N:20]2[N:19]=1.C(=O)([O-])O.[Na+]>O1CCCC1.N1C=CC=CC=1.CN(C)C=O>[C:45]([C:42]([C:38]1[CH:37]=[C:36]([C:35]([NH:34][C:29]2[CH:30]=[CH:31][C:32]([CH3:33])=[C:27]([CH:28]=2)[O:26][C:24]2[CH:23]=[CH:22][C:21]3[N:20]([N:19]=[C:18]([NH:17][C:8]([C:5]4[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=4)=[O:10])[N:48]=3)[CH:25]=2)=[O:47])[CH:41]=[CH:40][CH:39]=1)([CH3:44])[CH3:43])#[N:46]
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)nn2c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Nc2nc3ccc(Oc4cc(NC(=O)c5cccc(C(C)(C)C#N)c5)ccc4C)cn3n2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
To a solution of 6-methylpyridine-3-carboxylic acid (252 mg, 1.84 mmol) in tetrahydrofuran (6 mL) were added oxalyl chloride (200 μL, 2.30 mmol) and N,N-dimethylformamide (20 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure. The obtained residue and N-{3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]-4-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (196 mg, 0.460 mmol) were dissolved in pyridine (7 mL), and the mixture was stirred at room temperature for 7 days. A saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL, 10 mL). The combined organic layer was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate/methanol=100/0→99.5/0.5), and fractions containing the desired product were concentrated under reduced pressure. The obtained residue was recrystallized from methanol to give the title compound (124 mg, 49%) as colorless crystals.
Reaction SMILES: C1(C)C=C[C:4]([S:7](NC2C=CC(C)=CC=2/C=C/C(OC)=S)(=O)=O)=CC=1.Cl[C:26]1[CH:34]=[C:33]2[C:29]([C:30]([CH2:44][C:45]([OH:47])=[O:46])=[C:31]([C:35]([C:37]3[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][N:38]=3)=[O:36])[NH:32]2)=[CH:28][CH:27]=1>>[CH3:43][C:41]1[CH:40]=[CH:39][N:38]=[C:37]([C:35]([C:31]2[NH:32][C:33]3[C:29]([C:30]=2[CH2:44][C:45]([OH:47])=[O:46])=[CH:28][C:27]([S:7][CH3:4])=[CH:26][CH:34]=3)=[O:36])[CH:42]=1
Reactant: COC(=S)/C=C/c1cc(C)ccc1NS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2CC(=O)O)c1
Product: CSc1ccc2[nH]c(C(=O)c3cc(C)ccn3)c(CC(=O)O)c2c1

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-2-p-toluenesulfonylamino-5-methylthiocinnamate (step 2) and 2-bromoacetyl-4-methylpyridine hydrobromide (Preparation is described in step 2 of Example 31).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([Cl:15])=[N:10][C:11](I)=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[F:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([Cl:15])=[N:10][C:11]([C:32]2[CH:33]=[N:34][C:29]([F:28])=[CH:30][CH:31]=2)=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(I)nc1Cl
Reactant: OB(O)c1ccc(F)nc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(-c2ccc(F)nc2)nc1Cl

Procedure:
By carrying out the operation analogously to example 1, starting from 2-chloro-6-iodo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation X, and 6-fluoro-3-pyridineboronic acid, the desired product is obtained in the form of a white powder (yield=43%).
Reaction SMILES: C(Cl)(Cl)Cl.[F:5][C:6]([F:23])([F:22])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[C:17]([OH:18])=[C:16]([C:19]([CH3:21])=[O:20])[CH2:15][S:14]2)=[CH:9][CH:8]=1.S(Cl)(Cl)(=O)=O>O>[F:22][C:6]([F:5])([F:23])[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:14][CH:15]=[C:16]([C:19]([CH3:21])=[O:20])[C:17]=2[OH:18])=[CH:11][CH:12]=1
Reactant: CC(=O)C1=C(O)C(c2ccc(C(F)(F)F)cc2)SC1
Solvent: O
Solvent: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(=O)c1csc(-c2ccc(C(F)(F)F)cc2)c1O
Temperature: -4 °C
Reaction time: 0.17 h
Yield: 74.3 %

Procedure:
A chloroform (223 mL) solution of 2-(4-trifluoromethylphenyl)-3-hydroxy-4-methylcarbonyl-2,5-dihydrothiophene (22.25 g, 69.46 mmol, purity: 90%) was cooled to −46° C., and to this solution, a chloroform (334 mL) solution of sulfuryl chloride (6.70 mL, 1.2 equivalent amounts) was dropwise added over a period of 10 minutes, followed by stirring at −4° C. for 10 minutes. The temperature of the solution was raised to 0° C., and water (45 mL) was dropwise added thereto over a period of 15 minutes, followed by liquid separation. The obtained chloroform solution was sequentially washed with water, a saturated salt solution, a saturated sodium hydrogencarbonate aqueous solution, a saturated sodium thiosulfate aqueous solution and a saturated salt solution, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off to obtain a crude product. The obtained crude product was isolated and purified by silica gel column chromatography (eluent: hexane/chloroform=1/1 (v/v)) to give the desired product as a yellow solid (14.78 g, yield: 69%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[CH3:14])=[O:6].[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.O>CN(C)C=O>[CH3:14][C:8]1[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]=1[C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: Cc1ccc(C(=O)CCCCl)c(C)c1
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(=O)CCCn2ccnc2)c(C)c1
Yield: 59 %

Procedure:
1-Chloro-4-(2,4-dimethylphenyl)-4-butanone (5.16 g) and imidazole (8.34 g) in dimethylformamide (10 ml) at 0° C. were stirred overnight at ambient temperature, then one day at 80° C. The resulting mixture was poured into water (200 ml), extracted with ether (3×75 ml) and the extracts were dried (magnesium sulfate) and evaporated. Chromatography of the product on silica gel eluting with 7% methanol in methylene chloride gave 3.5 g of 1-[4-(2,4-dimethylphenyl)butan-4-on-1-yl]imidazole.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:13][S:12][C:11]=2[CH:22]=1.[CH3:23][O:24][CH2:25][CH2:26][NH:27][CH3:28]>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:27]([CH2:26][CH2:25][O:24][CH3:23])[CH3:28])=[CH:22][C:11]=3[S:12][CH:13]=2)=[CH:16][CH:17]=1
Reactant: CNCCOC
Reactant: Fc1ccc(-c2csc3cc(OCCCCBr)ccc23)cc1
Product: COCCN(C)CCCCOc1ccc2c(-c3ccc(F)cc3)csc2c1

Procedure:
In analogy to example 3.1, 6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and N-(2-methoxyethyl)methylamine were converted to yield {4-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-(2-methoxy-ethyl)-methyl-amine as colorless oil, MS: 388 (MH+).