Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.Cl[C:34]([C@@H:36]([O:38]C(=O)C)[CH3:37])=[O:35]>>[OH:38][C@@H:36]([CH3:37])[C:34]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:5][CH2:6]1)=[O:35]
Reactant: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCNCC4)c[nH]c13)OCO2
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Product: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c[nH]c13)OCO2

Procedure:
Starting from 4-[5-(2-methoxy-ethoxy)-benzo[1,3]dioxol-4-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A187) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound was obtained as colorless solid.
Reaction SMILES: CO[C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[NH2:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1.C[O-].[Mg+2].C[O-].CO>>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([CH:4]([CH2:5][CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]2)[C:3]([NH:19][C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[O:18])=[CH:16][CH:15]=1
Reactant: Nc1nccs1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(Cl)cc1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(Cl)cc1
Temperature: 100 °C
Yield: 35.1 %

Procedure:
A mixture of 2-(4-chloro-phenyl)-3-cyclopentyl-propionic acid methyl ester (648 mg, 2.43 mmol) and 2-aminothiazole (487 mg, 4.86 mmol) in a solution of magnesium methoxide in methanol (7.4 wt %, 14.0 mL, 9.72 mmol) was heated under reflux at 100° C. for 20 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 2-(4-chloro-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (286 mg, 35%) as a white solid: mp 156.6-159.8° C.; EI-HRMS m/e calcd for C17H19ClN2OS (M+) 334.0906, found 334.0910.
Reaction SMILES: O[C:2]1[C:3]2[CH2:11][CH2:10][O:9][C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.NC1N=C([Cl:19])C(CCCl)=C(Cl)N=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>>[Cl:19][C:2]1[C:3]2[CH2:11][CH2:10][O:9][C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: Nc1nc(Cl)c(CCCl)c(Cl)n1
Reactant: Nc1nc(O)c2c(n1)OCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1nc(Cl)c2c(n1)OCC2

Procedure:
5,6-Dihydro-4-hydroxyfuro[2,3-d]pyrimidine-2-amine [Svab, Budesinski and Vavrina, Collection Czech. Chem. Commun. 32, 1582 (1967)] can be converted to 2-amino-5-(2-chloroethyl)-4,6-dichloropyrimidine by heating with phosphorus oxychloride. The product can be subsequently cyclized by treatment with two equivalents of aqueous sodium hydroxide to afford 4-chloro-5,6-dihydrofuro[2,3-d]pyrimidin-2-amine, which is then converted to 5,6-dihydro-4-methoxyfuro[2,3-d]pyrimidin-2-amine by heating with excess sodium methoxide in methanol. ##STR38##
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:24][C:25](O)([C:27]#[CH:28])[CH3:26].O>O1CCCC1>[Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([O:9][C:25]([CH3:26])([CH3:24])[C:27]#[CH:28])=[O:8]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: C#CC(C)(C)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: C#CC(C)(C)OC(=O)c1cnc(Cl)c(Cl)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 19.4 %

Procedure:
5,6-Dichloronicotinic acid (1.92 g, 10.0 mmol) was slurried in 10 mL tetrahydrofuran to which carbonyldiimidazole (CDI) (1.78 g, 11.0 mmol) was added. The mixture was stirred at 40° C. for one hour to a uniform solution. 2-Methyl-3-butyn-2-ol (1.01 g, 12.0 mmol) was added via pipette and the solution refluxed overnight. The solution was poured into 4-5 volumes of water and extracted with Et2O (2×100 mL). The organics were washed with 2.0 N NaOH, dried over MgSO4, and concentrated to 1.2 g pale yellow oil. Crude product was chromatographed on medium column using silica gel (23-400 mesh) with descending solvent gradient from 100% petroleum ether to 50/50 pet. ether/ethyl acetate as the mobile phase. Elution and concentration gave (dimethyl)propargyl 5,6-dichloronicotinate (0.50 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[Si](C)(C)CC[Si]2(C)C)[CH:5]=[CH:6][CH:7]=1.C([Li])(CC)C.[S:22]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23]1>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[CH:6][C:7]=1[C:24]1([OH:27])[CH2:25][CH2:26][S:22][CH2:23]1
Reactant: O=C1CCSC1
Reactant: C[Si]1(C)CC[Si](C)(C)N1c1cccc(F)c1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: Nc1ccc(C2(O)CCSC2)c(F)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of 1-(3-fluorophenyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane (EXAMPLE 20, Step 1, 1.00 g) in dry tetrahydrofuran (16 mL) at -78° C. under N2 is treated with sec-butyllithium (1.3 M in cyclohexane, 3.30 mL) dropwise over 2 mins, and the resulting mixture is stirred at -78° C. for 2 hrs. The mixture is then treated with a solution of tetrahydrothiophen-3-one (423 mg) in dry tetrahydrofuran (4.1 mL) dropwise over 2 mins and is stirred at -78° C., allowing the cooling bath to expire over 4 hrs. The mixture is then quenched with saturated aqueous ammonium chloride (25 mL), diluted with water (25 mL), the layers are separated, and the combined organic phase is washed with saline (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is dissolved in methanol (16 mL) and treated with anhydrous potassium carbonate (1.09 g), and the mixture is stirred at ambient temperature for 30 mins, concentrated under reduced pressure, diluted with water (20 mL) and extracted with diethyl ether (2×20 mL). The combined organic phase is washed with saline (10 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude 3-fluoro-4-[3-(hydroxy)tetrahydrothiophen-3-yl]benzenamine intermediate (Rf =0.37 by TLC, ethyl acetate/hexane (50/50)). A solution of this intermediate in tetrahydrofuran (16 mL) and water (8 mL) is then treated with sodium bicarbonate (662 mg) and benzyl chloroformate (0.56 mL), and the resulting mixture is stirred at ambient temperature for 4 hrs, diluted with water (8 mL), the layers are separated, and the organic phase is washed with saline (10 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel (230-400 mesh, 150 g), eluting with ethyl acetate/hexane (25/75), and those fractions with an Rf =0.19 by TLC (ethyl acetate/hexane, 25/75) are pooled and concentrated to give the title compound, mp 134-135° C.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[NH2:9][C:10]1[N:15]=[C:14]([S:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[N:13]=[C:12]([NH:25][C@H:26]([CH3:29])[CH2:27][OH:28])[C:11]=1[N:30]=O.S(=O)(=O)(O)O>O.CN(C=O)C>[NH2:30][C:11]1[C:12]([NH:25][C@H:26]([CH3:29])[CH2:27][OH:28])=[N:13][C:14]([S:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])=[N:15][C:10]=1[NH2:9]
Reactant: C[C@H](CO)Nc1nc(SCc2ccccc2F)nc(N)c1N=O
Agent: O=S(=O)(O)O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](CO)Nc1nc(SCc2ccccc2F)nc(N)c1N
Reaction time: 0.17 h
Yield: 12.4 %

Procedure:
Sodium dithionite (4 g) was added in portions to a suspension of the product from example 4, step (d) (8.4 g) in a mixture of water (35 ml) and DMF (15 ml) at 100° C. The resultant yellow solution was cooled in an ice bath and 50% aqueous sulphuric acid (15 ml) was added, giving a grey precipitate. The mixture was stirred for 10 min, then filtered, washing with water, ethanol and diethyl ether, to afford the subtitled product as a grey solid (1.0 g).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:9]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)S[CH2:16][CH2:15][C:14]3=[O:21])=[O:10])[CH:5]=[N:4]1)[CH3:2].OO.C(O)(=O)C.[S:28]([O-:31])(O)=[O:29].[Na+]>O>[CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:9]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[S:28](=[O:31])(=[O:29])[CH2:16][CH2:15][C:14]3=[O:21])=[O:10])[CH:5]=[N:4]1)[CH3:2]
Reactant: O=S([O-])O
Reactant: CCn1ncc(C(=O)c2ccc3c(c2)C(=O)CCS3)c1O
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCn1ncc(C(=O)c2ccc3c(c2)C(=O)CCS3(=O)=O)c1O
Temperature: 60 °C

Procedure:
1.0 Gram (3.31 mmol) of 6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-4-one and 0.83 g (7.28 mmol) of a 30 wt % hydrogen peroxide aqueous solution were added to 3 ml of glacial acetic acid, and then stirred under heat of 60° C. for 2.5 hours. While the reaction mixture was cooled in an ice bath after allowed to cool, a 1 wt % sodium hydrogensulfite aqueous solution was added to decompose excess hydrogen peroxide, and then the reaction mixture was diluted with water. A precipitated solid was extracted with ethyl acetate. An organic layer was washed with water and then with a saturated sodium chloride aqueous solution once, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 1.11 g (yield: quantitative) of the titled compound. Table 24 shows the physical property data of the titled compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][N:7]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[N:8]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1n[nH]c2c1CCCC2
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(Cc2ccccc2)c2c1CCCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35.9 %

Procedure:
To a stirring solution of 2.0 g (10.30 mmol) of 4,5,6,7-Tetrahydro-1H-indazole-3-carboxylic acid ethyl ester (Ainsworth, C. J. Am. Chem. Soc. 1957, 79, 5242) in 50 mL of DMF is added 1.85 g (13.838 mmol, 1.3 equiv) of K2CO3, followed by 1.35 mL (11.33 mmol, 1.1 equiv) of benzyl bromide. The reaction mixture is stirred 15 min at RT then heated at 60° C. for 16 h. The reaction is cooled to RT, poured into 100 mL 1N HCl, and extracted with Et2O (2×100 mL). The organic layers were washed with H2O (2×100 mL), dried (MgSO4), and the solvent removed in vacuo. Purification of the crude material by silica gel flash column chromatography using a gradient elution of hexane/EtOAc 6/1 to 3/1 afforded 1.05 g of 4,5,6,7-Tetrahydro-1-Benzyl-1H-indazole-3-carboxylic acid ethyl ester as a yellow oil which later solidified: 1H NMR (CDCl3, 300 MHz) δ7.37-7.23 (m, 3H), 7.13 (m, 2H), 5.31 (s, 2H), 4.39 (q, 2H, J=7.2), 2.74 (m, 2H), 2.40 (m, 2H), 1.72 (m, 4H), 1.39 (t, 3H, J=7.2).
Reaction SMILES: Cl.Cl.[I:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[N:10][C:11]=2[NH2:13])[N:6]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[N:5]=1.C(=O)(O)[O-].[Na+].[CH2:25]([O:32][C:33](Cl)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O.O1CCOCC1>[NH2:13][C:11]1[N:10]=[CH:9][N:8]=[C:7]2[N:6]([CH:14]3[CH2:19][CH2:18][N:17]([C:33]([O:32][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:34])[CH2:16][CH2:15]3)[N:5]=[C:4]([I:3])[C:12]=12
Reactant: Nc1ncnc2c1c(I)nn2C1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ncnc2c1c(I)nn2C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.1 %

Procedure:
To a mixture of 3-iodo-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (13.86 g, 0.0333 mol) and sodium bicarbonate (8.4 g, 0.0999 mol) in water (140 mL) was added benzylchloroformate (6.48 g, 0.0383 mol) in dioxane (120 mL) at room temperature. The mixture was stirred at room temperature under an atmosphere of nitrogen for 18 hours. The yellow solid was filtered and washed with ethyl ether to yield benzyl 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate (12 g, 0.025 mol).
Reaction SMILES: [C:1](O)(=O)C#C.[C:6]1([C:12]#[C:13][C:14]([OH:16])=[O:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CI.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:6]1([C:12]#[C:13][C:14]([O:16][CH3:1])=[O:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C#CC(=O)O
Reactant: O=C(O)C#Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
Typical Procedure for Methylation of Propiolic Acid with Iodomethane (1b as Example) CH3I (2.2 mmol) and K2CO3 (2.2 mmol) were added to the solution of Propiolic acid (1b, 2 mmol) in acetonitrile and the obtained mixture was stirred at room temperature. The reaction was monitored by TLC until the starting 1b disappeared. After 3 hours, the mixture was extracted with ether (3×5 mL). The combined ether part was purified by column chromatography on silica gel (dichloromethane:hexane=1:3) to give pure methyl 3-phenylpropiolate in 98% yield. GC/Ms: m/z: 160. Data for 1H and 13C NMR of methyl 3-phenylpropiolate was conducted in CDCl3 and consistent with the data in reported literature.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH3:11][O-:12].[Na+].CO>CO.O>[NH2:1][C:2]1[N:3]=[C:4]([O:12][CH3:11])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: C[O-]
Reactant: N#Cc1ncc(N)nc1Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nc(N)cnc1C#N
Temperature: 80 °C
Yield: 58 %

Procedure:
5-Amino-3-chloropyrazine-2-carbonitrile (52 mg, 0.34 mmol) was suspended in NaOMe/MeOH (2M, 2 mL). The reaction mixture was heated at 80° C. for 30 min using microwave irradiation. After cooling, the mixture was diluted with MeOH (3 mL) and water (2 mL). The solvents were concentrated and the resulting precipitate was filtered off, washed with water (3 mL) and dried in vacuo to give the title compound as a yellow solid (33 mg, 58%).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[C:4]1[CH2:20][NH2:21].[C:22]([NH:41][CH2:42][C:43](O)=[O:44])([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:2][N:3]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[C:4]1[CH2:20][NH:21][C:43](=[O:44])[CH2:42][NH:41][C:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cn1c(CN)c(-c2ccccc2Cl)c2cc(Cl)ccc21
Reactant: O=C(O)CNC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Product: Cn1c(CNC(=O)CNC(c2ccccc2)(c2ccccc2)c2ccccc2)c(-c2ccccc2Cl)c2cc(Cl)ccc21

Procedure:
Using 1-methyl-2-aminomethyl-3-o-chlorophenyl-5-chloroindole hydrochloride and N-tritylglycine, the reaction is effected as in Example 12 (1), whereby 1-methyl-2-(N-trityl-glycylaminomethyl)-3-o-chlorophenyl-5-chloroindole is obtained as crystals melting at 198° to 200° C.
Reaction SMILES: I[CH2:2][C:3]([NH2:5])=[O:4].[NH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:23]=[C:22]([NH2:24])[CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1>>[C:3]([NH:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[N:23]=[C:22]([NH2:24])[CH:21]=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)[CH2:8][CH2:7]1)(=[O:4])[CH3:2]
Reactant: NC(=O)CI
Reactant: Nc1cccc(-c2ccc(C3CCNCC3)cc2)n1
Product: CC(=O)NN1CCC(c2ccc(-c3cccc(N)n3)cc2)CC1

Procedure:
Prepared from Example 13, using iodoacetamide to alkylate 6-[4-(piperidin-4-yl)-phenyl]-pyridin-2-ylamine, in 55%, mp 224-227° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:24])[NH:10][N:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[C:25]12([O:35][C:36](F)=[O:37])[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2.CN(C1C=CC=CN=1)C.C(N(CC)CC)C>C(Cl)Cl>[C:25]12([O:35][C:36]([N:10]3[C:9](=[O:24])[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[C:13]([C:14]4[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=4)[CH:12]=[N:11]3)=[O:37])[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2-c2ccc(F)cc2)cc1
Reactant: O=C(F)OC12CC3CC(CC(C3)C1)C2
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(-c2cnn(C(=O)OC34CC5CC(CC(C5)C3)C4)c(=O)c2-c2ccc(F)cc2)cc1
Yield: 18 %

Procedure:
A solution of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared according to the procedure of Example 11 (200 mg, 0.58 mmol) in CH2Cl2 (8 ml) was prepared and stirred. 1-Adamantylfluoroformate (172 mg, 0.87 mmol), dimethylaminopyridine (14 mg, 0.011 mmol) and triethylamine (0.12 ml, 0.87 mmol) were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with CH2Cl2 (50 ml) and washed with 10% citric acid (50 ml), brine (50 ml) and dried over MgSO4, and concentrated in vacuo. The resulting crude residue was purified using flash chromatography (SiO2, eluting with 15:1 CH2Cl2:diethyl ether) to provide the desired product (yield: 55 mg, 18%). 1H NMR (300 MHz, DMSO-d4) δ 1.66 (bs, 6H), 2.25 (bd, 10H), 3.21 (s, 3H), 7.15 (t, 2H), 7.24 (m, 2H), 7.6 (dd, 2H), 7.88 (d, J=9 Hz, 2H), 8.15 (s, 1H). MS (ESI) m/z 521 (M−H)+. Anal. calc. for C21H15F N2O3S2: C 64.35; H, 5.20; N, 5.36.
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[C:24]([C:27]#[N:28])[CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[CH:12][C:11]=2[Cl:37])C=CC=CC=1.[CH3:39][N:40](C)C=O.CN.O1CCCC1>O>[CH2:30]([O:29][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([O:16][C:13]3[CH:14]=[CH:15][C:10]([NH:9][C:8]([NH:40][CH3:39])=[O:7])=[C:11]([Cl:37])[CH:12]=3)=[CH:18][CH:19]=[N:20]2)=[CH:25][C:24]=1[C:27]#[N:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CN(C)C=O
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)Oc4ccccc4)c(Cl)c3)ccnc2cc1OCc1ccccc1
Agent: CN
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)Nc1ccc(Oc2ccnc3cc(OCc4ccccc4)c(C#N)cc23)cc1Cl
Reaction time: 0.17 h

Procedure:
[4-(7-Benzyloxy-6-cyanoquinolin-4-yloxy)-2-chlorophenyl]carbamic acid phenyl ester (1.17 g) was added to dimethylformamide (6 ml), and then a methylamine-containing 2N tetrahydrofuran solution (0.4 ml) was added and the mixture was stirred for 10 minutes. Water (15 ml) was added, and the precipitated crystals were filtered out and washed with diethyl ether to obtain the title compound (968 mg).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:13][OH:14])=[C:4]([OH:12])[CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1.[Br:15][CH2:16][CH:17](OC)OC.OS(O)(=O)=O.O>C1COCC1>[Br:15][CH2:16][CH:17]1[O:12][C:4]2[CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=[C:2]([F:1])[C:3]=2[CH2:13][O:14]1
Reactant: CS(=O)(=O)c1cc(O)c(CO)c(F)c1
Reactant: COC(CBr)OC
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cc(F)c2c(c1)OC(CBr)OC2
Temperature: 60 °C
Yield: 43.2 %

Procedure:
3-fluoro-2-(hydroxymethyl)-5-(methylsulfonyl)phenol (0.11 g, 0.52 mmol) was dissolved in THF (dry) (5 ml). 2-bromo-1,1-dimethoxyethane (0.63 ml, 5.2 mmol) was added followed by concentrated H2SO4 (1 ml). The mixture was heated at 60° C. for 1 h. Water was added and the mixture extracted with EtOAc twice. The combined extracts were washed with brine and concentrated. Purification by flash column chromatography (isooctane/EtOAc) gave the title compound (0.073 g). MS m/z (rel. intensity, 70 eV) 326 (M+, 8), 324 (M+, 8), 231 (17), 202 (bp), 139 (21), 95 (42), 75 (34).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[NH:2][NH2:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=O)[CH3:28])=[C:23]([CH3:30])[CH:22]=1>C1(C)C=CC=CC=1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24](/[C:27](=[N:3]/[NH:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])/[CH3:28])=[C:23]([CH3:30])[CH:22]=1
Reactant: CCOC(=O)NN
Reactant: CC(=O)c1ccc(Cl)cc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)N/N=C(\C)c1ccc(Cl)cc1C

Procedure:
Ethyl carbazate (2.970 g, 28.53 mmol) and p-toluenesulfonic acid monohydrate (4.456 g, 28.53 mmol) were added to a stirred solution of 1-(4-chloro-2-methylphenyl)ethanone (4.81 g, 28.53 mmol) in toluene (50 mL). The mixture was heated to relux in a Dean-Stark apparatus. After 2 h the solution was evaporated and the viscous red-orange oil was purified by flash chromatography on silica (eluting with an EtOAc/hexanes gradient, 5–40% EtOAc). Ethyl (2E)-2-[1-(4-chloro-2-methylphenyl)ethylidene]hydrazine carboxylate was obtained as white crystals. MS m/z=255.6; 1H NMR (CDCl3, 400 MHz) δ 1.34 (t, J=6.8 Hz, 3H), 2.20 (s, 3H), 2.35 (s, 3H), 4.31 (q, J=6.8 Hz, 2H), 7.19 (m, 3H), 7.72 (s, 1H).
Reaction SMILES: Br[C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:17])=[C:7]([Cl:16])[CH:8]=2)[N:3]=1.S[C:19]1[O:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1>>[O:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:17])=[C:7]([Cl:16])[CH:8]=2)[N:3]=1
Reactant: Sc1nc2ccccc2o1
Reactant: FC(F)(F)c1nc2cc(Cl)c(Cl)cc2nc1Br
Product: FC(F)(F)c1nc2cc(Cl)c(Cl)cc2nc1-c1nc2ccccc2o1

Procedure:
The title compound was prepared from 2-bromo-6,7-dichloro-3-trifluoromethylquinoxaline and 2-mercaptobenzoxazole in analogy with the method outlined in example 1.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:17]=O)[C:12]([CH:15]=[O:16])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.Cl.[NH2:24][CH2:25][C:26]#[N:27].C(N(CC)CC)C>CN(C=O)C>[O:16]=[C:15]1[C:12]2[C:11](=[CH:10][C:9]([O:8][CH2:7][C:6]3[CH:19]=[CH:20][C:3]([C:2]([F:22])([F:21])[F:1])=[CH:4][CH:5]=3)=[CH:14][CH:13]=2)[CH2:17][N:27]1[CH2:26][C:25]#[N:24]
Reactant: O=Cc1ccc(OCc2ccc(C(F)(F)F)cc2)cc1C=O
Reactant: N#CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CCN1Cc2cc(OCc3ccc(C(F)(F)F)cc3)ccc2C1=O
Temperature: 25 °C
Yield: 7 %

Procedure:
To a cooled (0° C.) solution of 4-(4-trifluoromethyl-benzyloxy)-benzene-1,2-dicarbaldehyde (250.0 mg, 0.81 mmol) in DMF (7 mL) was added aminoacetonitrile HCl (150.1 mg, 1.62 mmol) and triethylamine (164.1 mg, 1.62 mmol) and the resulting mixture was warmed up to RT over 1 h and then heated at 50° C. for 1 h. After cooling to RT, the mixture was evaporated and the residue partioned between ethyl acetate and hydrochloric acid (1 N). The organic layer was then dried over sodium sulfate, filtered and evaporated to leave a clear oil which was purified by chromatography (SiO2, DCM:MeOH 9:1) to afford the title product (19.6 mg, 7%) as a light brown solid. MS m/e 345.2 (M−H−).
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:10].[Br:11]Br>CN(C)C=O>[Br:11][C:7]1[CH:8]=[C:9]2[O:1][C:2](=[O:10])[NH:3][C:4]2=[N:5][CH:6]=1
Reactant: O=c1[nH]c2ncccc2o1
Reactant: BrBr
Solvent: CN(C)C=O
Product: O=c1[nH]c2ncc(Br)cc2o1
Temperature: 25 °C

Procedure:
0.01 mol of oxazolo[4,5-b]pyridin-2-one is dissolved in 100 ml of dimethylformamide. 0.011 mol of bromine is added via a dropping funnel. Stirring is maintained for 1 hour 30 minutes at room temperature and an ice/water mixture is added. The product is filtered off. It is washed with water. The product is dried.