Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.[CH:13]1([CH:23]2[CH2:25][CH2:24]2)[CH2:15][CH:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH2:22]>C1(C)C=CC=CC=1>[CH:13]1([CH:23]2[CH2:25][CH2:24]2)[CH2:15][CH:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:8]([C:7]1[C:3]([CH:2]([F:12])[F:1])=[N:4][N:5]([CH3:11])[CH:6]=1)=[O:9]
Reactant: Nc1ccccc1C1CC1C1CC1
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Solvent: Cc1ccccc1
Product: Cn1cc(C(=O)Nc2ccccc2C2CC2C2CC2)c(C(F)F)n1
Temperature: 85 °C
Reaction time: 0.75 h

Procedure:
16.7 g (0.086 mol, 98% pure) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride were dissolved at 25° C. in 48.0 g of toluene. The solution was evacuated to 400 mbar and heated to 85° C. Subsequently, within 45 min, 15.0 g (0.087 mol) of 2-bicyclopropyl-2-ylphenylamine, dissolved in 51.6 g of toluene, were metered in and the reaction mixture was stirred for another 1 h. After venting and cooling to 25° C., the mixture was stirred overnight. Subsequently, the mixture was concentrated under reduced pressure and dried. The yield was 27.3 g (96%).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[SH:10][C:11]1[S:15][C:14]([CH3:16])=[N:13][N:12]=1.N.C[Si](C)(C)SC1SC(C)=NN=1.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>S1(C2C(=CC=CC=2)C(=O)N1)(=O)=O.CN(C)P(=O)(N(C)C)N(C)C.C(#N)C>[CH2:29]([S:10][C:11]1[S:15][C:14]([CH3:16])=[N:13][N:12]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: Cc1nnc(S)s1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cc1nnc(S[Si](C)(C)C)s1
Agent: N
Solvent: CC#N
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1nnc(SCc2ccccc2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
15 ml (72 mmoles) of hexamethyldisilazane were added to a refluxing mixture of 9.9 g (75 mmoles) of 5-mercapto-2-methyl-1,3,4-thiadiazole, 27 mg (0.15 mmole) of saccharin, 50 ml of acetonitrile and 20 ml of hexamethylphosphoric triamide and after refluxing for 4.5 hours, the calculated amount of ammonia had been evolved. Refluxing was continued for 30 minutes and the mixture containing 5-trimethylsilylthio-2-methyl-1,3,4-thiadiazole was cooled to room temperature and 9.9 ml (80 mmoles) of benzyl bromide were added thereto which raised the temperature to about 50° C. All starting material was consumed within 5 minutes. The acetonitrile was removed by evaporation and 100 ml of ethyl acetate were added to the residue. The solution was poured into 250 ml of water and the aqueous layer was extracted three times with 30 ml of ethyl acetate. The combined organic extracts were washed with a 10% sodium chloride solution, dried, filtered and evaporated to dryness. The solid residue was washed with hexane containing some diethyl ether to obtain 15.91 g (96.4% yield) of 5-benzylthio-2-methyl-1,3,4-thiadiazole melting at 60°-63° C. Crystallization from a mixture of ethyl acetate and petroleum ether (boiling range 40°-60° C.) provided 14.27 g of the pure substance melting at 62.5°-63.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:3]=1[O:4][CH:5]1[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1.[ClH:21]>O1CCOCC1>[ClH:21].[Br:1][C:2]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:3]=1[O:4][CH:5]1[CH2:8][NH:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(F)ccc2Br)C1
Agent: Cl
Solvent: C1COCCO1
Product: Fc1ccc(Br)c(OC2CNC2)c1
Reaction time: 18 h

Procedure:
To tert-butyl 3-(2-bromo-5-fluorophenoxy)azetidine-1-carboxylate (2.28 g, 6.59 mmol) in dioxane (40 mL) was added 4 M HCl in dioxane (4.49 mL, 19.8 mmol). After a period of 18 h, the white solid was filtered and washed with cold dioxane to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1.CCO.C([O-])([O-])=O.[K+].[K+].[O:27]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28]1>C1(C)C=CC=CC=1.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.O>[O:27]1[CH:31]=[CH:30][C:29]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=2)=[CH:28]1
Reactant: OB(O)c1ccoc1
Reactant: CC(C)CNC(=O)C(C)(C)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)CNC(=O)C(C)(C)c1ccc(-c2ccoc2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 36.9 %

Procedure:
2-(4-Bromophenyl)-N-isobutyl-2-methylpropanamide (Example 1a) (850 mg, 2,85 mmol) was dissolved in 30 ml of toluene, 6 ml of EtOH and 4.5 ml of water followed by 1.38 g (10 mmol) of K2CO3 and 560 mg (5 mmol) of 3-furanboronic acid. The suspension was degassed using argon stream and sonication (30 min). Then 1.16 g (1 mmol) of tetrakis(triphenylphosphine)palladium was added under argon and the mixture was stirred at 80° C. overnight. The solution was dried down on vacuum, diluted with EtOAc and extracted with water. The organic phase was dried over MgSO4 and evaporated on vacuum providing a crude product that was further purified using RP HPLC yielding 300 mg (41%) of the title compound as a white solid. 1H NMR (400 MHz, dDMSO): δ 0.74-0.75 (d 6H), 1.45 (s, 6H), 1.67-1.70 (m,1H), 2.83-2.86 (dd, 2H), 6.94-6.95 (dd, 1H), 7.30-7.32 (m, 3H), 7.54-7.57 (m, 2H), 7.72-7.73 (t, 1H), 8.15-8.16 (t, 1H). MS (M+H, 286).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:67]([CH3:69])[CH3:68])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[CH:25]=[C:24]([C:29]2[CH:34]=[CH:33][C:32]([C:35]4[NH:39][C:38]([C@@H:40]5[CH2:44][CH2:43][CH2:42][N:41]5[C:45]([C@H:47]5[C:56]6[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=6)[CH2:50][CH2:49][N:48]5C(OCC5C=CC=CC=5)=O)=[O:46])=[N:37][CH:36]=4)=[CH:31][CH:30]=2)[CH:23]=[CH:22]3)=[CH:17][N:18]=1)=[O:8])=[O:4]>C(O)C.[Pd]>[CH3:68][CH:67]([CH3:69])[C@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[C:7](=[O:8])[N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:29]4[CH:34]=[CH:33][C:32]([C:35]5[NH:39][C:38]([C@@H:40]6[CH2:44][CH2:43][CH2:42][N:41]6[C:45]([C@H:47]6[C:56]7[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=7)[CH2:50][CH2:49][NH:48]6)=[O:46])=[N:37][CH:36]=5)=[CH:31][CH:30]=4)[CH:25]=3)[CH:20]=2)=[CH:17][N:18]=1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)[C@H]6c7ccccc7CCN6C(=O)OCc6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Agent: [Pd]
Solvent: CCO
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)[C@@H]6NCCc7ccccc76)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Reaction time: 18 h

Procedure:
(R)-Benzyl 1-((S)-2-(5-(4-(6-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (137 mg, 0.148 mmol) was dissolved in ethyl alcohol (5 mL) and under Argon charged with 10% Pd/C (79 mg, 0.074 mmol) in a round bottom flask. The flask was then sealed with a rubber septa and the air was removed by vacuum and replaced with H2 from a balloon. This process repeated three times and the mixture was stirred under H2 atmosphere for 18 hours. The resulting mixture was then passed through a celite plug and concentrated down on rotovap. (117 mg, 99%).
Reaction SMILES: C[O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[H-].[Na+].[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][C:16]=1[C:27]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]=O)[CH:31]=1)=[NH:28].C([O-])(O)=O.[Na+]>C1COCC1>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][C:16]=1[C:27]([NH:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:5][C:3]([OH:2])=[O:4])[CH:33]=[CH:34][CH:35]=1)=[NH:28]
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: N=C(Nc1cccc(C=O)c1)c1cc(-c2ccccc2)ccc1F
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N=C(Nc1cccc(C=CC(=O)O)c1)c1cc(-c2ccccc2)ccc1F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Trimethyl phosphonoacetate (176 mg, 0.97 mmol) in THF (1.5 mL) was added dropwise (caution—vigorous reaction!) to sodium hydride (60% in oil) (58 mg, 1.46 mmol) under an atmosphere of nitrogen at 0° C. The reaction mixture was stirred for 15 minutes at 0° C. and then aldehyde (57) (307 mg, 0.97 mmol) in THF (1.50 mL) was added. After 3-hours further sodium hydride (60% in oil) (1.5 eq) was added and the reaction mixture stirred at ambient temperature overnight. Saturated NaHCO3 solution was added and washed with EtOAc. The aqueous layer was acidified to pH 1 using 1.2 M HCl and extracted with EtOAc. The aqueous layer was then neutralised to pH 7 and extracted into EtOAc. The organic layers were combined, dried (MgSO4) and the solvent concentrated in vacuo. The residue was purified by Flash Master Jones Chromatography using a 2 g silica cartridge and a gradient of EtOAc in heptane and MeOH in EtOAc to yield the title compound. Yield: 25 mg, 7%; LC-MS tr 1.77 min; HPLC Purity: 91%; MS (ES+) m/z 361 (M+H); NMR (400 MHz; MeOH): δ 6.6 (d, 7.35-7.80 (m, 11H), 8.05 (m, 1H), 8.15 (d, 1H)
Reaction SMILES: [CH:1]1[C:6](N=C=S)=[CH:5][C:4]2[C:10]([O:12][C:13]3([C:23]4[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=4[O:21][C:15]4[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:14]3=4)[C:3]=2[CH:2]=1)=[O:11].C(=O)([O-])[O-]>C(O)C>[CH:1]1[CH:6]=[CH:5][C:4]([C:10]([OH:12])=[O:11])=[C:3]([C:13]2[C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[O:21][C:22]3[C:23]=2[CH:24]=[CH:25][C:26]([CH:27]=3)=[O:28])[CH:2]=1
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Agent: O=C([O-])[O-]
Solvent: CCO
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12

Procedure:
Fluoresceinisothiocyanate (FITC) is dissolved in ethanol (5 mg solid/ml). To 2 ml of a 5 mg/ml protein solution from (I), 0.5 ml carbonate buffer (1M NaHCO3 --Na2CO3 buffer pH 9) is added, followed by 50 μl FITC solution. The mixture is shaken well and the free FITC is chromatographically separated from the bound molecules on a Sephadex G50 column using a buffer comprising 10 mM Tris, 1 mM EDTA, 50 mM KCl, pH 7.4. The labeled protein is collected in the void volume.
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1>C(#N)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][CH:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([OH:5])=[O:4])=[CH:15][CH:14]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(O)C(Br)c1ccccc1
Solvent: CC#N
Product: O=C(O)C(Nc1ccc(Cl)cc1)c1ccccc1
Temperature: 100 °C
Yield: 47 %

Procedure:
To a solution of α-bromophenylacetic acid (1.00 g, 4.65 mmol) in acetonitrile (20 ml), was added 4-chloro-phenylamine (1.18 g, 9.30 mmol), and the mixture was heated under microwave irradiation at 100° C. for 1 hour (UPLC-MS monitoring: complete conversion). The solvent was evaporated, and the residue was positioned between EtOAc and 1N HCl. The organic phase was dried over Na2SO4, filtered and evaporated to dryness to obtain intermediate I11 (0.57 g; 47% yield).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10]([CH:19]=[O:20])=[CH:9][C:8]1=[O:21].P([O-])(O)(O)=O.[Na+].OO.Cl([O-])=O.[Na+].[N+](=C)=[N-].[C:37](=O)([O-])[OH:38].[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.C(OCC)C.C(OCC)(=O)C.O.C(#N)C>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10]([C:19]([O:38][CH3:37])=[O:20])=[CH:9][C:8]1=[O:21]
Reactant: COc1ccc2c(C=O)cc(=O)n(CC3OCCO3)c2c1
Reactant: O=C([O-])O
Agent: C=[N+]=[N-]
Agent: O=P([O-])(O)O
Agent: OO
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(=O)n(CC2OCCO2)c2cc(OC)ccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixed solution of 2 mL of acetonitrile containing 0.30 g of 1-(1,3-dioxolan-2-ylmethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-4-carbaldehyde and 1 mL of water, a solution of 1 mL of water containing 0.88 g of sodium dihydrogen phosphate, 0.18 mL of a 30% hydrogen peroxide solution and 0.19 g of a sodium chlorite were added, and the mixture was stirred at room temperature for 1 hour and 30 minutes. Water and ethyl acetate were added thereto. The organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was dissolved in chloroform, thereto was added a diethyl ether solution containing 0.09 g of diazomethane, and the resultant solution was left to stand for 10 minutes. After adding 0.5 mL of acetic acid, an aqueous saturated sodium hydrogen carbonate solution was added thereto. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=100:1] to obtain 0.20 g of a pale yellow oily substance, methyl 1-(1,3-dioxolan-2-ylmethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxylate.
Reaction SMILES: [CH3:1][C:2]1(C)[CH2:6][CH:5](C)[CH2:4][C:3]1=O.[C:10]([O-:13])(=[O:12])[CH3:11].[Na+].C(OO)(=O)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:6])[CH2:3][CH:4]([CH3:5])[O:12][C:10](=[O:13])[CH2:11]1
Reactant: CC(=O)[O-]
Reactant: CC1CC(=O)C(C)(C)C1
Agent: CC(=O)OO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC1CC(C)(C)CC(=O)O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3.84 gm of 2,2,4-trimethyl-cyclopentanone were dissolved in 50 ml of chloroform and cooled in the ice bath. At 0° C., a solution of 0.2 gm of sodium acetate in 11.4 gm of a 40% aqueous peracetic acid was added. The reaction mixture was stirred for 18 hours at room temperature, then neutralized with a sodium hydrogen carbonate solution. The organic phase was separated, dried and concentrated. By distillation, 3.4 gm of 4,6,6-trimethyl-tetrahydropyran-2 -one (I) were recovered with the following characteristics:
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]1=2.[CH2:28]([O:30][C:31](=[O:38])[C:32]([CH3:37])([CH3:36])[C:33](O)=[O:34])[CH3:29]>>[CH2:28]([O:30][C:31](=[O:38])[C:32]([CH3:37])([CH3:36])[C:33]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]1=2)=[O:34])[CH3:29]
Reactant: N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Reactant: CCOC(=O)C(C)(C)C(=O)O
Product: CCOC(=O)C(C)(C)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using (S)-7-amino-5-(2-benzyloxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and 2,2-dimethyl-malonic acid monoethyl ester, the title compound was prepared in the same manner as described for example 1c. Colorless oil (>98%). MS: m/e=501(M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH:9]=[C:10]([C:12]([OH:14])=O)[NH:11][C:6]2=[CH:5][CH:4]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:39][C:40]1[CH:45]=[CH:44][C:43]([B:46]2[O:54][C:51]([CH3:53])([CH3:52])[C:48]([CH3:50])([CH3:49])[O:47]2)=[CH:42][C:41]=1[O:55][CH3:56]>ClCCl.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH:9]=[C:10]([C:12]([NH:39][C:40]3[CH:45]=[CH:44][C:43]([B:46]4[O:47][C:48]([CH3:49])([CH3:50])[C:51]([CH3:53])([CH3:52])[O:54]4)=[CH:42][C:41]=3[O:55][CH3:56])=[O:14])[NH:11][C:6]2=[CH:5][CH:4]=1
Reactant: COc1ccc2[nH]c(C(=O)O)cc2n1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc2[nH]c(C(=O)Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3OC)cc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.1 %

Procedure:
5-Methoxy-1 h-pyrrolo[3,2-b]pyridine-2-carboxylic acid (0.602 mmol, 116 mg) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.662 mmol, 252 mg) were added to a solution of 4-amino-3-methoxyphenylboronic acid pinacol ester (0.602 mmol, 150 mg) in dichloromethane (2.5 ml) and pyridine (0.5 ml) at 0° C. After stirring the reaction mixture overnight at room temperature it was concentrated in vacuo. Dichloromethane and water were added to the residue, the organic layer separated and washed with water. Both aqueous layers were extracted with dichloromethane. The combined organic layers were dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane) to give 5-methoxy-N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide (278 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[Cl:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>C1(C)C=CC=CC=1>[Cl:16][CH2:17][CH2:18][CH2:19][C:20]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:21]
Reactant: O=C(Cl)CCCCl
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Solvent: Cc1ccccc1
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)CCCCl)cc1
Yield: 93.3 %

Procedure:
6.0 g (29.6 millimoles) of 6-(p-aminophenyl)-5-methyl-4,5-dihydropyridaz-3-one and 4.6 g (32.6 millimoles) of 4-chlorobutyryl chloride in 100 ml of absolute toluene are kept for 6 hours at 80° C. The product is filtered off at 10° C., washed with water and dried under reduced pressure at 50° C. 8.5 g (93% of theory) of 6-[p-(4-chlorobutyrylamino)-phenyl]-5-methyl-4,5-dihydropyridaz-3-one are obtained as beige crystals which, after recrystallization from methanol, melt at 176°-178° C.
Reaction SMILES: [C:1]1([S:7][C:8]2[N:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[NH:27][CH:28]([CH:32]([CH3:34])[CH3:33])[C:29](O)=[O:30]>>[Cl:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[NH:27][CH:28]([CH:32]([CH3:34])[CH3:33])[C:29]([O:15][CH2:14][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:13]=1)=[O:30]
Reactant: OCc1cccc(Sc2ccccc2)n1
Reactant: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O
Product: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(=O)OCc1cccc(Sc2ccccc2)n1

Procedure:
Using the procedure of Example 11, (6-phenylthio-2-pyridyl)methanol is reacted with 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoic acid to yield (6-phenylthio-2-pyridyl)methyl 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoate, MS m/e 494 (M+).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[NH:17][CH:16]=[CH:15][C:14]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:27])=O>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:24])[NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][CH:15]=[C:14]2[Cl:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2[nH]ccc(=O)c2cc1NC(=O)OCc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc2nccc(Cl)c2cc1NC(=O)OCc1ccccc1

Procedure:
(7-Methoxy-4-oxo-1,4-dihydroquinolin-6-yl)carbamic acid benzyl ester (2 g) was added to a mixture of thionyl chloride (20 ml) and N,N-dimethylformamide (0.5 ml), and the mixture was heated to reflux for 2 hours. After completion of the reaction, the thionyl chloride was distilled off, and a procedure of toluene addition and concentration was repeated 3 times to obtain the title compound (2.4 g) as a solid.
Reaction SMILES: [ClH:1].Cl.[N:3]1([CH:7]2[CH2:12][CH2:11][N:10](CC3C=CC=CC=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1.O>CC(O)C.[C].[Pd]>[ClH:1].[ClH:1].[N:3]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1
Reactant: c1ccc(CN2CCC(N3CCC3)CC2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: C1CN(C2CCNCC2)C1
Temperature: 25 °C
Reaction time: 23 h
Yield: 185.1 %

Procedure:
After adding 10% palladium-carbon (600 mg) to a solution of the crude 4-(azetidin-1-yl)-1-benzylpiperidine dihydrochloride (6.55 g) in 2-propanol (50 ml)-water (50 ml), the mixture was stirred for 23 hours at room temperature under a hydrogen atmosphere. The catalyst was filtered and washed with 2-propanol, and then the filtrate was concentrated. Ethanol (10 ml)-hexane (50 ml) was added to the residue to produce suspended precipitate. It was then filtered and washed with 10 ml of ethanol. The filtered precipitate was subjected to aeration drying to provide the title compound (4.26 g) as white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([I:32])=[CH:28][C:27]=2[F:33])[C:5]([N+:22]([O-])=O)=[C:6]([CH:21]=1)[O:7][C:8]1[C:9]([CH3:20])=[C:10]([NH:14][S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])[CH:11]=[CH:12][CH:13]=1>C1COCC1.CCO>[NH2:22][C:5]1[C:4]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([I:32])=[CH:28][C:27]=2[F:33])=[CH:3][C:2]([F:1])=[CH:21][C:6]=1[O:7][C:8]1[C:9]([CH3:20])=[C:10]([NH:14][S:15]([CH2:18][CH3:19])(=[O:16])=[O:17])[CH:11]=[CH:12][CH:13]=1
Reactant: CCS(=O)(=O)Nc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2[N+](=O)[O-])c1C
Solvent: CCO
Solvent: C1CCOC1
Product: CCS(=O)(=O)Nc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2N)c1C
Yield: 65.9 %

Procedure:
1.6 g crude N-(3-{5-fluoro-3-[(2-fluoro-4-iodophenyl)amino]-2-nitrophenoxy}-2-methylphenyl)-ethanesulfonamide (2.7 mmol, 1 eq.) were dissolved in 40 mL THF/EtOH 1:1 and treated with 3.1 g stannous chloride dihydrate (SnCl2 2H2O) (13.6 mmol, 5 eq.) and the resulting mixture was refluxed for 16 h. The reaction mixture was concentrated, the residue quenched with 26% NH3 and extracted with DCM. The combined organic layers were washed with ammonium chloride solution and saturated sodium chloride solution, dried, filtered and concentrated in vacuo. The residue was purified by flash column chromatography to give 996 mg of the target compound (65% yield).
Reaction SMILES: Br.[CH3:2][C@@:3]1([C:9]([F:12])([F:11])[F:10])[CH2:7][NH:6][C:5]([NH2:8])=[N:4]1.C[O-].[Na+].[C:16](OCC)(=[O:23])[CH2:17][C:18](OCC)=[O:19].Cl>CO>[OH:23][C:16]1[N:8]=[C:5]2[NH:4][C@:3]([CH3:2])([C:9]([F:12])([F:10])[F:11])[CH2:7][N:6]2[C:18](=[O:19])[CH:17]=1
Reactant: C[C@@]1(C(F)(F)F)CNC(N)=N1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Br
Agent: C[O-]
Agent: Cl
Solvent: CO
Product: C[C@@]1(C(F)(F)F)Cn2c(nc(O)cc2=O)N1
Reaction time: 3 h
Yield: 107.5 %

Procedure:
36.90 g (148.76 mmol) of (S)-4-methyl-4-trifluoromethyl-4,5-dihydro-1H-imidazol-2-ylamine hydrobromide and 24.10 g (446 mmol) of sodium methoxide are added to a mixture of 29.50 g (216.43 mmol) of diethyl malonate in 200 mL of methanol. The resulting mixture is refluxed for 18 hours. After cooling, the mixture obtained is concentrated to dryness under vacuum. 65 mL of cold water are added to the residue obtained, to obtain a thick suspension, to which is added 25% hydrochloric acid to pH 5. The resulting suspension is stirred in an ice bath for 3 hours and then filtered. The insoluble matter obtained is rinsed with water and then dried to give 37.60 g of (S)-7-hydroxy-2-methyl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one in the form of a white solid, the characteristics of which are as follows: