Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:26]2[N:31]=[C:30]3[NH:32][N:33]=[C:34]([C:35]4[CH:40]=[CH:39][N:38]=[C:37]([S:41][CH3:42])[N:36]=4)[C:29]3=[CH:28][N:27]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>ClCCl.CO>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:26]2[N:31]=[C:30]3[NH:32][N:33]=[C:34]([C:35]4[CH:40]=[CH:39][N:38]=[C:37]([S:41]([CH3:42])=[O:9])[N:36]=4)[C:29]3=[CH:28][N:27]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nccc(-c2n[nH]c3nc(NC4CCN(C(=O)OC(C)(C)C)CC4)ncc23)n1
Solvent: ClCCl
Solvent: CO
Product: CS(=O)c1nccc(-c2n[nH]c3nc(NC4CCN(C(=O)OC(C)(C)C)CC4)ncc23)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
m-CPBA (428 mg, 2.4 mmol) was added slowly to a solution of 4-[3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (from Example 12 supra) (550 mg, 1.2 mmol) in a mixture of dichloromethane and methanol (100 mL, 1:1). The reaction mixture was stirred at room temperature for 20 minutes. The solvent was then removed under reduced pressure and the solid was purified by column chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1) to afford 4-[3-(2-methanesulfinyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-piperidine-1-carboxylic acid tert-butyl ester. (Yield 180 mg, 31.5%).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([S:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[N:23](C(=O)C)[CH2:22][CH2:21]4)(=[O:17])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1>O1CCOCC1>[F:30][C:2]([F:1])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([S:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[NH:23][CH2:22][CH2:21]4)(=[O:16])=[O:17])[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: CC(=O)N1CCc2cc(S(=O)(=O)N3CCN(c4ccc(C(F)(F)F)cc4)CC3)ccc21
Solvent: C1COCCO1
Product: O=S(=O)(c1ccc2c(c1)CCN2)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Yield: 75 %

Procedure:
1-{5-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-2,3-dihydro-indol-1-yl}-ethanone was refluxed in 1,4-dioxane (5 mL) and concentrate HCl (2.5 mL) for 2 h. The reaction was then diluted with dichloromethane and washed with 1N HCl, saturated sodium bicarbonate, dried (Na2SO4), filtered and concentrated to provide 5-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-2,3-dihydro-1H-indole (1.03 g, 75%) as an off-white solid. 1H NMR (400 MHz, CDCl3) 7.48-7.20 (m, 4H), 6.88 (d, 2H), 6.60 (d, 1H), 3.70 (t, 2H), 3.36-3.33 (m, 4H), 3.15-3.12 (m, 4H), 3.10 (t, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:8][C:9](=[O:13])[NH:10][C:11]=1[CH3:12])=[O:5])[CH3:2].C[Li].Cl[C:23]([O:25][CH3:26])=[O:24]>O1CCCC1.C(OCC)C>[C:23]([N:8]1[CH:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:11]([CH3:12])[NH:10][C:9]1=[O:13])([O:25][CH3:26])=[O:24]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)C1=C(C)NC(=O)NC1c1ccccc1
Agent: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C)NC(=O)N(C(=O)OC)C1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of ethyl-6-methyl-4-phenyl-3,4-dihydropyrimidine-2(1H)one-5-carboxylate (5.0 mmol) in dry tetrahydrofuran (b 10 mL) under nitrogen at -78° C. was added dropwise 1.5 M methyllithium (11 mmol) in diethyl ether and the reaction mixture allowed to warm to 25° C. After 30 minutes, the reaction mixture was recooled to -78° C. and methyl chloroformate (5.5 mmol) was added. The reaction mixture was allowed to warm to 25° C., then quenched with saturated aqueous ammonium chloride and extracted with methylene chloride. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluted with methanol:methylene chloride (5:95) and recrystallized from acetonitrile to give the title product as a solid (mp=179°-180.5° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][C:20]([CH3:26])([CH3:25])[C:19]=3[CH:27]=2)=[CH:5][CH:4]=1.[OH:28]O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][C:20]([CH3:25])([CH3:26])[C:19]=3[CH:27]=2)=[O:28])=[CH:7][CH:8]=1
Reactant: COc1ccc(SCCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc1
Reactant: OO
Product: COc1ccc(S(=O)CCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-methoxy-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:11])[C:5]([F:10])=[C:6]([CH2:8][OH:9])[CH:7]=1.[O:12]=[C:13]1[NH:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1>>[F:11][C:4]1[CH:3]=[C:2]([N:18]2[CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:14][C:13]2=[O:12])[CH:7]=[C:6]([CH2:8][OH:9])[C:5]=1[F:10]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: OCc1cc(Br)cc(F)c1F
Product: CC(C)(C)OC(=O)N1CCN(c2cc(F)c(F)c(CO)c2)C(=O)C1

Procedure:
tert-butyl 4-(3,4-difluoro-5-(hydroxymethyl)phenyl)-3-oxopiperazine-1-carboxylate was prepared following the procedure in Example 27 (Step ii) using (5-bromo-2,3-difluorophenyl)methanol and tert-butyl 3-oxopiperazine-1-carboxylate.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([C:9]([CH2:14][CH3:15])([C:12]#[N:13])[C:10]#[N:11])[CH3:8]>CCOCC>[CH2:7]([C:9]([CH2:14][CH3:15])([CH2:12][NH2:13])[CH2:10][NH2:11])[CH3:8]
Reactant: CCC(C#N)(C#N)CC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCC(CC)(CN)CN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of LiAlH4 (4.66 g) in dry Et2O (100 mL) was cooled in an ice bath, and a solution of 2,2-diethyl-malononitrile (5.0 g) in Et2O (50 mL) was added dropwise at such a rate that the temperature was kept below 20° C. The mixture was stirred overnight at room temperature, cooled in an ice bath, and quenched by adding H2O (5 mL), 2M aqueous NaOH (10 mL) and again H2O (5 mL). The suspension was filtered, the filter cake was washed with Et2O, and the combined filtrates were evaporated to dryness under reduced pressure to give 5.0 g of a clear, light-yellow liquid. 1H NMR (400 MHz, CDCl3) δ 0.80 (t, J=8 Hz, 6H), 1.08 (br s, 4H), 1.22 (q, J=8 Hz, 4H), 2.52 (s, 4H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]=[C:5]1[CH2:14][CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:7][CH2:6]1.[N+:16]([CH3:19])([O-:18])=[O:17].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1([CH2:19][N+:16]([O-:18])=[O:17])[CH2:6][CH2:7][C:8]2([O:9][CH2:10][CH2:11][O:12]2)[CH2:13][CH2:14]1
Reactant: COC(=O)C=C1CCC2(CC1)OCCO2
Reactant: C[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CC1(C[N+](=O)[O-])CCC2(CC1)OCCO2
Yield: 75.4 %

Procedure:
A solution of (1,4-dioxa-spiro[4.5]dec-8-ylidene)-acetic acid methyl ester (5.50 g, 25.9 mmol) in 14 mL of dry THF was treated by nitromethane (2.10 mL, 38.9 mmol) followed by a 1M solution of tetrabutylammonium fluoride in THF (26.5 mL, 26.5 mmol). The resulting mixture was stirred at reflux for 20 h under nitrogen. After cooling, the mixture was diluted with water and extracted with three portions of ether. The etheral portions were combined, washed with a 10% aqueous solution of potassium hydrogensulfate, dried over anhydrous Na2SO4 and concentrated. The crude was purified by silica gel column chromatography using a 20% EtOAc:hexanes mixture as eluent to afford (8-Nitromethyl-1,4-dioxa-spiro[4.5]dec-8-yl)-acetic acid methyl ester (5.34 g, 75%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[C:10]3[C@@H:9]3[CH2:22][CH2:23][CH2:24][N:8]3[C:7](=[O:25])[C:6]=2[CH:26]=1.[Br:27]N1C(=O)CCC1=O.O>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])=[C:10]3[C@@H:9]3[CH2:22][CH2:23][CH2:24][N:8]3[C:7](=[O:25])[C:6]=2[C:26]=1[Br:27]
Reactant: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1cc(N)ccc1-2
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c-2ccc(N)c1Br

Procedure:
1.5 g (4.2 mmol) of t-butyl (S)-7-amino-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate and 0.783 g (4.4 mmol) of N-bromosuccinimide in 15 ml of dimethylformamide are stirred at room temperature for 45 minutes, subsequently poured into 250 ml of water and extracted three times with chloroform. The chloroform solution is washed three times with water, dried over magnesium sulphate and evaporated. The residue obtained is chromatographed on silica gel using chloroform containing 4% methanol for the elution. Recrystallization of the material obtained from ethyl acetate yields t-butyl (S)-7-amino-8-bromo-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 245°-246°.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[O:12][CH2:13][O:14][C:9]2=[CH:8][C:3]=1[C:4]([O:6]C)=O.Cl[C:16]1[N:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19].CO>CN(C=O)C>[CH2:13]1[O:12][C:10]2[CH:11]=[C:2]3[C:3]([C:4](=[O:6])[N:24]4[CH:23]=[CH:22][CH:21]=[C:17]([C:18]([OH:20])=[O:19])[C:16]4=[N:1]3)=[CH:8][C:9]=2[O:14]1
Reactant: COC(=O)c1cc2c(cc1N)OCO2
Reactant: O=C(O)c1cccnc1Cl
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(O)c1cccn2c(=O)c3cc4c(cc3nc12)OCO4

Procedure:
A mixture of 2.00g (10.4 mmol) of methyl 2-amino-4,5-methylenedioxybenzoate, 1.67g (10.4 mmol) of 2-chloronicotinic acid and 50mg of KI was heated at 170° for 1 hour. The fusion or melt gradually solidified to an orange cake. The solid material was heated in boiling methanol (250 ml) and then filtered to yield 1.60g of crude product, mp. 273°-280° dec. The analytical sample was obtained by recrystallization from DMF, mp. 300°-304° dec.
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14](=[S:16])[NH2:15])=[CH:8][CH:7]=1)([F:4])[F:3].[Cl:17][CH2:18][C:19]([CH2:21]Cl)=O>CC(C)=O>[Cl:17][CH2:18][C:19]1[N:15]=[C:14]([CH:13]=[CH:12][C:9]2[CH:8]=[CH:7][C:6]([S:5][C:2]([F:1])([F:4])[F:3])=[CH:11][CH:10]=2)[S:16][CH:21]=1
Reactant: NC(=S)C=Cc1ccc(SC(F)(F)F)cc1
Reactant: O=C(CCl)CCl
Solvent: CC(C)=O
Product: FC(F)(F)Sc1ccc(C=Cc2nc(CCl)cs2)cc1
Yield: 70.5 %

Procedure:
2.00 g (7.6 mmol) 3-(4-trifluoromethylsulfanyl-phenyl)-acrylthioamide, 2.90 g (22.8 mmol) 1,3-dichloroacetone and 60 ml acetone were stirred at room temperature for 4 days, then refluxed for 4 h. The product was precipitated by addition of water, isolated and dried, and purified on silica. Elution with ethyl acetate/heptane 1:1 yielded 1.80 g (71%) 4-chloromethyl-2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-thiazole as yellow solid, melting at 133-134° C.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[CH2:39][C:40]([OH:42])=O)=[CH:33][CH:32]=2)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.Cl.[NH2:47][CH2:48][C:49]([NH2:51])=[O:50].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(N(CC)CC)C>[C:49]([CH2:48][NH:47][C:40]([CH2:39]/[CH:38]=[CH:37]/[C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C:29]2[C:25]([O:24][C@@H:6]3[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]3[OH:4])=[N:26][NH:27][C:28]=2[CH:43]([CH3:44])[CH3:45])=[CH:32][CH:33]=1)=[O:42])(=[O:50])[NH2:51]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CC(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NCC(N)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(/C=C/CC(=O)NCC(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.7 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole (0.34 g) in N,N-dimethylformamide (1 mL) were added glycinamide hydrochloride (0.12 g), 1-hydroxybenzotriazole (0.09 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.15 g) and triethylamine (0.27 g), and the mixture was stirred at room temperature overnight. The insoluble material was removed by filtration. To the filtrate was added 5 mol/L aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred at room temperature for 1 hour. The insoluble material was removed by filtration, and the filtrate was purified by preparative reverse phase column chromatography (Shiseido CAPCELL PAK UG120 ODS, 5 μm, 120 Å, 20×50 mm, flow rate 30 mL/minute linear gradient, water/acetonitrile=90/10-10/90) to give 4-({4-[(1E)-3-(carbamoylmethylcarbamoyl)prop-1-enyl]phenyl}methyl)-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole (0.03 g). This material was dissolved in methanol (1 mL). To the solution was added 10% palladium-carbon powder (0.01 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give the title compound (0.02 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[OH:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[C:27]([O:30][CH2:31][CH2:32]Br)(=[O:29])[CH3:28].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:28][C:27]([O:30][CH2:31][CH3:32])=[O:29])[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OCCBr
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(Cl)cc1OC1CN(C(=O)OC(C)(C)C)C1
Reaction time: 18 h
Yield: 101.1 %

Procedure:
To 3-(5-Chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (1.5 g, 5.0 mmol) in DMF (20 mL) was added Cs2CO3 (2.1 g, 6.4 mmol), KI (0.84 g, 5.0 mmol) and bromoethyl acetate (0.84 g, 0.55 mL, 5.0 mmol). After 18 h, H2O was added and the mixture extracted with EtOAc (2×). The combined organics were washed with brine and dried. Silica gel chromatography (5-30% EtOAc in hexanes) gave 1.95 g (99%) of the title compound as a clear oil. 1H NMR (CDCl3): 6.91 (dd, J=8.7, 2.4 Hz, 1H), 6.79 (d, J=8.7 Hz, 1H), 6.58 (d, J=2.4 Hz, 1H), 4.91-4.87 (m, 1H), 4.65 (s, 2H), 4.32-4.25 (m, 4H), 4.01 (dd, J=10.5, 4.2 Hz, 2H), 1.44 (s, 9H), 1.30 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9]/[C:10](/[C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)=[N:28]\[OH:29])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C(CC(=O)c1cc(F)cc(F)c1)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1cc(F)cc(F)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 1, step 2, from 3-(4-bromo-phenyl)-1-(3,5-difluoro-phenyl)-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a white foam, MS (EI): m/z=429 ([M]+, 1Br).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19](O)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([O:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Oc1cccc(I)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(I)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
3-Iodophenol (1.00 g, 4.55 mmol) and 1-tert-butoxycarbonyl-4-hydroxypiperidine (1.37 g, 6.82 mmol) were dissolved in toluene (30 mL), and the mixture was stirred at room temperature for 1 hour after adding triphenylphosphine (1.79 g, 6.82 mmol) and a 40% toluene solution of diethyl azodicarboxylate (3.09 mL, 6.82 mmol). The mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give 1-tert-butoxycarbonyl-4-(3-iodophenoxy)piperidine (1.81 g, 98%).
Reaction SMILES: [CH2:1]([O:6][C:7]1[C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:9][NH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:18]SC1C(C2C=NC=CC=2)=NNC=1>>[CH2:1]([O:6][C:7]1[C:8]([C:12]2[CH2:13][N:14]([CH3:18])[CH2:15][CH2:16][CH:17]=2)=[N:9][NH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOc1c[nH]nc1-c1cccnc1
Reactant: CSc1c[nH]nc1-c1cccnc1
Product: CCCCCOc1c[nH]nc1C1=CCCN(C)C1

Procedure:
Compound 32G was converted to the title compound (33G), using the methodology described for the conversion of 21A to 22A (see Scheme 3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[Cl:8].C[Al](C)C.C(O[C:18](=O)[CH:19]([O:26][CH:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:18]([CH:19]([O:26][CH:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: CCOC(=O)C(OC1CCN(C)CC1)c1ccccc1
Agent: C[Al](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CN1CCC(OC(c2ccccc2)c2nc3cc(Cl)c(Cl)cc3[nH]2)CC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A round-bottom flask is charged with 4,5-dichlorobenzene-1,2-diamine (354 mg) and toluene (2 mL); a solution of trimethylaluminum 2M in toluene (1 mL) is added dropwise. The reaction mixture is heated at 60° C. for one hour. A solution of (1-methyl-piperidin-4-yloxy)phenylacetic acid ethyl ester in toluene (1 mL) is added dropwise and heating is pursued for one hour. The reaction mixture is cooled to room-temperature and a solution of sodium hydroxide is added dropwise to pH 10. The slurry is filtered on celite, cake washed with water (4×5 mL) and ethyl acetate (4×5 mL). After decantation, the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue is diluted with glacial acetic acid (3 mL) and the reaction mixture is heated at reflux for one hour. Acetic acid is removed on a rotary evaporator and the residue is purified by chromatography (gradient dichloromethane/methanol/ammonia from 98/2/0 to 95/5/0.5 to give 5,6-dichloro-2-[(1-methylpiperidin-4-yloxy)phenylmethyl]-1H-benzimidazole melting at 221° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[O:19][CH2:20][O:21][CH3:22])C.O>C1COCC1>[CH3:22][O:21][CH2:20][O:19][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][CH2:10][OH:9]
Reactant: CCOC(=O)CCc1ccncc1OCOC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COCOc1cnccc1CCCO
Yield: 99.7 %

Procedure:
Lithium aluminum hydride (6.0 g, 0.16 mmol) is suspended in THF (500 ml), and thereto is added with stirring 3-(3-methoxymethoxypyridin-4-yl)propionic acid ethyl ester (21 g, 89 mmol) obtained in Reference Example 25 at 50° C. over a period of time for 30 minutes. The mixture is heated under reflux for 30 minutes, and thereto are added successively water (6 ml), a 15% sodium hydroxide (6 ml) and water (18 ml) in order to quench the reaction. The reaction solution is filtered to remove the insoluble materials, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: ethyl acetate) to give the title compound (17.5 g) as a colorless oil.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1([CH3:28])[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[C:14]([CH3:21])[CH:13]=2)[C@H:7]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[CH3:5][C:6]1([CH3:28])[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([Cl:3])=[O:17])=[C:14]([CH3:21])[CH:13]=2)[C@H:7]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(N2C(=O)OC(C)(C)[C@@H]2c2ccccc2)ccc1C(=O)O
Solvent: ClCCl
Product: Cc1cc(N2C(=O)OC(C)(C)[C@@H]2c2ccccc2)ccc1C(=O)Cl
Temperature: 40 °C

Procedure:
Thionyl chloride (0.287 mL, 3.93 mmol) was added to a solution of (S)-4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)-2-methylbenzoic acid (0.128 g, 0.393 mmol) in DCM (2.5 mL) and the mixture was heated at 40° C. for 1 hour. The reaction mixture was concentrated to afford (S)-4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)-2-methylbenzoyl chloride as a yellow-orange solid. The yellow-orange solid was dissolved in DCM (2.5 mL) and the solution was cooled to 0° C. 1,5-Naphthyridin-4-amine (commercially available from Astatech Inc., Bristol, Pa.) (0.063 g, 0.433 mmol) and N,N-diisopropylethylamine (0.144 mL, 0.826 mmol) were added and the ice bath was removed. The resulting reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated and the residue was purified using column chromatography on silica gel (RediSep 40 g column, gradient elution with 50-100% EtOAc-hexane) to afford (S)-4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)-2-methyl-N-(1,5-naphthyridin-4-yl)benzamide (0.070 g, 0.155 mmol, 39% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.93 (s, 3H), 1.65 (s, 3H), 2.44 (s, 3H), 5.54 (s, 1H), 7.17-7.51 (m, 6H), 7.61 (d, J=2.15 Hz, 1H), 7.67 (d, J=8.51 Hz, 1H), 7.86 (dd, J=8.56, 4.16 Hz, 1H), 8.44 (dd, J=8.56, 1.61 Hz, 1H), 8.54 (d, J=5.09 Hz, 1H), 8.81-9.09 (m, 2H), 10.31 (s, 1H). m/z (ESI) 453 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][C:8]2[C:9](=[O:15])[NH:10][C:11](=[S:14])[NH:12][CH:13]=2)[CH:4]=[N:3]1.I[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([C:33]([F:36])([F:35])[F:34])[CH:27]=2)=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([O:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][S:14][C:11]3[NH:12][CH:13]=[C:8]([CH2:7][C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)[C:9](=[O:15])[N:10]=3)=[CH:20][CH:21]=2)=[CH:27][C:28]=1[C:33]([F:34])([F:35])[F:36]
Reactant: Cn1cc(Cc2c[nH]c(=S)[nH]c2=O)cn1
Reactant: FC(F)(F)c1cc(Oc2ccc(CCI)cc2)ccc1Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(Cc2c[nH]c(SCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Temperature: 120 °C
Yield: 21.9 %

Procedure:
A mixture of 5-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (98 mg, 0.442 mmol), 4-chloro-3-(trifluoromethyl)phenyl 4-(2-iodoethyl) phenyl ether (157 mg, 0.368 mmol) and DIPEA (0.193 mL, 1.104 mmol) in chloroform (2 mL) was heated with a microwave reactor at 120° C. for 0.5 h. Purification via reverse phase flash chromatography then afforded the title compound (42 mg, 21.91% yield). LCMS: rt=3.63 min, [M+H+]=521