Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:12][CH:11]([OH:13])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:17]1[N:22]=[CH:21][N:20]=[C:19]2[N:23]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[N:24]=[CH:25][C:18]=12>CC(N(C)C)=O>[CH2:2]([N:9]1[CH2:12][CH:11]([O:13][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([C:26]4[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:30][CH:31]=4)[N:24]=[CH:25][C:18]=23)[CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(Cl)ncnc32)cc1
Reactant: OC1CN(Cc2ccccc2)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CN(Cc5ccccc5)C4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.2 %

Procedure:
1-Benzyl-azetidin-3-ol hydrochloride salt (0.59 mmol, 117 mg) and sodium hydride were dissolved in dimethyl acetamide (2 mL) and stirred at room temperature for 30 minutes. 4-Chloro-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (0.49 mmol, 150 mg) was added slowly and the mixture was stirred at 70° C. for 20 minutes. The reaction mixture was quenched with water followed by an extraction with ethyl acetate. Removal of organic solvents in vacuo and purification by flash chromatography provided compound A23 as a white solid (88 mg, 41%). 1H NMR (400MHz, DMSO-d6) δ (ppm): 8.90 (s, 1H); 8.53 (s, 1H); 8.30 (d, 2H); 8.16 (d, 2H); 7.43 (m, 5H); 6.19 (m, 1H); 4.59 (m, 2H); 4.42 (d, 1H); 4.00 (d, 1H); 3.65 (d, 1H); 3.35 (m, 1); 3.30 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[CH:8][C:7]=1[O:15][CH3:16]>C(O)C.[Pd]>[CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH:9]=[CH:8][C:7]=1[O:15][CH3:16])[NH2:12]
Reactant: COc1ccc([N+](=O)[O-])cc1OCCN(C)C
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N)cc1OCCN(C)C
Yield: 100 %

Procedure:
A solution of 2-(2-dimethylaminoethoxy)-4-nitroanisole (D13, 11.8 g, 0.049 mole) in ethanol (200 ml) was hydrogenated over 10% Pd-C (1 g) at atmospheric temperature and pressure. The catalyst was filtered off through kieselguhr and the filtrate concentrated in vacuo to afford the title compound as a beige solid (10.3 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=O.[CH3:14][N:15]([CH3:17])[NH2:16]>[Cl-].[Na+]>[CH3:14][N:15]([CH3:17])[N:16]=[C:8]1[C:9]2[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1
Reactant: COc1cccc2c1CCCC2=O
Reactant: CN(C)N
Agent: [Cl-]
Agent: [Na+]
Product: COc1cccc2c1CCCC2=NN(C)C
Yield: 83 %

Procedure:
35.25 g of 5-methoxy-1-tetralone and 61 ml of N,N-dimethylhydrazine were heated to about 80° under argon for 5 hours. The mixture was left to cool, 200 ml of 10% sodium chloride solution were added and the mixture was extracted several times with diethyl ether. The mixture was dried over sodium sulfate, filtered and evaporated. The oily residue was distilled over a 10 cm Vigreux column. At 85°-95°/0.1 mbar there were obtained 36.4 g (83%) of 5-methoxy-1-tetralone N,N-dimethylhydrazone as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:16][N:17]2[C:25]3[C:20](=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=[CH:23][CH:24]=3)[C:19](Br)=[N:18]2)=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:30]1(B(O)O)[CH2:32][CH2:31]1.C([O-])([O-])=O.[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=C(S([O-])(=O)=O)C=2OC)CCCCC1.[Na+]>C(O[Pd]OC(=O)C)(=O)C.O1CCOCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:16][N:17]2[C:25]3[C:20](=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=[CH:23][CH:24]=3)[C:19]([CH:30]3[CH2:32][CH2:31]3)=[N:18]2)=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(Cn2nc(Br)c3c([N+](=O)[O-])cccc32)ccc1OCc1ccccc1
Reactant: OB(O)C1CC1
Agent: CC(=O)O[Pd]OC(C)=O
Agent: COc1ccc(S(=O)(=O)[O-])c(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(Cn2nc(C3CC3)c3c([N+](=O)[O-])cccc32)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A first flask was charged with 1,4-dioxane/H2O (50 mL/10 mL). The flask was cooled to 0° C. and vacuum was applied for 20 minutes. A second flask was charged with 1-((5-(benzyloxy)-6-methylpyridin-2-yl)methyl)-3-bromo-4-nitro-1H-indazole (6.07 g, 13.4 mmol), cyclopropylboronic acid (4.60 g, 53.6 mmol), diacetoxypalladium (0.150 g, 0.670 mmol), K2CO3 (5.55 g, 40.2 mmol) and sodium 2′-(dicyclohexylphosphino)-2,6-dimethoxybiphenyl-3-sulfonate (0.686 g, 1.34 mmol). The second flask was also evacuated with vacuum and back filled with N2 for 3 times. The cold degassed dioxane/H2O was added to the second flask, which was evacuated with vacuum and back filled with argon for 5 times. The reaction mix was then heated to 80° C. for 3 hours. A sample (1H NMR) taken from the flask showed complete reaction at this point. The reaction was cooled to ambient temperature, filtered and concentrated under reduced pressure. The residue was diluted with EtOAc (200 mL). The organic layer was washed with saturated NaHCO3, dried (Na2SO4) and concentrated to give desired product, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[S:4][N:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:25]=[C:26]([Cl:28])[CH:27]=1)[CH2:18][N:19]1[CH:23]=[N:22][C:21]([NH2:24])=[N:20]1>>[Cl:28][C:26]1[CH:25]=[C:17]([CH:16]=[C:15]([Cl:14])[CH:27]=1)[CH2:18][N:19]1[CH:23]=[N:22][C:21]([NH:24][CH:10]2[CH2:11][CH2:12][N:7]([C:5]3[S:4][N:3]=[C:2]([CH3:1])[N:6]=3)[CH2:8][CH2:9]2)=[N:20]1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Reactant: Nc1ncn(Cc2cc(Cl)cc(Cl)c2)n1
Product: Cc1nsc(N2CCC(Nc3ncn(Cc4cc(Cl)cc(Cl)c4)n3)CC2)n1

Procedure:
Prepared in analogy to example 1 step h) starting from 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one (example 1c) and 1-(3,5-dichloro-benzyl)-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a white solid (yield=27%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11]C)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].B(Br)(Br)Br.O>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1cc(O)ccc1Br
Temperature: -60 °C
Reaction time: 1 h

Procedure:
A mixture of 2-bromo-5-methoxybenzoic acid (10 g, 0.043 mol) in methylene chloride is cooled to -60° C., treated with boron tribromide (3.59 g, 0.143 mol), stirred at -60° C. for 1 hour, stirred at room temperature for 1 hour, cooled to -70° C., treated with additional boron tribromide (3.59 g, 0.143 mol), stirred at -70° C. for 1 hour, stirred at room temperature for 1 hour and poured into water. The aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title product as a white solid which is identified by 1H and 13CNMR spectral analyses.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([C:4](=[O:15])[C:5]#[C:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:3].[H][H]>CO.[Ni]>[CH3:3][C:2]([CH3:16])([C:4](=[O:15])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:1]
Reactant: [H][H]
Reactant: CC(C)(C)C(=O)C#CCOc1ccccc1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)C(=O)CCCOc1ccccc1
Reaction time: 0.67 h
Yield: 95.6 %

Procedure:
20 g (0.0926 mol) of 2,2-dimethyl-6-phenoxy-hex-4-in-3-one are dissolved in 180 ml of methanol, and 5 g of Raney nickel are added. The mixture is hydrogenated with hydrogen under a pressure of 50 to 60 bar at 37° C. The hydrogenation has ended after 40 minutes. The reaction mixture is filtered and the filtrate is concentrated by stripping off the solvent under reduced pressure. 19.5 g (95.7% of theory) of 2,2-dimethyl-6-phenoxy-hexan-3-one are obtained in this manner.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[C:9]([OH:12])[CH:8]=[C:7]2[C:3]=1[CH:4]([OH:18])[C:5]1([CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:6]2[OH:13].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([O:29]CC)=[O:28].[OH-].[Na+].Cl>CN(C)C=O.O>[OH:13][CH:6]1[C:7]2[C:3](=[C:2]([Cl:1])[C:10]([CH3:11])=[C:9]([O:12][CH2:26][C:27]([OH:29])=[O:28])[CH:8]=2)[CH:4]([OH:18])[C:5]21[CH2:17][CH2:16][CH2:15][CH2:14]2
Reactant: Cc1c(O)cc2c(c1Cl)C(O)C1(CCCC1)C2O
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(OCC(=O)O)cc2c(c1Cl)C(O)C1(CCCC1)C2O
Temperature: 55 °C

Procedure:
A stirred mixture of 4'-chloro-5'-methylspiro(cyclopentane-1,2'-indan)-1',3',6'-triol (4.0 g., 0.015 mole), potassium carbonate (3.6 g.) and ethyl bromoacetate (3.1 ml.) in dimethylformamide (35 ml.) is heated at 55° C. for one-half hour in an inert atmosphere, treated with water (50 ml.) and 10N sodium hydroxide (5 ml.) then heated at 95° for one-half hour and poured into cold dilute hydrochloric acid affording [1',3'-dihydroxy-4'-chloro-5'-methylspiro(cyclopentane-1,2'-indan)-6'-yloxy]acetic acid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]2[N:15]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:14]3[CH:24]=[CH:25][C:26]([O:28]C)=[CH:27][C:13]=3[N:12]=2)[CH2:6][CH2:5]1.[BrH:30]>O>[OH2:28].[BrH:30].[BrH:30].[BrH:30].[NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]2[N:15]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:14]3[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:13]=3[N:12]=2)[CH2:6][CH2:5]1
Reactant: COc1ccc2c(c1)nc(NC1CCN(CCN)CC1)n2Cc1ccc(F)cc1
Agent: Br
Solvent: O
Product: NCCN1CCC(Nc2nc3cc(O)ccc3n2Cc2ccc(F)cc2)CC1
Temperature: 80 °C
Yield: 95.7 %

Procedure:
A mixture of 12 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-5-methoxy-1H-benzimidazol-2-amine and 150 parts of a hydrobromic acid solution 48% in water was stirred and heated for 48 hours at 80° C. The reaction mixture was evaporated and the residue was suspended in 2-propanol. The product was filtered off and dried, yielding 18.5 parts (95.7%) of 2-[[1-(2-aminoethyl)-4-piperidinyl]amino]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-5-ol trihydrobromide monohydrate mp. +250° C. (intermediate 122).
Reaction SMILES: [C:1]12([CH2:11][C:12]([OH:14])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.S(Cl)([Cl:17])=O>>[C:1]12([CH2:11][C:12]([Cl:17])=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)CC12CC3CC(CC(C3)C1)C2
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C

Procedure:
A solution of 1-adamantaneacetic acid (4.5 g) in thionyl chloride (20 ml) was heated at reflux temperature for 24 hours and then allowed to cool to ambient temperature. The excess thionyl chloride was removed under reduced pressure to leave the sub-title compound as a syrup (4.9 g).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]3[C:25]([CH:26]=O)=[CH:24][CH:23]=[C:9]3[C:10]3([CH2:16][CH2:15][N:14]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:13][CH2:12]3)[O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[NH2:29]O.C([O-])(=O)C.[Na+].CC(OC(C)=O)=O.C([O-])(O)=O.[Na+]>C(O)C.O>[F:1][C:2]1[C:7]2[N:8]3[C:25]([C:26]#[N:29])=[CH:24][CH:23]=[C:9]3[C:10]3([CH2:12][CH2:13][N:14]([C:17](=[O:22])[C:18]([F:19])([F:20])[F:21])[CH2:15][CH2:16]3)[O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc2n1-c1c(F)cccc1OC21CCN(C(=O)C(F)(F)F)CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CCO
Product: N#Cc1ccc2n1-c1c(F)cccc1OC21CCN(C(=O)C(F)(F)F)CC1
Temperature: 60 °C
Yield: 6.9 %

Procedure:
To a solution of 9′-fluoro-1-(2,2,2-trifluoroacetyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1′-carbaldehyde (715 mg, 1.9 mmol) in ethanol (3.5 mL) heated at 70° C. was added an aqueous solution of hydroxylamine hydrochloride (587 mg, 8.4 mmol) and sodium acetate (1.16 g, 14.20 mmol) in water (3.6 mL). The mixture was heated at 60° C. for 2 h. The mixture was cooled to 25° C., water added and the precipitate formed was collected by filtration and washed thoroughly with water and dried under vacuum. The residue was dissolved in Ac2O (3.37 mL, 35.74 mmol) and heated at 140° C. for 5 h. The reaction was cooled down to 25° C., poured onto ice, basified by addition of NaHCO3 (solid) until no more foaming occurred and was extracted with dichloromethane (3×5 mL). The combined organic phases were dried, filtered and concentrated to yield a residue that was purified by silica gel chromatography (gradient: 0.5-45% EtOAc in hexanes) to yield 9-fluoro-1′-(2,2,2-trifluoroacetyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbonitrile (50 mg, 7%). ESI-MS m/z calc. 379.1. found 380.3 (M+1)+; Retention time 1.82 minutes (3 min run).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][CH:8]=[CH:9][C:10]=1[CH:11]([F:13])[F:12])=[O:5])C>C(O)C.O1CCCC1.[OH-].[Na+]>[F:13][CH:11]([F:12])[C:10]1[CH:9]=[CH:8][S:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1sccc1C(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1sccc1C(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Formyl-2-thiophenecarboxylic acid (3.12 g) was dissolved in N,N-dimethylformamide (30 ml), and iodoethane (1.76 ml) and potassium carbonate (2.76 g) were added. The mixture was stirred at room temperature for 15 hours and poured into water. The mixture was extracted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 3-formyl-2-thiophenecarboxylic acid ethyl ester (2.91 g). 3-Formyl-2-thiphenecarboxylic acid ethyl ester (1.84 g) in methylene chloride (10 ml) was slowly added dropwise to diethylaminosulfur trifluoride (DAST) (1.45 ml) in methylene chloride (10 ml) at room temperature. The mixture was stirred at room temperature for 3 hours, and saturated aqueous sodium bicarbonate was added. The organic layer was collected, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-difluoromethyl-2-thiophenecarboxylic acid ethyl ester (1.58 g). 3-Difluoromethyl-2-thiophenecarboxylic acid ethyl ester was dissolved in a mixture of ethanol (10 ml) and tetrahydrofuran (10 ml), and 1N aqueous sodium hydroxide (11 ml) was added. The mixture was stirred at room temperature for 2 hours and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced ppressure to give 3-difluoromethyl-2-thiophenecarboxylic acid (1.12 g) as crystals.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][O:30][CH:31]2[CH2:36][CH2:35][S:34](=[O:38])(=[O:37])[CH2:33][CH2:32]2)[N:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][O:30][CH:31]3[CH2:36][CH2:35][S:34](=[O:37])(=[O:38])[CH2:33][CH2:32]3)[N:24]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: O=S1(=O)CCC(OCc2cccc(Br)n2)CC1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(COC4CCS(=O)(=O)CC4)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 with 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.10 g, 0.32 mmol) and 2-bromo-6-{[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy]methyl}pyridine (0.10 g, 0.32 mmol) as the starting materials.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][CH:12]1[CH2:15][N:14]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])[CH2:13]1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:32])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([CH:12]1[CH2:13][N:14]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])[CH2:15]1)=[O:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)c1ccccc1SC1CN(C(=O)c2ccccc2)C1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)c1ccccc1S(=O)C1CN(C(=O)c2ccccc2)C1
Temperature: 25 °C
Yield: 90.5 %

Procedure:
To an ice-cold stirred solution of (3-(2-tert-butylphenylthio)azetidin-1-yl)(phenyl)methanone (0.18 g, 0.55 mmol) in methylene chloride (10.0 mL) was added m-CPBA (0.15 g, 0.61 mmol). After 10 min a saturated solution of sodium thiosulfate and sodium hydrogen carbonate was added to the reaction mixture and the resulting reaction mixture was warmed to room temperature. After 30 min the reaction mixture was diluted with methylene chloride and separated. The organic layer was washed with saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 50:50 heptane/ethyl acetate) to provide (3-(2-tert-butylphenylsulfinyl)azetidin-1-yl)(phenyl)methanone (0.17 g, 66%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]3=[N:11][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][N:7]3[C:6]=2[CH:18]=1.[C:19](Cl)(=[O:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C)C=O>[C:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]3=[N:11][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][N:7]3[C:6]=2[CH:18]=1)([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:25]
Reactant: CCOC(=O)C(=O)Cl
Reactant: COC(=O)c1cn2c(n1)COc1ccc(N)cc1-2
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)Nc1ccc2c(c1)-n1cc(C(=O)OC)nc1CO2
Yield: 65 %

Procedure:
By the procedure of Step C in Example 1, methyl 8-amino-4H-imidazo-[2,1-c][1,4]-benzoxazine-2-carboxylate and ethyl chlorooxalate were reacted in dimethylformamide as solvent to obtain a 65% yield of methyl 8-(ethoxalylamino)-4H-imidazo-[2,1-c][1,4]-benzoxazine-2-carboxylate with a melting point of 186°-8° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:14]([C:16]1[C:17]([F:25])=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)#[N:15].O>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCO>[F:25][C:17]1[C:18]([C:2]2[CH:3]=[N:4][CH:5]=[N:6][CH:7]=2)=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]#[N:15]
Reactant: Brc1cncnc1
Reactant: N#Cc1cccc(B(O)O)c1F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: N#Cc1cccc(-c2cncnc2)c1F
Temperature: 70 °C
Yield: 23.9 %

Procedure:
A sealed tube apparatus was charged with a solution containing 5-bromopyrimidine (1 g, 6.29 mmol), sodium carbonate (3.33 g, 31.4 mmol), and 3-cyano-2-fluorophenylboronic acid (1.037 g, 6.29 mmol) in a mixture of DME (Ratio: 2, Volume: 31.4 ml), water (Ratio: 1.000, Volume: 15.72 ml), and EtOH (Ratio: 1.000, Volume: 15.72 ml) at ambient temperature. Tetrakis(triphenylphosphine) palladium(0) (0.363 g, 0.314 mmol) was then added and the system was purged with nitrogen, sealed, and heated to 70° C. for 12 h. The vessel was cooled to room temperature and diluted with EtOAc and water. The mixture was further diluted with brine and extracted three times with EtOAc. The combined organics were dried over MgSO4, filtered, and concentrated to give the crude product. The crude material was purified by flash chromatography on silica using an ISCO machine (40 g SiO2 column, 40 mL/min, 0-40% EtOAc/hexanes over 15 minutes, tr=8 minutes) to afford the title compound (300 mg, 24%). ESI MS (M+H)+=200.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.28 (1 hr, s), 9.09 (2 hr, d, J=1.54 Hz), 8.02-8.12 (2 hr, m), 7.59 (1 hr, t, J=7.81 Hz).
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH2:14][CH2:15][S:16][CH3:17])[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>CN(C=O)C>[CH3:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:2]2[C:3](=[O:18])[N:4]([CH2:14][CH2:15][S:16][CH3:17])[C:5](=[O:13])[C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(N)cc1
Reactant: CSCCN1C(=O)C(Cl)=C(c2ccccc2)C1=O
Solvent: CN(C)C=O
Product: COc1ccc(NC2=C(c3ccccc3)C(=O)N(CCSC)C2=O)cc1
Temperature: 150 °C

Procedure:
3-Chloro-1-[2-(methylthio)ethyl]-4-phenyl-1H-pyrrole-2,5-dione (0.40 mmol, 113 mg) and 4-methoxyaniline (0.88 mmol, 109 mg) were dissolved in DMF (1 mL). The mixture was heated in a microwave reactor at 150° C. for 10 min. After cooling, the solvent was evaporated under reduced pressure. The residue was partitioned between water and CH2Cl2. The organic phase was evaporated and purified by flash chromatography using a pre-packed silica column. The desired product was eluted with heptane/EtOAc 2:1. Yield 118 mg (80%).1H NMR (400MHz, CDCl3) δ 7.26 (bs, 1H), 7.15-7.06 (m, 3H), 7.01-6.96 (m, 2H), 6.63-6.52 (m, 4H), 3.83 (t, J=7.0 Hz, 2H), 3.69 (s, 3H), 2.79 (t, J=7.0 Hz, 2H), 2.18 (s, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:15][C:16]1[CH:17]=[C:18]([CH2:23][C:24]([CH3:26])=[O:25])[CH:19]=[CH:20][C:21]=1[OH:22].O>CN(C=O)C>[CH2:7]([O:22][C:21]1[CH:20]=[CH:19][C:18]([CH2:23][C:24]([CH3:26])=[O:25])=[CH:17][C:16]=1[Br:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)Cc1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Cc1ccc(OCc2ccccc2)c(Br)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Potassium carbonate (2.7 g) and benzyl bromide (2.3 ml) were added to a solution of 1-(3-bromo-4-hydroxyphenyl) acetone (4.0 g) in DMF (40 ml) and the mixture was stirred at room temperature for six hours. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-n-hexane) to obtain 1-[4-(benzyloxy)-3-bromophenyl]acetone (3.65 g).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]2[C:14]3[CH:15]=[CH:16][C:17]([OH:19])=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:20][N:21]=[C:22]=[O:23].CO.C(Cl)Cl>CCOC(C)=O.[Cu]Cl>[CH3:20][NH:21][C:22](=[O:23])[O:19][C:17]1[CH:16]=[CH:15][C:14]2[C:10]([NH:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[N:11][O:12][C:13]=2[CH:18]=1
Reactant: CN=C=O
Reactant: Oc1ccc2c(NCCN3CCOCC3)noc2c1
Agent: Cl[Cu]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: CNC(=O)Oc1ccc2c(NCCN3CCOCC3)noc2c1
Yield: 28.8 %

Procedure:
To a stirred solution of 3-[[2-(4-morpholinyl)ethyl]amino]-1,2-benzisoxazol-6-ol (2 g) and copper(I)chloride (0.3 g) in EtOAc (60 ml) was added methyl isocyanate (0.5 g). After 3.5 hours TLC (silica gel, 10% MeOH/DCM) showed no starting material. The reaction was filtered through neutral alumina eluting with EtOAc (2 l) and the filtrate was concentrated in vacuo. Flash column chromatography (silica gel) eluting with 1:1:20 acetone/MeOH/DCM afforded a white solid which was recrystallized from EtOAc/pet. ether to yield 0.7 g of the expected product, m.p. 127°-128° C.