Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[C:5]([CH3:12])=[C:4]2[O:13][CH2:14][O:15][C:3]=12.[CH:16]([O:19][C:20]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:21]=1[C:22](O)=[O:23])([CH3:18])[CH3:17]>>[CH3:1][C:2]1[C:11]2[CH2:10][N:9]([C:22]([C:21]3[CH:25]=[C:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:27]=[CH:28][C:20]=3[O:19][CH:16]([CH3:18])[CH3:17])=[O:23])[CH2:8][CH2:7][C:6]=2[C:5]([CH3:12])=[C:4]2[O:13][CH2:14][O:15][C:3]=12
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: Cc1c2c(c(C)c3c1OCO3)CNCC2
Product: Cc1c2c(c(C)c3c1OCO3)CN(C(=O)c1cc(S(C)(=O)=O)ccc1OC(C)C)CC2

Procedure:
Prepared in analogy to example 1.1 from 4,9-dimethyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1). MS (m/e): 446.3 (M+H+).
Reaction SMILES: C(OC[C@H]1OC(OC)(CO)[C@@H](O)C1)(=O)C1C=CC=CC=1.C(Cl)(=O)C1C=CC=CC=1.[C:30]([O:38][CH2:39][C@@:40]1([O:47][C@H:46]([CH2:48][O:49][C:50](=[O:57])[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH2:45][C@@H:43]1[OH:44])[O:41][CH3:42])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(OC[C@]1(O[C@H](COC(=O)C2C=CC=CC=2)C[C@@H]1O)OC)(=O)C1C=CC=CC=1>ClCCl.N1C=CC=CC=1>[C:30]([O:38][CH2:39][C:40]1([O:47][C@H:46]([CH2:48][O:49][C:50](=[O:57])[C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH2:45][C@@H:43]1[OH:44])[O:41][CH3:42])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CO[C@@]1(COC(=O)c2ccccc2)O[C@H](COC(=O)c2ccccc2)C[C@@H]1O
Agent: COC1(CO)O[C@H](COC(=O)c2ccccc2)C[C@@H]1O
Agent: CO[C@]1(COC(=O)c2ccccc2)O[C@H](COC(=O)c2ccccc2)C[C@@H]1O
Solvent: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC1(COC(=O)c2ccccc2)O[C@H](COC(=O)c2ccccc2)C[C@@H]1O
Temperature: -40 °C
Reaction time: 5 h

Procedure:
To about 1 g of crude methyl 6-O-benzoyl-4-deoxy-α,β-D-fructofuranoside (prepared as described in Example 1, Step 6) in dichloromethane (25 mL) containing 4 Å molecular sieves and pyridine (0.28 mL) and maintained at -40° C., benzoyl chloride (0.4 mL) was added and the solution was stirred between -30° to -20° C. for 5 h. The reaction mixture was filtered, diluted with dichloromethane and washed with ice cold 0.5M HCl, sat. aqueous NaHCO3 solution, dried over magnesium sulfate and evaporated. Final purification was effected by chromatography on a column of silica gel. The yields of the separated anomers were 0.582 g of methyl 4-deoxy-1,6-di-O-benzoyl-α-D-fructofuranoside and 0.200 g of methyl 4-deoxy-1,6-di-O-benzoyl-β-D-fructofuranoside.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[O:11]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12]1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])O.[Na+]>C(COC)OC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:11]1[CH:15]=[CH:14][C:13]([C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=2[OH:10])=[CH:12]1
Reactant: OB(O)c1ccoc1
Reactant: Cc1cc(C)c(O)c(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: O
Solvent: COCCOC
Product: Cc1cc(C)c(O)c(-c2ccoc2)c1
Reaction time: 1 h
Yield: 53.7 %

Procedure:
2-Bromo-4,6-dimethylphenol (1.8 g, 8.9 mmol) was dissolved in dimethoxyethane/water (2:1). Furan-3-ylboronic acid (1 g, 8.9 mmol), Pd(dppf)Cl2 (0.36 g, 0.45 mmol) and sodium carbonate (3.7 g, 45 mmol) were added thereto, followed by stirring for 1 hour under reflux. After the completion of the reaction, the reaction mixture was added with a saturated sodium hydrogen carbonate aqueous solution, and extracted with ethyl acetate. The obtained organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 2-(furan-3-yl)-4,6-dimethylphenol (0.9 g, 54%).
Reaction SMILES: [CH2:1]([S:4][C:5]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6][CH:7]=[C:8](N(C)C)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:2]=[CH2:3].Cl.C([OH:25])C>>[CH2:1]([S:4][C:5]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6][CH:7]=[C:8]([OH:25])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:2]=[CH2:3]
Reactant: C=CCSC(=CC=C(C(=O)OCC)N(C)C)C(=O)OCC
Reactant: CCO
Agent: Cl
Product: C=CCSC(=CC=C(O)C(=O)OCC)C(=O)OCC
Temperature: 20 °C
Reaction time: 0.05 h

Procedure:
The procedure is as in Example 2, starting with diethyl 5-allylthio-2-dimethylamino-2,4-hexadienedioate (5.1 g) and 1N aqueous hydrochloric acid solution (24.4 cc) in ethanol (24.4 cc). The mixture is heated to boiling for 3 minutes, and then cooled to a temperature in the region of 20° C. After purification by chromatography on a silica column with a mixture of cyclohexane and ethyl acetate (75:25 by volume) as eluent, diethyl 5-allylthio-2-hydroxy-2,4-hexadienedioate (2.3 g) is obtained in the form of a yellow oil [Rf=0.2; thin layer chromatography on silica gel; eluent: cyclohexane/ethyl acetate (75:25 by volume)].
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=[N:3]1.[CH:10](=[O:15])[CH2:11][CH2:12][CH:13]=[CH2:14].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH3:1][N:2]1[C:6]([CH:10]([OH:15])[CH2:11][CH2:12][CH:13]=[CH2:14])=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=[N:3]1
Reactant: Cn1cc([N+](=O)[O-])cn1
Reactant: C=CCCC=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCCC(O)c1c([N+](=O)[O-])cnn1C
Temperature: -40 °C
Yield: 35.5 %

Procedure:
A solution of 1-methyl-4-nitro-1H-pyrazole (9.7 g, 76.7 mmol) and 4-pentenal (10 g, 84.4 mmol) in dry THF (250 mL) was cooled to −78° C. and stirred under nitrogen. A solution of LiHMDS (1 M in THF, 192 mL, 191.7 mmol) was added dropwise over a period of 3 hr. The reaction mixture was allowed to warm and to −40° C. and stirred for 2 hr, quenched by dropwise addition of saturated ammonium chloride solution (100 mL), warmed to room temperature and diluted with EtOAc (200 mL). The organic layer was washed with saturated ammonium chloride solution (50 mL), separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel chromatography (0-100% EtOAc/DCM) followed by silica gel chromatography (0-100% EtOAc/isohexane) to gave 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)pent-4-en-1-ol as a pale yellow oil (5.75 g, 36%). 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 5.85-5.78 (m, 1H), 5.32-5.26 (m, 1H), 5.12-5.04 (m, 2H), 3.98 (s, 3H), 3.45 (d, J=8.7 Hz, 1H), 2.92-2.09 (m, 3H), 1.90-1.86 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11](=[O:15])[C:12]([O-:14])=O.[K+].[CH3:17][C@H:18]1[NH:23][CH2:22][CH2:21][N:20]([C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:19]1>>[N:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:24]([N:20]1[CH2:21][CH2:22][N:23]([C:12](=[O:14])[C:11]([C:7]2[C:6]3[C:10](=[C:2]([Br:1])[N:3]=[CH:4][CH:5]=3)[NH:9][CH:8]=2)=[O:15])[C@H:18]([CH3:17])[CH2:19]1)=[O:31]
Reactant: O=C([O-])C(=O)c1c[nH]c2c(Br)nccc12
Reactant: C[C@@H]1CN(C(=O)c2ccccn2)CCN1
Agent: [K+]
Product: C[C@@H]1CN(C(=O)c2ccccn2)CCN1C(=O)C(=O)c1c[nH]c2c(Br)nccc12

Procedure:
Precursor 5m, (R)-1-picolinoyl-3-methyl-4-[(7-bromo-6-azaindol-3-yl)-oxoacetyl]piperazine was prepared by the same method as Precursor 5a starting from Potassium (7-bromo-6-azaindol-3-yl)oxoacetate, Precursor 4g, and (R)-3-methyl-1-picolinoyl-piperazine. MS m/z: (M+H)+ Calc'd for C20H19BrN5O3: 456.07; Found 456.11. HPLC retention time: 1.12 minutes (column A).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]2[N:17]=[C:16]([NH:18][CH3:19])[C:15]([C:20]([F:23])([F:22])[F:21])=[CH:14][N:13]=2)[C:8]([O:24][CH3:25])=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C(O[N:34]1N=N[C:36]2C=CC=[N:40][C:35]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.ONC(=N)C>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[C:3]([C:4]2[O:5][N:40]=[C:35]([CH3:36])[N:34]=2)=[CH:7][C:8]([O:24][CH3:25])=[C:9]([NH:11][C:12]2[N:17]=[C:16]([NH:18][CH3:19])[C:15]([C:20]([F:21])([F:22])[F:23])=[CH:14][N:13]=2)[CH:10]=1
Reactant: CNc1nc(Nc2cc(F)c(C(=O)O)cc2OC)ncc1C(F)(F)F
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CC(=N)NO
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nc(Nc2cc(F)c(-c3nc(C)no3)cc2OC)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 14.3 %

Procedure:
A mixture of 2-fluoro-5-methoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)benzoic acid (0.1 g, 0.28 mmol), HATU (127 mg, 0.33 mmol) and DIPEA (60 uL, 6.33 mmol) in DMF (2 mL) was stirred at room temperature for 5 min. N-Hydroxyacetimidamide (25 mg, 0.33 mmol) was added and the mixture was stirred at room temperature for 30 min followed by 100° C. for 18 h. Additional HATU (127 mg, 0.33 mmol), DIPEA (60 uL, 6.33 mmol) and N-hydroxyacetimidamide (25 mg, 0.33 mmol) were added and the reaction was heated at 100° C. for a further 8 h. The mixture was cooled and diluted with ethyl acetate (10 mL). The organic layer was washed with saturated aqueous NaHCO3 (2×5 mL) and the combined aqueous washes were extracted with further ethyl acetate (2×10 mL). The combined organics were passed through a phase separation cartridge and the solvent removed under reduced pressure. Purification of the residue via silica gel column chromatography (0-100% ethyl acetate/isohexane) afforded N2-(5-fluoro-2-methoxy-4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine as a white solid (16 mg, 15%). LCMS (10 cm_ESCI_Formic_MeCN): [MH+]=399 at 4.51 min. 1H NMR (400 MHz, CDCl3): δ 8.67 (d, J=13, 1H); 8.23 (s, 1H); 8.01 (s, 1H); 7.48 (d, J=6.1, 1H); 5.33 (s, 1H); 4.00 (s, 3H); 3.16 (d, J=4.7, 3H); 2.51-2.44 (m, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[NH:5][C:4]=2[CH:3]1[C:16]1C=CC=C[CH:17]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:45]#[C:46][C:47]1[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=1>C1(C)C=CC=CC=1>[Cl:53][C:50]1[CH:51]=[CH:52][C:47]([C:46]#[C:45][N:5]2[C:6]3[C:11](=[CH:10][C:9]([CH3:15])=[CH:8][CH:7]=3)[C:12]3[CH2:13][CH2:14][N:2]([CH3:1])[CH:3]([CH2:16][CH3:17])[C:4]2=3)=[CH:48][CH:49]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)C3c1ccccc1
Reactant: Clc1ccc(C#CBr)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Product: CCC1c2c(c3cc(C)ccc3n2C#Cc2ccc(Cl)cc2)CCN1C
Temperature: 80 °C

Procedure:
2,6-dimethyl-1-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (276 mg, 1 mmol) was mixed with CuSO4.5H2O (50 mg, 0.2 mmol), 1,10-phenanthroline (72 mg, 0.4 mmol), K3PO4 (425 mg, 2 mmol) and 1-(bromoethynyl)-4-chlorobenzene (237 mg, 1.1 mmol) in toluene (8-10 ml). The reaction mixture was flushed with nitrogen and heated at 80° C. for 16 h. The reaction mixture was filtered through Celite, and the Celite bed was rinsed with dichloromethane. Combined organic layer was concentrated under reduced pressure and the residue was purified by silica gel chromatography (100-200 mesh) eluting with 60-80% ethyl acetate in hexane to obtain 9-((4-chlorophenyl)ethynyl)-1-ethyl-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole as brown semi solid (90 mg). The product was dissolved in 50% aqueous TFA:acetonitrile (1:1) and stirred at 50° C. to obtain the title compound as TFA salt (off white solid). 1H NMR (CD300D) TFA SALT 7.65 (d, 1H), 7.45-7.3 (m, 4H), 7.2 (m, 3H), 7.05 (m, 2H), 6.7 (d, 2H), 6.25 (s, 1H), 4.25 (d, 1H), 4.15 (d, 1H), 3.4 (m, 2H), 3.2 (m, 2H), 2.9 (bs, 3), 2.4 (s, 3H).
Reaction SMILES: CC1(C)[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])O1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18]/[N:19]=[C:20](\[CH3:23])/[CH:21]=O)=[CH:14][CH:13]=1>C1(C)C=CC=CC=1.C(O)(=O)C.N1CCCCC1>[F:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[C:4](=[O:9])[C:5]([C:6]([OH:7])=[O:8])=[CH:21][C:20]([CH3:23])=[N:19]2)=[CH:16][CH:17]=1
Reactant: C/C(C=O)=N\Nc1ccc(F)cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 57.9 %

Procedure:
A suspension of 2,2-dimethyl-1,3-dioxane-4,6-dione (0.71 g, 4.93 mmol) and (E)-2-(2-(4-fluorophenyl)hydrazono)propanal (0.889 g, 4.934 mmol) in toluene (20 mL) was treated with acetic acid (5 drops) and with piperidine (5 drops). The reaction mixture was then stirred at room temp for 17 hours. The precipitated condensation/cyclization product was filtered off and thoroughly washed with light petroleum to afford 0.709 g (58%) of the desired product. LRMS (ESI pos) m/e 249.1 (M+1). 1H-NMR (400 MHz, CD3OD) δ 7.96 (s, 1H), 7.61 (m, 2H), 7.24 (t, 2H), 2.45 (s, 3H); 19F NMR (376 MHz, CD3OD) δ −115.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[CH3:16])[N:3]=1.[NH2:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][N:22]=[CH:21]2>>[Cl:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[CH3:16])[N:3]=[C:2]([NH:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][N:22]=[CH:21]3)[N:7]=1
Reactant: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Cl)n1
Reactant: Nc1ccc2[nH]ncc2c1
Product: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Nc2ccc3[nH]ncc3c2)n1
Yield: 7 %

Procedure:
The reaction of 2,4-dichloro-6-(5-chloro-2-methyl-phenyl)-[1,3,5]triazine and 5-aminoindazole using the method described in Example 37 provided the title compound (7% yield). 1H NMR (DMSO-d6) 12.95 (s, 1H), 9.52 (br s, 1H), 8.25 (s, 1H), 7.94 (s, 1H), 7.75 (m, 1H), 7.52 (m, 2H), 7.35-7.45 (m, 3H), 7.30 (m, 1H), 7.12)br s, 2H), 2.50 (s, 3H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]=[C:6]2[C:12]([I:13])=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[Cl:3][C:4]1[N:5]=[C:6]2[C:12]([I:13])=[CH:11][N:10]([S:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:22])=[O:21])[C:7]2=[N:8][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Clc1cnc2[nH]cc(I)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1cc(I)c2nc(Cl)cnc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
Sodium hydride (60% in mineral oil, 404 mg, 10.09 mmol) was added to an ice-cold solution of EXAMPLE 33A (2.35 g, 8.41 mmol) in anhydrous DMF (20 mL) under nitrogen. The reaction mixture was stirred at 0° C. for 30 minutes and benzenesulfonyl chloride (1.19 mL, 9.25 mmol) was then added. The ice-bath was removed and the mixture was stirred at room temperature overnight. This reaction was quenched with the addition of 50 mL of water. An off white solid material was collected by filtration, washed with water and hexane, and dried to give 3.38 g of the title product. Yield: 96%. MS (DCI+) m/z 280 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1.[NH2:16][C:17]1[C:22]2[CH:23]=[C:24]([CH2:26][CH:27]([NH:37]S(C3C=CC(OC4CCOCC4)=CC=3)(=O)=O)[C:28]([N:30]3[CH2:35][CH2:34][CH:33]([CH3:36])[CH2:32][CH2:31]3)=[O:29])[S:25][C:21]=2[CH:20]=[CH:19][N:18]=1>>[NH2:16][C:17]1[C:22]2[CH:23]=[C:24]([CH2:26][CH:27]([NH:37][S:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][CH:8]=3)(=[O:14])=[O:13])[C:28]([N:30]3[CH2:31][CH2:32][CH:33]([CH3:36])[CH2:34][CH2:35]3)=[O:29])[S:25][C:21]=2[CH:20]=[CH:19][N:18]=1
Reactant: COCCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1CCN(C(=O)C(Cc2cc3c(N)nccc3s2)NS(=O)(=O)c2ccc(OC3CCOCC3)cc2)CC1
Product: COCCOc1ccc(S(=O)(=O)NC(Cc2cc3c(N)nccc3s2)C(=O)N2CCC(C)CC2)cc1

Procedure:
This compound was prepared from 0.6 mmol 4-(2-methoxy-ethoxy)-benzenesulfonyl chloride and 210 mg (0.5 mmol) of 30a using the procedure described for 58c . Yield: 30 mg (white crystals), m.p. 210° C. (decomp.), EI-MS: 532 (M+).
Reaction SMILES: CCCCC.[H-].[Na+].[Br:8][C:9]1[N:14]=[C:13]2[CH2:15][C:16](=[O:18])[NH:17][C:12]2=[CH:11][CH:10]=1.Cl[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:22][N+:21]=1[O-:33]>CN(C=O)C>[Br:8][C:9]1[N:14]=[C:13]2[C:15]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)=[CH:22][N+:21]=3[O-:33])=[C:16]([OH:18])[NH:17][C:12]2=[CH:11][CH:10]=1
Reactant: [O-][n+]1cc(CN2CCOCC2)ccc1Cl
Reactant: O=C1Cc2nc(Br)ccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCC
Product: [O-][n+]1cc(CN2CCOCC2)ccc1-c1c(O)[nH]c2ccc(Br)nc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of previously pentane-washed sodium hydride on mineral oil (75 mg, 1.88 mmol) in DMF (2 mL) was added slowly 5-bromo-1H-pyrrolo[3,2-b]pyridin-2(3H)-one (300 mg, 1.41 mmol). The resulting green solution was further stirred for 10 minutes at RT. Then a solution of 215 mg (0.939 mmol) of 2-chloro-5-(morpholinomethyl)-pyridine 1-oxide prepared like in example 2.2 in DMF was added and the resulting mixture was heated to 130° C. and stirred for further 30 min. The reaction was cooled to RT and all volatiles were removed under reduced pressure. The residue was taken up in 2 M HCl (60 mL) and washed with ethyl acetate. The aqueous layer was carefully saturated with solid NaHCO3 and extracted with ethyl acetate. The combined organic phases were dried over MgSO4, filtered, and evaporated yielding the titled compound as a red oil.
Reaction SMILES: [CH:1]([OH:3])=[O:2].C(OC(=O)C)(=O)C.[CH2:11]([O:13][C:14]1[N:23]=[C:22]2[C:17]([C:18](=[O:30])[C:19]([C:27]([OH:29])=[O:28])=[CH:20][N:21]2[CH:24](O)[CH3:25])=[CH:16][CH:15]=1)[CH3:12]>N1C=CC=CC=1>[CH2:11]([O:13][C:14]1[N:23]=[C:22]2[C:17]([C:18](=[O:30])[C:19]([C:27]([OH:29])=[O:28])=[CH:20][N:21]2[CH2:24][CH2:25][O:2][CH:1]=[O:3])=[CH:16][CH:15]=1)[CH3:12]
Reactant: O=CO
Reactant: CCOc1ccc2c(=O)c(C(=O)O)cn(C(C)O)c2n1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CCOc1ccc2c(=O)c(C(=O)O)cn(CCOC=O)c2n1
Reaction time: 0.75 h

Procedure:
Formic acid (1 ml) was added to acetic anhydride (2 ml) which was cooled to 0°. The mixture was warmed to 50° for 15 minutes, cooled to 0° and added to a suspension of 7-ethoxy-1,4-dihydro-1-hydroxyethyl-4-oxo-1,8-naphthyridine-3-carboxylic acid (0.78 g) in dry pyridine (10 ml). The mixture was stirred at 0° for 45 minutes and then for 1 hour at room temperature. The solid was collected and washed with water and dried, m.p. 208.5°-210° (d). (71%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[S:25])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])[CH2:10][CH2:9]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[N:11]1([C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:22])[F:23])=[S:25])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=S)c2ccccc2C(F)(F)F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccccc1C(=S)N1CCNCC1
Yield: 95.5 %

Procedure:
A solution of 4-(2-trifluoromethylthiobenzoyl)piperazine-1-carboxylic acid tert-butyl ester (2.1 g, 5.61 mmol) in dichloromethane and trifluoroacetic acid (30 mL, 2:1) was stirred at ambient temperature overnight, the solvents were removed by evaporation. The residue was dissolved in ethyl acetate, and washed with aqueous saturated NaHCO3 and brine, dried over anhydrous Na2SO4 and concentrated to give piperazin-1-yl-(2-trifluoromethylphenyl)methanethione (1.47 g, 5.36 mmol) which was used directly for next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=[O:15])[N:6]([CH3:14])[C:7](=[O:13])[NH:8]2.[H-].[Na+].Br[CH2:19][CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22]>CN(C)C=O.O>[CH2:4]([CH:3]([CH2:12][CH3:11])[CH2:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=[O:15])[N:6]([CH3:14])[C:7](=[O:13])[N:8]2[CH2:19][CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:5]
Reactant: COc1cccc2[nH]c(=O)n(C)c(=O)c12
Reactant: CCC(CC)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)COc1cccc2c1c(=O)n(C)c(=O)n2CC(CC)CC
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 33.2 %

Procedure:
To a solution of 5-methoxy-3-methylquinazoline-2,4(1H,3H)-dione (47 mg, 0.228 mmol) [example 5] in N,N-dimethylformamide (1 ml) was added sodium hydride (8.6 mg, 0.342 mmol). The mixture was stirred at 80° C. for 15 min and 1-bromo-2-ethylbutane (0.064 ml, 0.0753 mmol) was added. The resulting mixture was stirred at 80° C. for 18 h and diluted with water. The aqueous solution was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography eluting 50% ethyl acetate/n-hexane to afford 20 mg (32%) of 1-(2-ethylbutyl)-5-hydroxy-3-methyl-2,4(1H,3H)-dione (A) and 9 mg (11%) of 5-(2-ethylbutoxy)-1-(2-ethylbutyl)-3-methylquinazoline-2,4(1H,3H)-dione (B).
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12](=[O:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([CH3:21])[CH:14]=2)[CH2:8][CH2:7]1)C.[Li+].[OH-].[Li+].[Cl-]>C1COCC1.CO>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]([CH:9]2[CH2:10][CH2:11][N:6]([CH2:5][C:4]([OH:23])=[O:3])[CH2:7][CH2:8]2)=[O:22])=[CH:14][C:15]=1[CH3:21]
Reactant: CCOC(=O)CN1CCC(C(=O)c2ccc(OC)c(C)c2)CC1
Agent: [Cl-]
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1C
Temperature: -78 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
To a stirred solution of [4-(4-methoxy-3-methyl-benzoyl)-piperidin-1-yl]-acetic acid ethyl ester (0.19 g, 0.60 mmol) in 6 mL of THF and 2 mL of MeOH, was added LiOH (0.13 g, 3.0 mmol in 3 mL of water). After 1.5 hours at ambient temperature the solvent was removed in vacuo, then diluted with 20 mL of water (pH 14). The residue was treated with 12 mL of 1N HCl (pH 4), frozen at −78° C. then lyophilized for 24 hours to yield the title product (0.17 g, 0.54 mmol, 90%) with LiCl salt. MS (ESI) m/z 291.8 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) t 1.58 min.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14](OCC)=[O:15])=[CH:5][CH:4]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][OH:15])=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cnoc1-c1ccc(SC)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: CSc1ccc(-c2oncc2CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a solution of ethyl 5-(4-methylthiophenyl)isoxazole-4-carboxylate (10.0 g) in tetrahydrofuran (100 ml) was gently added diisobutylaluminum hydride (0.95 M hexane solution, 92 ml) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained crystals were recrystallized from ethyl acetate-isopropyl ether to give 5-(4-methylthiophenyl)-4-isoxazolylmethanol (7.50 g, yield 89%) as a colorless prism. melting point: 102–103° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[C:25]1([OH:35])[C:34]2[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=2[CH:28]=[CH:27][CH:26]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:35][C:25]3[C:34]4[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=4[CH:28]=[CH:27][CH:26]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: Oc1cccc2c1CCCC2
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: CC(NC(=O)c1coc(Oc2cccc3c2CCCC3)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 89.2 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 5,6,7,8-tetrahydro-naphthalen-1-ol (38.7 mg, 0.26 mmol) to give the title compound (57 mg, 89%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).