Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]1([CH2:16][O:17][C:18]2[CH:19]=[C:20]([CH2:24][C:25](Cl)=[O:26])[CH:21]=[CH:22][CH:23]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:25](=[O:26])[CH2:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([O:17][CH2:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:19]=1
Reactant: O=C(Cl)Cc1cccc(OCc2ccccc2)c1
Reactant: Nc1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1cccc(OCc2ccccc2)c1)Nc1ccc(Cl)cc1Cl
Reaction time: 3 h
Yield: 69 %

Procedure:
To a solution of 2,4-dichloroaniline (2.67 g, 0.0165 mol) in dichloromethane (20 ml) was slowly added a solution of 2-[3-(phenylmethoxy)phenyl]acetyl chloride (3.84 g, 0.015 mol) in dichloromethane (10 ml). After stirring for three hours, triethylamine (2 ml, 0.015 mol) was added to the reaction and the reaction was allowed to stir overnight. To the reaction was added an aqueous solution of sodium bicarbonate. The mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The solid was triturated with ether and hexane, then filtered to provide the title compound (4.0 g, 70% yield): ES-MS (m/z) 372 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8](B(O)O)[CH:9]=2)[CH:4]=[CH:3]1.[OH:14]O>CCOCC>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:14])[CH:9]=2)[CH:4]=[CH:3]1
Reactant: OO
Reactant: Cn1ccc2ccc(B(O)O)cc21
Solvent: CCOCC
Product: Cn1ccc2ccc(O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
1-Methyl-1H-indol-6-yl-boronic acid (1.4 g, 8.0 mmol) was dissolved in ether (25 mL). Hydrogen peroxide (15%, 6 mL) was added over 5 minutes and the reaction mixture was stirred at room temperature for 1 h. The mixture was extracted with NaOH (1N, 2×50 mL) and the aqueous extracts were washed with ether (2×50 mL). The aqueous layers were cooled to 0° C. and acidified to pH 4.0 with 6 N HCl. The mixture was extracted with ether (3×100 mL) and the organic extracts were washed with water. The organic extracts were dried (MgSO4), filtered through a pad of silica gel and the pad was washed with ether (100 mL). After the filtrate was concentrated, the residue was chromatographed over silica gel with 10% to 20% ethyl acetate/hexanes to give 1-methyl-1H-indol-6-ol as a yellow solid (0.56 g, 47%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].CS([O:11][CH2:12][C:13]([CH3:18])([N+:15]([O-:17])=[O:16])[CH3:14])(=O)=O.O[C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:22][C:21]=1[C:30]1[N:31]([CH3:35])[N:32]=[CH:33][CH:34]=1>CC(N(C)C)=O>[CH3:35][N:31]1[C:30]([C:21]2[CH:22]=[C:23]([NH:26][C:27](=[O:29])[CH3:28])[CH:24]=[CH:25][C:20]=2[O:11][CH2:12][C:13]([CH3:18])([N+:15]([O-:17])=[O:16])[CH3:14])=[CH:34][CH:33]=[N:32]1
Reactant: CC(C)(COS(C)(=O)=O)[N+](=O)[O-]
Reactant: CC(=O)Nc1ccc(O)c(-c2ccnn2C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1ccc(OCC(C)(C)[N+](=O)[O-])c(-c2ccnn2C)c1
Temperature: 160 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
Cesium carbonate (7.04 g, 21.6 mmol) was added to a solution of 2-methyl-2-nitropropyl methanesulfonate (2.39 g, 12.1 mmol) and N-(4-hydroxy-3-(2-methyl-2H-pyrazol-3-yl)phenyl)acetamide (2.00 g, 8.65 mmol) in dimethylacetamide (15 mL) and the mixture was stirred at 160° C. After 2 h, the solvent was evaporated, and the residue was triturated with water. The precipitate was isolated by filtration, washed with water and dried in vacuo to afford the product (2.38 g, 83%) as a tan solid. LCMS m/z (%)=333.4 (M+H 100%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.47 (s, 6H), 2.02 (s, 3H), 3.53 (s, 3H), 4.32 (s, 2H), 6.15 (d, J=2.02 Hz, 1H), 7.14 (d, J=8.84 Hz, 1H), 7.44 (d, J=1.77 Hz, 1H), 7.49 (d, J=2.78 Hz, 1H), 7.62 (dd, J=8.97, 2.65 Hz, 1H), 9.94 (s, 1H).
Reaction SMILES: [SH:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].C(N(CC)CC)C>C(O)C>[C:17]1(=[O:26])[N:16]([CH2:15][CH2:14][CH2:13][CH2:12][S:1][C:2]2[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]12
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: Sc1cccc2nccn12
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CCCCSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a suspension of 5-mercaptoimidazo[1,2-a]pyridine (3.00 g, 20 mmoles) and N-[4-(bromo)butyl]phthalimide (6.21 g, 22 mmoles) in ethanol (200 ml) was added triethylamine (4.2 ml, 30 mmoles) and the mixture was stirred at room temperature for 1 hour and heated at reflux for 45 minutes. After the solvent was distilled off, chloroform was added to the residue, which was washed with saturated saline, dried over anhydrous magnesium sulfate and the solvent was distilled off. Then, the residue was purified by column chromatography (eluent:ethyl acetate) to obtain 4.50 g of the desired product (64.1%, pale yellow crystals).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[O:9]=[C:10]([CH3:26])[CH2:11][N:12]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13]1>CS(C)=O>[CH3:26][C:10]1([CH2:11][N:12]2[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13]2)[CH2:2][O:9]1
Reactant: C[S+](C)(C)=O
Reactant: CC(=O)CN1CCCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCCN(CC2(C)CO2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
Trimethylsulfoxonium iodide (22.95 g, 104 mmol) was gradually added to a suspension of sodium hydride (4.3 g, 109 mmol) in DMSO (200 ml), and the mixture was stirred at room temperature for 2 hours. To which a solution tert-butyl 4-(2-oxopropyl)homopiperazine-1-carboxylate (24.3 g, 94.8 mmol) prepared in Reference Example 10 in DMSO (25 ml) was gradually added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water, and extracted with diethyl ether. The extract was washed with water, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) to afford tert-butyl 4-(2-methyl-2-oxiranylmethyl)homopiperazine-1-carboxylate (15.38 g, yield 60%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:8][CH2:9][C:10](=O)[CH2:11]Cl>C(#N)C>[Cl:8][CH2:9][C:10]1[N:1]=[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]2[CH:11]=1
Reactant: Nc1ccccn1
Reactant: O=C(CCl)CCl
Solvent: CC#N
Product: ClCc1cn2ccccc2n1
Yield: 34 %

Procedure:
A mixture of 2-aminopyridine (12.5 g), 1,3-dichloro-2-propanone (17.7 g) and acetonitrile (100 ml) was heated under reflux for 2 hours and concentrated. An aqueous saturated solution of sodium bicarbonate was added to the residue and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain crystals from an ethyl acetate-hexane hexane (3:2, v/v)-eluted fraction. Recrystallization from ethyl acetate-hexane gave 2-chloromethylimidazo[1,2-a]pyridine (7.52 g, yield 34%) as pale-yellow crystals. m.p. 93-94° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH:7]([CH3:14])[CH2:8][C:9]1[CH2:13][CH2:12][CH2:11][CH:10]=1)(=[O:3])[CH3:2].[H][H]>[Ni].[Pd].C(O)(C)C>[C:1]([O:4][CH2:5][CH2:6][CH:7]([CH3:14])[CH2:8][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCC(C)CC1=CCCC1
Reactant: [H][H]
Agent: [Ni]
Agent: [Pd]
Solvent: CC(C)O
Product: CC(=O)OCCC(C)CC1CCCC1
Yield: 93 %

Procedure:
A solution of 4-cyclopentenyl-3-methylbutyl acetate (1.96 kg, 10.0 mols), isopropyl alcohol (1000 ml) and Raney nickel (100 g), Pd/C 100 g) or other suitable sponge-metal catalyst was hydrogenated at 400 psi, at 140° C. for 10-12 h until the theoretical amount of hydrogen was taken up. The mixture was cooled and filtrated. The isopropyl alcohol was evaporated and the residue obtained was distilled under reduced pressure to provide 4-cyclopentyl-3-methylbutyl acetate (1.84 kg, yield: 93%, purity: 98%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10](=[O:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1.C[O:14][C:15]1C=CC=C[C:16]=1C1CC(=O)CC(=O)C1>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:16][C:15](=[O:14])[CH2:11][C:10](=[O:12])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1C1CC(=O)CC(=O)C1
Reactant: CC(=O)C=Cc1cccc(F)c1
Product: O=C1CC(=O)CC(c2cccc(F)c2)C1

Procedure:
The title compound was prepared from 4-(3-fluoro-phenyl)-but-3-en-2-one stage 1 (940 mg, 5.73 mmol), following the procedure describing the synthesis of 5-(2-methoxy-phenyl)-cyclohexane-1,3-dione (example 1/a stage 2).
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[O:12][CH2:11][CH2:10]2.Cl.C(OCC)(=O)C>O1CCOCC1>[O:17]=[C:13]1[C:14]2[C:9](=[CH:8][C:7]([CH2:6][CH:2]=[O:1])=[CH:16][CH:15]=2)[CH2:10][CH2:11][O:12]1
Reactant: O=C1OCCc2cc(CC3OCCO3)ccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=CCc1ccc2c(c1)CCOC2=O
Temperature: 25 °C

Procedure:
6-(1,3-Dioxolan-2-ylmethyl)-3,4-dihydro-1H-isochromen-1-one (4.42 g, 18.9 mmol) was dissolved in dioxane (25 mL) and treated with 3 M HCl (40 mL). The reaction mixture was stirred at RT over night, and then was warmed to 50° C. for 2 hrs to drive the reaction to completion. Ethyl acetate was added and the layers were separated. The aqueous layer was extracted again with ethyl acetate, and the combined organic layers were washed with brine and dried over MgSO4 to afford the title compound. LCMS: m/z 191 (M+1)+.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[C:11](C([O-])=O)=[CH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([C:20]([O:22]C)=[O:21])=[CH:15][CH:14]=3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[OH2:28].[OH-].[Na+]>CO>[OH:28][C:11]1[C:10]([C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:20]([OH:22])=[O:21])[CH:17]=2)[CH:12]=1
Reactant: O
Reactant: COC(=O)c1ccc2cc(C(=O)[O-])c(C(=O)Nc3ccccc3)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2cc(O)c(C(=O)Nc3ccccc3)cc2c1
Reaction time: 8 h
Yield: 85 %

Procedure:
Sodium 3-phenylaminocarbonyl-6-methoxycarbonyl-2-naphthoate (0.081 g) obtained in Example 29 was suspended in methanol (8.10 g) and deionized water (8.13 g) and 1N-sodium hydroxide (4.0 g) was added dropwise under ice-cooling, followed by stirring overnight. The reaction solution was freeze-dried and the resultant solid was dissolved in water. The solution was acidified with diluted hydrochloric acid and the deposited crystal was filtered. The crystal was dried under reduced pressure to obtain 0.057 g of 2-hydroxy-3-phenylaminocarbonyl-6-hydroxycarbonylnaphthalene.
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[C:30]([OH:38])(=[O:37])[CH:31]([CH2:33][C:34]([OH:36])=[O:35])[OH:32].C1(C)C=CC=CC=1>CN1CCCC1=O>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[CH2:33]([C:34]([OH:36])=[O:35])[C@H:31]([OH:32])[C:30]([OH:38])=[O:37]
Reactant: O=C(O)CC(O)C(=O)O
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Product: O=C(O)C[C@H](O)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1 g of sunitinib base was dissolved in 3 ml of N-methyl pirrolidone, at RT 0.336 g of Malic acid added (as solid): the solution was heated to 40° C. than 15 ml of toluene was added and precipitation was observed. The suspension was kept at 40° C. for 1 hour than cooled to 0° C., filtered and washed with toluene. Dried at 60° C. under vacuum for 16 h.
Reaction SMILES: Br[CH2:2][B:3]1[O:7][C:6]([CH3:9])([CH3:8])[C:5]([CH3:11])([CH3:10])[O:4]1.[I-:12].[Na+]>CC(C)=O>[I:12][CH2:2][B:3]1[O:7][C:6]([CH3:9])([CH3:8])[C:5]([CH3:11])([CH3:10])[O:4]1
Reactant: [I-]
Reactant: CC1(C)OB(CBr)OC1(C)C
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1(C)OB(CI)OC1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
To the mixture of 2-(bromomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.0 g, 8.3 mmol) synthesized in Production Example 2 and acetone (17 ml), sodium iodide (1.9 g, 13 mmol) was added at room temperature, and the obtained reaction mixture was stirred at room temperature for 2 hours. Impurities were removed by filtration, and the solvents were evaporated under reduced pressure from the filtrate. Hexane was added to the obtained residue, and insoluble matter was removed by filtration. The solvents were evaporated under reduced pressure from the filtrate, thereby obtaining the entitled compound (2.2 g, 97%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[S:8][CH2:7][C@@H:6]([CH3:9])[NH:5][C:4]1=[O:10].N1C=CN=C1.[C:16]([Si:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:19])([CH3:18])[CH3:17].O>C(Cl)Cl>[Si:20]([O:1][CH2:2][C@@H:3]1[S:8][CH2:7][C@@H:6]([CH3:9])[NH:5][C:4]1=[O:10])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C[C@@H]1CS[C@@H](CO)C(=O)N1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: C[C@@H]1CS[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C(=O)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the above crude compound (11, 9.0 g, 0.057 mol) in DCM (150 mL) was added imidazole (7.70 g, 0.113 mol) followed by tert-butyl(chloro)diphenylsilane (17.2 g, 0.0630 mol) under N2 atmosphere. After the addition, the resulting solution was stirred at ambient temperature for 2 hours. Water (100 mL) was added and the mixture was extracted with DCM (3×200 mL). The combined organic fractions were concentrated in vacuo, and the resultant residue was purified by silica gel chromatography (PE: EtOAc=10:1 to 2:1) to give (2S,5R)-2-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-methylthiomorpholin-3-one (12) that gave a proton NMR spectra consistent with theory.
Reaction SMILES: [C:1]([O:4][NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2].[H-].[Na+].[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH:17]=[C:16]1[S:24](Cl)(=[O:26])=[O:25]>>[C:1]([O:4][N:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[S:24]([C:16]1[O:15][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH:17]=1)(=[O:25])=[O:26])(=[O:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: CC(=O)ONC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Product: CC(=O)ON(C(=O)OC(C)(C)C)S(=O)(=O)c1cc2ccccc2o1

Procedure:
N-[(tert-Butoxy)carbonyl]1-benzofuran-2-sulfonamido acetate (105) is prepared from [(tert-butoxy)carbonyl]amino acetate, sodium hydride and 1-benzofuran-2-sulfonyl chloride according to Scheme 2. δH (250 MHz, DMF) 8.07 (1H, d, 0.9 Hz), 7.91 (1H, d, 7.3 Hz), 7.82 (1H, dd, 8.5, 0.8 Hz), 7.64 (1H, td, 7.8, 1.4 Hz), 7.41-7.52 (1H, m), 2.32 (3H, s), 1.37 (9H, s).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([S:5]([C:8]2[CH:28]=[CH:27][C:11]3[N:12]([CH2:20][CH2:21][O:22][C:23]([F:26])([F:25])[F:24])[C:13]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:14][C:10]=3[CH:9]=2)(=[O:7])=[O:6])[CH2:2]1.C[Si]([N:33]=[C:34]=[O:35])(C)C>>[CH2:15]([C:13]1[N:12]([CH2:20][CH2:21][O:22][C:23]([F:24])([F:26])[F:25])[C:11]2[CH:27]=[CH:28][C:8]([S:5]([CH:3]3[CH2:2][N:1]([C:34]([NH2:33])=[O:35])[CH2:4]3)(=[O:7])=[O:6])=[CH:9][C:10]=2[N:14]=1)[C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)C3CNC3)ccc2n1CCOC(F)(F)F
Reactant: C[Si](C)(C)N=C=O
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)C3CN(C(N)=O)C3)ccc2n1CCOC(F)(F)F

Procedure:
The title compound was prepared according to the procedure described in STEP D of Example 6 using 5-(azetidin-3-ylsulfonyl)-2-neopentyl-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazole (STEP C of Example 7) and trimethylsilyl isocyanate instead of methanesulfonyl chloride.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([N+]([O-])=O)=[CH:15][C:14]=3[N+:22]([O-:24])=[O:23])[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1B(O)O>>[N:1]1([C:6]2[CH:7]=[C:8]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:26]4[O:25][CH:29]=[CH:28][CH:27]=4)=[CH:15][C:14]=3[N+:22]([O-:24])=[O:23])[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: OB(O)c1ccco1
Reactant: O=[N+]([O-])c1ccc(Nc2cccc(-n3cccc3)c2)c([N+](=O)[O-])c1
Product: O=[N+]([O-])c1cc(-c2ccco2)ccc1Nc1cccc(-n2cccc2)c1
Yield: 83 %

Procedure:
N-(3-(1-Pyrrolyl)phenyl)-4-(2-furanyl)-2-nitroaniline (7n) was prepared analogously from 6k (Example 9) and 2-furanylboronic acid. Yield: 83%. Isolated as a brownish-red oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][C:12]([C:25]#[N:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-:28].[Na+].[Na+]>S(=O)(=O)(O)O>[C:13]1([C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:11][CH2:10][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:9])[C:25]([NH2:26])=[O:28])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CN(CCC(C#N)(c1ccccc1)c1ccccc1)Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CN(CCC(C(N)=O)(c1ccccc1)c1ccccc1)Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 3-(N-benzyl-N-methylamino)-1-cyano-1,1-diphenylpropane (11.1 g-see Preparation 5) in 90% sulphuric acid (66 ml) was heated at 100° for 1 hour. The mixture was allowed to cool to room temperature and poured into ice/water (300 ml). The aqueous mixture was basified with saturated aqueous sodium carbonate and extracted with dichloromethane (3×100 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give the title compound, yield 10.6 g. A sample recrystallised from ethanol had a melting point of 145°-148°.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.[CH2:11]1[O:19][CH:12]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O.O.O.O.O.O.[N+]([O-])([O-])=O.[Y+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>[OH:19][CH2:11][CH:12]([N:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: c1ccc(C2CO2)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Y+3]
Solvent: O
Product: CCOC(=O)c1cnn(C(CO)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of ethyl 1H-pyrazole-4-carboxylate (1.5 g, 10.7 mmol), yttrium (III) nitrate hexahydrate (82.0 mg, 0.214 mmol) and styrene oxide (1.21 ml, 10.7 mmol) was stirred at rt for 17 h, before it was adsorbed on celite. Purification by column chromatography (CombiFlash Companion, 12 g SiO2, heptane to EA) afforded the title compound. LCMS RtM=1.72 min, [M+H]+=261.2.
Reaction SMILES: [NH2:1][C:2]1[N:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20](=[O:26])(=[O:25])[NH:21][CH:22]3[CH2:24][CH2:23]3)[CH:15]=2)=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[C:27]([C:31]1[CH:36]=[CH:35][C:34]([Mg]Br)=[CH:33][CH:32]=1)([CH3:30])([CH3:29])[CH3:28]>C1COCC1.C(Cl)Cl>[NH2:1][C:2]1[N:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]([S:20]([NH:21][CH:22]3[CH2:23][CH2:24]3)(=[O:25])=[O:26])[CH:17]=[CH:18][CH:19]=2)=[CH:10][C:3]=1[C:4](=[O:5])[C:34]1[CH:35]=[CH:36][C:31]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:32][CH:33]=1
Reactant: CON(C)C(=O)c1cc(-c2cccc(S(=O)(=O)NC3CC3)c2)cnc1N
Reactant: CC(C)(C)c1ccc([Mg]Br)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(=O)c2cc(-c3cccc(S(=O)(=O)NC4CC4)c3)cnc2N)cc1
Temperature: 25 °C

Procedure:
A solution of 2-amino-5-(3-cyclopropylsulfamoyl-phenyl)-N-methoxy-N-methyl-nicotinamide (Intermediate GA) (0.08 g, 0.21 mmol) in THF (3 ml) is cooled to 0° C. 2M 4-tert Butyl phenyl magnesium bromide in THF (0.32 ml, 0.64 mmol) is added dropwise, and the resulting solution is stirred and allowed to warm to room temperature overnight. The reaction is quenched with 2M HCl (5 ml). The solvent is removed in vacuo and the residue purified by reverse phase column chromatography (Isolute™ C18, 0-100% MeCN in water −0.1% TFA). The solid obtained is dissolved in DCM, washed with 2M NaOH. The solvent is removed in vacuo and the resulting solid is dried in vacuo at 40° C. overnight to yield the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.69 (1H, d), 8.01 (1H, d), 7.97-7.89 (3H, m), 7.78 (1H, d), 7.72-7.67 (5H, m), 7.64 (2H, d), 2.18-2.13 (1H, m), 1.38 (9H, s), 0.47-0.38 (4H, m); MS m/z 450 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N+:12]([O-])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:13]1[CH:14]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:10]=[CH:11][N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2cc[n+]([O-])cc2)cc1
Product: COc1ccc(-c2ccnc(Cl)c2)cc1

Procedure:
A mixture of 4-(4-methoxyphenyl)pyridine 1-oxide (1.68 g) and phosphorus oxychloride (15 mL) is heated under reflux for six hours and concentrated under reduced pressure. Toluene is added and the mixture concentrated under reduced pressure. The residue is dissolved in hot toluene (20 mL) and the organic phase washed with water (twice 10 mL) a saturated aqueous sodium hydrogenocarbonate solution (10 mL), dried over magnesium sulphate and concentrated under reduced pressure to give 1.45 g of 2-chloro-4-(4-methoxyphenyl)pyridine as an orange coloured crystalline material.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH:11]([NH2:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>CS(C)=O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:14][CH:11]([CH3:13])[CH3:12])([O-:10])=[O:9]
Reactant: CC(C)N
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1ccccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 97.8 %

Procedure:
To a solution of 1-fluoro-2-nitrobenzene (0.5 mL, 4.7 mmol) in DMSO (10 mL) is added isopropylamine (0.6 mL, 7.1 mmol), followed by Hunig's base (1.2 mL, 7.1 mmol). The reaction flask is sealed and heated to 80° C. 16 h. The reaction is cooled to room temperature and is poured over ice water and extracted ethyl acetate. The organic layer is washed with water, brine, dried (Na2SO4) and concentrated to afford the title compound (828 mg, 97%) as an orange oil.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+]>C(O)(C)C.O.[Pd]>[C:9]1([C:2]2[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: O=Cc1ccc(-c2ccccc2)s1
Yield: 96.1 %

Procedure:
A mixture of 5-bromo-thiophene-2-carbaldehyde (2.0 g, 10.5 mmol), phenylboronic acid (17 g, 11 mmol), K2CO3 (8.7 g, 62.8 mmol) and 10% Pd/C (0.56 g) in isopropanol/H2O (1:1, 40 mL) was refluxed for 5 h. The reaction mixture was filtered through a pad of Celite. After the isopropanol was removed, the product was collected on a filter, washed with hexane and dried in vacuo to yield the title compound (1.9 g, 82%).