Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:25]=[CH:24][C:9]2[N:10]=[C:11]([NH:14][C@H:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[CH3:26][O:27][CH2:28][CH:29]1[CH2:34][NH:33][CH2:32][CH2:31][N:30]1[CH3:35].C(N(C(C)C)CC)(C)C>C(#N)C>[C@H:15]1([NH:14][C:11]2[O:12][CH2:13][C:8]3[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:33]4[CH2:32][CH2:31][N:30]([CH3:35])[CH:29]([CH2:28][O:27][CH3:26])[CH2:34]4)[CH:25]=[CH:24][C:9]=3[N:10]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1
Reactant: COCC1CNCCN1C
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COCC1CN(CC(=O)Nc2ccc3c(c2)COC(N[C@@H]2CCc4ccccc42)=N3)CCN1C

Procedure:
Prepared from 2-chloro-N-[2-((R)-indan-1-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 3, step A) (70 mg, 0.197 mmol), commercially available rac-2-methoxymethyl-1-methyl-piperazine (CAS no. 734507-92-7) (28.5 mg, 0.197 mmol) and diisopropylethyl amine (167 ul, 0.984 mmol) in acetonitrile (2 ml) according to the procedure described for Example 3 step B. Obtained the title compound as a light yellow (50 mg, 55%), MS (ISP) m/e=464.3 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].I[CH2:32][C:33]([F:36])([F:35])[F:34]>>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:32][C:33]([F:36])([F:35])[F:34])[C:5]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: FC(F)(F)CI
Reactant: COC(=O)c1cccc(O)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Product: COC(=O)c1cccc(OCC(F)(F)F)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Yield: 48.4 %

Procedure:
In the same manner as described in Example 38, 0.40 g (0.937 mmol) of the product of Example 37 and 0.185 mL (1.873 mmol) of 2-iodo-1,1,1-trifluoroethane provided 0.231 g (48%) of the desired product as a colorless oil. Electrospray Mass Spec: 510.3 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1.S(Cl)(Cl)=O.[CH3:24][N:25]1[C:29]([NH2:30])=[CH:28][CH:27]=[N:26]1.N1C=CC=CC=1>C(Cl)Cl>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:30][C:29]2[N:25]([CH3:24])[N:26]=[CH:27][CH:28]=2)=[O:8])=[CH:4][C:3]=1[B:11]1[O:15][C:14]([CH3:16])([CH3:17])[C:13]([CH3:19])([CH3:18])[O:12]1
Reactant: Cn1nccc1N
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1ccc(C(=O)Nc2ccnn2C)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 50 mL round-bottomed flask was added 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (2.0 g, 7.6 mmol) and thionyl chloride (14 ml, 191 mmol) and the reaction mixture was stirred at RT for 1 h. Excess thionyl chloride was evaporated under vacuum and the remaining trace amount was removed azeotropically by addition of toluene (5 mL) and repeated concentration under reduced pressure. To the resulting residue was added DCM (10 mL) followed by 1-methyl-1H-pyrazol-5-amine (1.1 g, 11 mmol) and pyridine (1.2 ml, 15 mmol). The reaction was stirred at reflux for 1 h then cooled to RT. The mixture was diluted with DCM, washed with water followed by sat. NaHCO3, dried over MgSO4, filtered and concentrated in vacuo. The brown residue was loaded on an ISCO 40 g column (eluted with 25-65% EtOAc in Hexanes) and purified to provide the title compound as an off-white amorphous solid. MS (ESI, pos. ion) m/z: 342.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][C:20]=1[O:28][CH2:29][CH2:30][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1)(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.C(O)C.[Ni]>[C:1]([O:5][C:6](=[O:41])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][C:20]=1[O:28][CH2:29][CH2:30][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1)(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1OCCc1cccc2ccccc12
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(N)cc1OCCc1cccc2ccccc12
Yield: 91.2 %

Procedure:
A solution of N-methoxy-N-methyl-3-[2-(2-naphthalen-1-yl-ethoxy)-4-nitro-benzenesulfonylamino]-succinamic acid tert-butyl ester (0.52 g) in tetrahydrofuran (35 mL) and ethanol (35 mL) was treated with RaNi (0.3 g) and hydrogenated at 50 psi. The solution was filtered through Celite and evaporated to give the desired aniline derivative 3-[4-amino-2-(2-naphthalen-1-yl-ethoxy)-benzenesulfonylamino]-N-methoxy-N-methyl-succinamic acid tert-butyl ester (0.45 g) as an amorphous foam.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][NH:11]1>>[CH2:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][N:11]1[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccccc1F
Reactant: c1ccc2c(c1)CCNC2
Product: N#Cc1ccccc1N1CCc2ccccc2C1

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 2-fluorobenzonitrile and 1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:15][CH2:16][CH2:17][CH3:18])=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][N:6]([CH3:11])[C:7](=[O:10])[CH:8]=[CH2:9].C(N(C(C)C)CC)(C)C.Br[C:29]1[CH:42]=[N:41][C:32]2[NH:33][C:34](=[O:40])[C:35]([CH3:39])([CH3:38])[NH:36][CH2:37][C:31]=2[CH:30]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[C:3]([O:15][CH2:16][CH2:17][CH3:18])=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][N:6]([CH3:11])[C:7](=[O:10])/[CH:8]=[CH:9]/[C:29]1[CH:42]=[N:41][C:32]2[NH:33][C:34](=[O:40])[C:35]([CH3:39])([CH3:38])[NH:36][CH2:37][C:31]=2[CH:30]=1
Reactant: CC1(C)NCc2cc(Br)cnc2NC1=O
Reactant: C=CC(=O)N(C)Cc1cccc(Cl)c1OCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCOc1c(Cl)cccc1CN(C)C(=O)/C=C/c1cnc2c(c1)CNC(C)(C)C(=O)N2
Yield: 59.1 %

Procedure:
A solution of N-(3-chloro-2-propoxybenzyl)-N-methylacrylamide (0.392 g, 1.47 mmol) in propionitrile (5 mL) and DMF (1 mL) was deoxygenated with Ar for 20 min. The solution was treated with diisopropylethylamine (0.40 mL, 2.33 mmol) and 7-bromo-3,3-dimethyl-1,3,4,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-2-one (0.300 g, 1.11 mmol). The solution was deoxygenated with Ar for 20 min. Pd(OAc)2 (0.024 g, 0.111 mmol) and P(o-tol)3 (0.067 g, 0.222 mmol) were then added and the solution was deoxygenated again with Ar for 20 min. The mixture was heated to reflux for 18 h, then allowed to cool. The mixture was diluted with EtOAc (30 mL) and was washed with H2O (3×50 mL). The organic layer was washed with brine (1×100 mL), dried (Na2SO4) and concentrated to an orange oil. Purification by column chromatography (silica gel, CH2Cl2/MeOH, 100 to 98:2) gave the title compound (0.30 g, 59%) as a light yellow solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 9.80-9.78 (m, 1H), 8.40-8.37 (m, 1H), 8.01-7.92 (m, 1H), 7.54-7.49 (m, 1H), 7.41-7.25 (m, 2H), 7.15-7.05 (m, 2H), 4.86-4.68 (m, 2H), 3.91-3.84 (m, 4H), 3.14-2.95 (m, 4H), 1.83-1.76 (m, 2H), 1.31-1.29 (m, 6H), 1.05-0.99 (m, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:5])[CH:3]=O.C(Cl)(Cl)=O.[CH3:10][C:11]1[NH:12][CH:13]=[CH:14][N:15]=1.[F:16][P-:17]([F:22])([F:21])([F:20])([F:19])[F:18].[Na+]>C(Cl)(Cl)Cl>[F:16][P-:17]([F:22])([F:21])([F:20])([F:19])[F:18].[CH3:1][N:2]([CH3:5])[CH:3]=[C:10]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)[CH:1]=[N+:2]([CH3:5])[CH3:3]
Reactant: Cc1ncc[nH]1
Reactant: CN(C)C=O
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CN(C)C=C(C=[N+](C)C)c1ncc[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The Vilsmeier Haack reagent is prepared using 140 ml. (1.8 mole) of dimethylformamide and 500 ml. of 3N phosgene in chloroform. 2-Methylimidazole (30.8 g., 0.375 mole) is added in portions over one hour maintaining the temperature at or below 10° C. and the mixture is then stirred overnight at ambient temperature. The reaction mixture is poured onto ice (490 g.), shaken and separated. The chloroform solution is extracted with water (35 ml.) and the combined aqueous solutions treated with sodium hexafluorophosphate (63.0 g., 0.375 mole). After filtering, the filtrate is cooled in an ice-bath while sodium carbonate anhydrate (139 g., 1.313 mole) is added in small portions. The crystalline precipitate obtained weighs 50.70 g. (39%) and melts at 185°-187° C. Recrystallization of the crude product from water (5 parts volume by weight) gives purified product melting at 191°-192° C. in the form of colorless crystals.
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].[C:6](OC(C)(C)C)(=[O:11])[CH2:7][C:8]([CH3:10])=[O:9]>C1(C)C=CC=CC=1>[C:6]([O:5][CH2:4][CH:2]1[O:3][CH2:1]1)(=[O:11])[CH2:7][C:8]([CH3:10])=[O:9]
Reactant: OCC1CO1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)OCC1CO1
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
Glycidyl acetoacetate was prepared according to the method of Witzeman and Nottingham (J. Org. Chem, 1991, 56, 1713). Glycidol (Dixie Chemical Company, Pasadena, Tex.), 296 g, t-butyl acetoacetate, 632.8 g, and toluene, 500 ml, were mixed in a 1-liter reactor equipped with mechanical stirrer, thermocouple, condenser and nitrogen inlet. The reactor contents were heated to 110° C. and held at that temperature for 30 minutes. The reactor was then fitted with a distillation head and the toluene/t-butanol azeotrope was distilled from the reactor over 2 hours under moderate nitrogen flow. Peak temperature reached in the reactor was 120° C. After 4 hours total time, the reaction mixture was cooled and stripped on a rotary evaporator at 70° C. for 2 hours. The yellow liquid product was analyzed by proton NMR. Essentially quantitative conversion of glycidol to glycidyl acetoacetate was confirmed.
Reaction SMILES: [CH:1]([C:3]1[N:12]=[C:11]2[C:6]([C:7](=[O:16])[C:8]([C:13]([OH:15])=[O:14])=[CH:9][NH:10]2)=[CH:5][CH:4]=1)=[O:2].[C:17](NN)(=O)[CH3:18]>C(O)C>[CH2:17]([N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([CH:1]=[O:2])[N:12]=2)[C:7](=[O:16])[C:8]([C:13]([OH:15])=[O:14])=[CH:9]1)[CH3:18]
Reactant: CC(=O)NN
Reactant: O=Cc1ccc2c(=O)c(C(=O)O)c[nH]c2n1
Solvent: CCO
Product: CCn1cc(C(=O)O)c(=O)c2ccc(C=O)nc21
Yield: 118 %

Procedure:
A mixture containing 2 g of 7-formyl-3-carboxy-4-oxo-1, 4-dihydro-1,8-naphthyridine and 0.51 g of acethydrazide and 20 ml of ethanol are stirred and refluxed for 11/2 hours. The mixture was cooled and the solids were filtered and washed with a little ethanol and dried at room temperature. Several washings with hot cellosolve and dimethyl formamide yielded 2 g of 1-ethyl-3-carboxy-4-oxo-1, 4 dihydro-1,8 naphthyridine-7 carboxaldehyde acethydrazone m.p. 300°.
Reaction SMILES: [BH4-].[Na+].[S:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][C:13](O)=[O:14])=[CH:11][C:6]=2[CH:5]=[CH:4]1.S(=O)(=O)(O)O>O1CCCC1>[S:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][CH2:13][OH:14])=[CH:11][C:6]=2[CH:5]=[CH:4]1
Reactant: O=C(O)Cc1ccc2sccc2c1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCc1ccc2sccc2c1
Temperature: 66 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To 40 mL of tetrahydrofuran was suspended 4.72 g of sodium borohydride, to this solution were dropwise added tetrahydrofuran (60 mL) solution of 20 g of (1-benzothiophen-5-yl)acetic acid, and 6.12 g of sulfuric acid. The solution was heated to 66° C., followed by distilling off about 40 mL of the solvent under normal pressure, which was then stirred at same temperature for 1 hour. After cooling, to this reaction mixture was dropwise added 10 mL of acetone, which was then stirred for 30 minutes. Thereto were added 90 mL of water and 80 mL of toluene. The organic layer was separated, to which was added 60 mL of water, and the pH was adjusted to 13.6 with 5 mL of 5 mol/L sodium hydroxide aqueous solution. The organic layer was separated, washed with water, followed by distilling off the solvent, and thereto were added cyclohexane and toluene. The precipitate was collected by filtration to provide 16.5 g of 2-(1-benzothiophen-5-yl)ethanol as white solid form.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[C:16]12(C(O)=O)[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2.OS(O)(=O)=O.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].C(=O)=O.[NH4+].[OH-]>CC#N.O.[N+]([O-])([O-])=O.[Ag+]>[CH:16]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH:17]1[C:8]1[CH:7]=[CH:6][C:5]3[C:10](=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=1)[CH2:23]2
Reactant: COc1cc([N+](=O)[O-])c2ncccc2c1
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Agent: [Ag+]
Agent: O=C=O
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: O
Product: COc1cc([N+](=O)[O-])c2nc(C3C4CC5CC(C4)CC3C5)ccc2c1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
6-Methoxy-8-nitroquinoline (1 mmol) (scheme 1) was dissolved in CH3CN (5 mL) while reaction mixture was warmed to 70° C. Silver nitrate (0.6 mmol), 1-adamantanecarboxylic acid (2 mmol), and 10% H2SO4 (10 mL) was then added to the reaction mixture. A freshly prepared solution of ammonium persulfate (3 mmol) in water (10 mL) was added drop wise to the pre-heated (70° C.) mixture during 10 minutes. The heating source was then removed and reaction proceeded with evolution of carbon dioxide. After 10 minutes, reaction mixture was poured onto ice, and resulting mixture was made alkaline with addition of 30% NH4OH. Extracted with ethyl acetate (4×50 mL), and combined extracts were washed with NaCl solution (2×10 mL). Dried over Na2SO4 and solvent removed in vacuo to afford oil, which on flash column chromatography over silica gel (230-400 mesh) gave 2-adamantyl-6-methoxy-8-nitroquinoline in good yield.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[Cl:11].C(Cl)(=O)C([Cl:15])=O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:15])=[O:7])=[CH:4][C:3]=1[Cl:11]
Reactant: O=C(O)c1ccc(Br)c(Cl)c1
Reactant: O=C(Cl)C(=O)Cl
Product: O=C(Cl)c1ccc(Br)c(Cl)c1

Procedure:
Following the procedures described in Example 36: 4-bromo-3-chlorobenzoic acid and oxalyl chloride were reacted to provide 4-bromo-3-chloro-benzoyl chloride, which was then reacted with 3-methylamino-but-2-enoic acid methyl ester to provide 2-(4-bromo-3-chloro-benzoyl)-3-[(E)-methylimino]-butyric acid methyl ester. 2-(4-Bromo-3-chloro-benzoyl)-3-[(E)-methylimino]-butyric acid methyl ester and hydroxylamine hydrochloride were then reacted as described in Example 36, Step 3 to provide 5-(4-bromo-3-chloro-phenyl)-3-methyl-isoxazole-4-carboxylic acid methyl ester, which was then hydrolyzed to 5-(4-bromo-3-chloro-phenyl)-3-methyl-isoxazole-4-carboxylic acid as described in Example 36, Step 4. 5-(4-Bromo-3-chloro-phenyl)-3-methyl-isoxazole-4-carboxylic acid and (R)-1-(2-chloro-phenyl)-ethanol were reacted to provide [5-(4-bromo-3-chloro-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-chloro-phenyl)-ethyl ester as described in Example 36, Step 5.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4](Cl)[N:3]=1.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([O:20][CH3:21])=[C:15](B(O)O)[CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>O.C(O)C.O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(Cl)(Cl)Cl.CC(C)=O.C(COC)OC>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([C:13]2[CH:12]=[C:11]([Cl:10])[CH:16]=[CH:15][C:14]=2[O:20][CH3:21])[N:3]=1
Reactant: COc1ccc(Cl)cc1B(O)O
Reactant: Nc1cc(Cl)nc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)=O
Solvent: CCO
Product: COc1ccc(Cl)cc1-c1cc(N)nc(Cl)n1
Reaction time: 24 h
Yield: 15.5 %

Procedure:
Alternatively, to a mixture of 2,6-dichloro-pyrimidin-4-yl-amine (1.64 g, 10.0 mmol), 5-chloro-2-methoxy-phenyl boronic acid (1.84 g, 10.0 mmol), palladium (II) acetate (0.337 g, 1.0 mmol) and triphenylphosphine (0.786 g, 3.0 mmol) was added a solution of sodium carbonate (5.3 g, 50.0 mmol) in water (10 ml) followed by glyme (50 ml). The mixture was stirred under an argon atmosphere for 24 hours. After addition of acetone (50 ml), filtration and concentration of the filtrate provided the crude product which was treated with chloroform (50 ml) and stirred for 1 hour. Filtration provided a solid which was dissolved in ethanol (50 ml). A solution of hydrogen chloride in dioxane (4.0 M, 5 ml) was added and volatiles were evaporated under reduce pressure. The residue was treated with ethyl acetate (25 ml) and stirred for 2 hours. Filtration provided the hydrochloride salt of 2-chloro-6-(5-chloro-2-methoxy-phenyl)-pyrimidin-4-yl-amine (0.42 g, 14% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=[CH:15][C:13]=3[CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=[CH:15][C:13]=3[CH:14]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1cccc2cc(-c3ccc([N+](=O)[O-])cc3)oc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2cc(-c3ccc(N)cc3)oc12
Temperature: 70 °C
Yield: 93.3 %

Procedure:
A mixture of 3.1 g of methyl 2-(4-nitrophenyl)benzofuran-7-carboxylate, 11.7 g of stannous chloride dihydrate and 100 ml of ethyl acetate is heated at 70° C. for 1 hour. After cooling, the reaction mixture is alkalized with an aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract is washed with water, dried and evaporated to remove solvent to give 2.6 g of methyl 2-(4-aminophenyl)benzofuran-7-carboxylate as yellow crystals.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Br[C:22]#[C:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Na+].[Cl-].[NH4+].[OH-]>C1(C)C=CC=CC=1.[Cu]I.CCOCC>[C:16]([O:15][C:14](=[O:20])[N:13]([C:10]1[CH:9]=[CH:8][C:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[CH:12][CH:11]=1)[C:22]#[C:23][Si:24]([CH:25]([CH3:27])[CH3:26])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])([CH3:17])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N2CCOCC2)cc1
Reactant: CC(C)[Si](C#CBr)(C(C)C)C(C)C
Agent: [Cu]I
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)[Si](C#CN(C(=O)OC(C)(C)C)c1ccc(N2CCOCC2)cc1)(C(C)C)C(C)C
Temperature: 90 °C
Reaction time: 12 h
Yield: 40 %

Procedure:
A suspension of t-butyl 4-morpholinophenylcarbamate (1.45 g, 7.60 mmol), bromoethynyl-triisopropyl-silane, CuI (450 mg, 2.34 mmol) and 1,10-phenantroline (500 mg, 2.80 mmol) in dry toluene (15 ml) was warmed up to 90° C. under a nitrogen atmosphere. KHMDS (20 ml, 0.5 M in toluene) was added dropwise under nitrogen and the mixture was stirred for 12 hours at this temperature. The reaction was cooled down to RT; Et2O (30 ml) and NaCl/NH4OH (60/30 ml) were added and the organic phase was extracted with Et2O (3×30 ml), washed with NaCl/NH4 and dried over Na2SO4. The solvent was removed under reduced pressure and the title compound was obtained after purification by column chromatography (PE/AcOEt: 95/5).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=[N:12][OH:13])=[CH:10][C:5]=2[C:4]([CH3:15])([CH3:14])[O:3]1.C1C(=O)N([Cl:23])C(=O)C1>CN(C=O)C>[OH:13][N:12]=[C:11]([Cl:23])[C:9]1[CH:8]=[CH:7][C:6]2[B:2]([OH:1])[O:3][C:4]([CH3:15])([CH3:14])[C:5]=2[CH:10]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC1(C)OB(O)c2ccc(C=NO)cc21
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C(Cl)=NO)cc21
Temperature: 40 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
To a solution of 1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde oxime (8 mg, 0.039 mmol) in DMF (1.0 mL) at rt was added NCS (6.2 mg, 0.047 mmol). The reaction mixture was stirred for 2 h, warmed to 40° C. and stirred for 3 h. The mixture was cooled to rt, poured into ice-water (10 mL) and extracted with EA (20 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (8 mg; yield 86%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 12.50 (s, 1 H), 7.90 (s, 1 H), 7.70-7.79 (m, 2 H), 1.61 (s, 6 H) ppm.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:21][S:22][C:23]2[NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[N:24]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:15][O:14][C:13]2([CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[O:12][CH2:11]1.ClC1C=CC=C(C(OO)=[O:40])C=1.C(=O)([O-])O.[Na+]>CO.C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:3]([CH2:21][S:22]([C:23]2[NH:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[N:27]=2)=[O:40])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:15][O:14][C:13]2([CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[O:12][CH2:11]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1c(OCC2COC3(CCOCC3)OC2)ccnc1CSc1nc2ccccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1c(OCC2COC3(CCOCC3)OC2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reaction time: 0.92 h
Yield: 71.7 %

Procedure:
To a toluene (30 ml)-methanol (3 ml) solution of the 2-(((3-methyl-4-(1,5,9-trioxaspiro[5.5]undec-3-ylmethoxy)pyridin-2-yl)methyl)thio)-1H-benzimidazole (974 mg, 2.21 mmol) obtained in the step (10d), a toluene (1 ml)-methanol (1 ml) solution of 3-chloroperbenzoic acid (528 mg, 1.99 mmol as the content was regarded as 65%) was added dropwise at −65° C. for 5 minutes in a nitrogen atmosphere. The mixture was stirred for 55 minutes in the same conditions. To the reaction mixture, a saturated aqueous solution of sodium hydrogen carbonate was added. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (NH silica gel: 20 g, elution solvent: dichloromethane, dichloromethane/methanol=10/1). The fractions containing the title compound were collected with ethyl acetate and concentrated. After diethyl ether was added to the residue, the solvent was distilled off to obtain the title compound (725 mg, yield: 71.7%) as a pale grayish solid.