Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[CH3:12][C:13]1[S:14][C:15]2[CH:22]=[C:21](S(O)(=O)=O)[CH:20]=[CH:19][C:16]=2[N+:17]=1[CH3:18].Cl[C:28](=[O:36])[CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33]>N1C=CC=CC=1>[CH3:35][O:34][C:32]([CH2:31][CH2:30][CH2:29][C:28](=[O:36])[CH:12]=[C:13]1[N:17]([CH3:18])[C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[S:14]1)=[O:33]
Reactant: COC(=O)CCCC(=O)Cl
Reactant: Cc1sc2cc(S(=O)(=O)O)ccc2[n+]1C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: c1ccncc1
Product: COC(=O)CCCC(=O)C=C1Sc2ccccc2N1C
Temperature: 55 °C

Procedure:
To 1.7 g of 2,3-dimethyl-6-sulfobenzothiazolium tosylate in 20 mL of pyridine at room temperature is added 1 mL of methyl 5-chloro-5-oxovalerate. The mixture is heated at 50-60° C. for 3 hours. The pyridine solvent is removed under reduced pressure, and the reaction is worked up with chloroform and brine, and purified by silica gel column to yield 0.5 g of 2-(5-methoxycarbonyl-2-oxopentylidene)-3-methyl-3H-benzothiazole. A mixture of 0.45 g of this benzothiazole and 0.45 g of phosphorous oxychloride in 5 mL of dichloroethane is heated at reflux for 2 hours to generate 2-(2-chloro-2-methoxycarbonylpropylvinyl)-3-methylbenzothiazolium chloride. The volatile components are evaporated and the crude chloride is used without further purification. The crude chloride and 0.5 g of Compound 12 is stirred in 5 mL of dichloroethane in the presence of 0.45 mL of triethylamine for 2 hours. The volatile components are removed under reduced pressure, and the residue is dissolved in 5 mL of methanol and added dropwise to a solution of 4.5 g of sodium iodide in 30 mL water. The sticky solid is purified by HPLC to yield Compound 37.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:12](Cl)(=O)C>CO>[CH3:12][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([OH:1])[C:3]=1[CH3:11]
Reactant: CC(=O)Cl
Reactant: Cc1c(O)cccc1C(=O)O
Solvent: CO
Product: COC(=O)c1cccc(O)c1C
Temperature: 0 °C
Yield: 91 %

Procedure:
3-Hydroxy-2-methylbenzoic acid (0.5 g, 3.2 mmol) was dissolved in HPLC grade methanol (5 ml) and cooled to 0° C. under nitrogen. Acetyl chloride (5 ml) was added dropwise. Once the addition was complete, the ice bath was removed and the reaction mixture allowed warming to room temperature over a period of 18 hours. The reaction was complete by tlc (Rf=0.5, 1:1 ethyl acetate/hexanes) and quenched with saturated sodium bicarbonate. The reaction mixture was concentrated, diluted with dichloromethane and water and the layers separated. The aqueous layer was extracted with dichloromethane (3×). The organic layers were combined, dried (MgSO4), filtered and concentrated in vacuo, which afforded 0.5 g (91%) of 3-hydroxy-2-methylbenzoic acid methyl ester as a solid.
Reaction SMILES: [CH:1]([Cl:4])(Cl)Cl.[CH2:5]=[C:6]1[C@H:12]([CH3:13])[O:11]C(O)[CH2:8][C@@H:7]1[NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[CH2:5]=[C:6]1[C@H:12]([CH3:13])[O:11][CH:1]([Cl:4])[CH2:8][C@@H:7]1[NH:14][C:15](=[O:20])[C:16]([F:18])([F:19])[F:17]
Reactant: C=C1[C@@H](NC(=O)C(F)(F)F)CC(O)O[C@H]1C
Reactant: ClC(Cl)Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: C=C1[C@@H](NC(=O)C(F)(F)F)CC(Cl)O[C@H]1C
Reaction time: 8 h
Yield: 90 %

Procedure:
A solution of 0.51 g (2 mmol) of the intermediate VIII in 10 ml of acetic acid and 40 ml of water was heated at 100° C. for two hours, then evaporated to dryness to give 2,3,4,6-tetradeoxy-4-C-methylene-3-trifluoroacetamido-L-threo-hexopyranose (IX, 0.47 g, 99%) as a white solid: m.p. 168°-170° C., [α]D20° -160° (c=0.5, CHCl3). Treatment of IX (0.36 g, 1.5 mmol) in 25 ml of dry methylene dichloride with 4 ml of trifluoroacetic anhydride for 2 hours at 0° C. and 1 hour at 20° C. gave, after evaporation, the 1-0-trifluoroacetate (X), which was directly used for the preparation of the corresponding 1-chloro-derivative by treatment with dry hydrogen chloride in anhydrous diethyl ether at 0° C. After standing at 0° C. overnight, the reaction mixture was evaporated to dryness to give 2,3,4,6-tetradeoxy-4-C-methylene-3-trifluoroacetamido-L-threo-hexopyranosyl chloride (III-A, 0.35 g, 90%), suitable for the subsequent coupling reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[C:4]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](=[O:15])[CH3:14])[CH:8]=1)=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34]>C1COCC1.CN1C(=O)N(C)CCC1.C(OCC)(=O)C>[CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[C:4]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](=[O:15])[CH2:14][CH2:32][C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[CH:8]=1)=[O:5]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CC(=O)c1cccc(OC(=O)c2c(C)cccc2C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN1CCCN(C)C1=O
Product: Cc1cccc(C)c1C(=O)Oc1cccc(C(=O)CCC(=O)OCc2ccccc2)c1
Temperature: -65 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 3-Acetylphenyl 2,6-dimethylbenzoate (Step B, 2.90 g, 10.8 mmol) in dry THF (50 ml) and DMPU (17 ml) was added a solution of lithium bis(trimethylsilyl) amide (1.0M, 11.89 ml) at −65° C. under argon. After 10 minutes of stirring at −65° C., benzyl bromoacetate (3.72 g, 16.24 mmol) was added rapidly. The reaction mixture was stirred for an additional 10 minutes and then warmed to room temperature for 4 hours. The crude mixture was taken in ethyl acetate and washed with water and brine. The aqueous layer was extracted one more time with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (hex: ethyl acetate, 4:1) to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]3[O:15][C:14]([NH:16][S:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)(=[O:19])=[O:18])=[N:13][N:12]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:27][C:28](OC(C)=O)=[O:29]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[F:26][C:23]1[CH:22]=[CH:21][C:20]([S:17]([NH:16][C:14]2[O:15][C:11]([C:9]3[CH:8]=[CH:7][C:5]4[N:6]=[C:2]([NH:1][C:28](=[O:29])[CH3:27])[S:3][C:4]=4[CH:10]=3)=[N:12][N:13]=2)(=[O:18])=[O:19])=[CH:25][CH:24]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc2ccc(-c3nnc(NS(=O)(=O)c4ccc(F)cc4)o3)cc2s1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2ccc(-c3nnc(NS(=O)(=O)c4ccc(F)cc4)o3)cc2s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of N-(5-(2-aminobenzo[d]thiazol-6-yl)-1,3,4-oxadiazol-2-yl)-4-fluorobenzenesulfonamide, pyridine, Ac2O, and DMAP, was stirred at rt for 4 h. The product was isolated following standard procedures. MS (ESI pos. ion) m/z: calk's for C17H12FN5O4S2: 433.0. found: 434.0 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.[CH2:13]([NH:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:14]([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].C(I)C.C(O)C.[O-]CC.[Na+].Cl>O1CCCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6]([OH:8])=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:18]([CH2:13][C:14]([CH3:15])([CH3:16])[CH3:17])[C:9]2=[O:10])=[CH:11][CH:12]=1
Reactant: CCOC(=O)CNCC(C)(C)C
Reactant: O=C1OC(=O)c2cc(F)ccc21
Agent: CC[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: CCI
Product: CCOC(=O)c1c(O)c2ccc(F)cc2c(=O)n1CC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.9 %

Procedure:
A solution of 4-fluorophthalic anhydride (8.31 g, 50 mmol) and ethyl 2-(neopentylamino)acetate (10.40 g, 60 mmol) in tetrahydrofuran (50 ml) was stirred at room temperature for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (50 ml), and potassium carbonate (6.91 g, 50 mmol) and ethyl iodide (4.8 ml, 60 mmol) were added. The mixture was stirred at room temperature for 3 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethanol (50 ml) and 20% sodium ethoxide ethanol solution (34.04 g, 100 mmol) was added. The mixture was stirred at room temperature for 1 h. The reaction mixture was poured into 1N hydrochloric acid (150 ml) and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue, was purified by silica gel column chromatography and the component eluted earlier was concentrated to give ethyl 7-fluoro-4-hydroxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (5.12 g, 31.9%) as crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[Ca+2].[Cl-]>C(O)C>[N:13]1([CH2:12][CH2:11][S:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: O=[N+]([O-])c1ccc(SCCn2cncn2)cc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: Nc1ccc(SCCn2cncn2)cc1
Temperature: 25 °C
Yield: 83 %

Procedure:
To 1-[2-[(4-nitrophenyl)sulfanyl]ethyl]-1,2,4-triazole (1.3 g) was added 85% ethanol solution (38 ml), calcium chloride (0.28 g) and reduced iron (1.4 g) were added to the mixture, and the mixture was heated to reflux for 3 hours. After cooling to room temperature, the mixture was filtered with Celite, and washed with ethyl acetate. The solvent was removed under reduced pressure, and the obtained residue was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 4-[[2-(1,2,4-triazol-1-yl)ethyl]sulfanyl]phenylamine (0.95 g).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12]1>C(OCC)(=O)C.N1C(C)=CC=CC=1C>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CCC(=O)O1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Product: O=C(O)CCC(=O)Nc1ccc([N+](=O)[O-])cc1

Procedure:
p-Nitroaniline (PNA) (0.1 g, 0.724 mmol) and succinic anhydride (SA) (0.29 g, 2.898 mmol) were dissolved in ethyl acetate (EtOAc) (4 mL). Slight warming was required to dissolve both PNA and SA. The reaction was started by adding 2 drops of 2,6-lutidine. The reaction was held at a temperature of 70° C. overnight (19 hrs). The reaction vessel was placed in the refrigerator and the cold EtOAc was decanted from the solid reaction products. The reaction products were then rinsed with cold EtOAc (1 mL). The crude product, p-nitrosuccinanilic acid, was obtained by removing some reaction co-products using thin layer chromatography (TLC). The solid reaction products were dissolved in N,N-dimethylformamide (DMF) and spotted on Kieselgel 60 F254 HPTLC plates containing a concentration zone (EM Science No. 13728). The plates were developed using solvent system chloroform (CHCl3):EtOAc:methanol (MeOH):formic acid, 86:10:4:1%. The desired product remained at the origin. The origin band was scraped and eluted with DMF. The DMF was removed with a stream of argon gas. The sample was dissolved in 30% MeOH/H2O and made slightly basic using a solution of sodium hydroxide (4 N). The product was collected from HPLC using a 15 cm×4.6 mm, 5 μm, Supelcosil LC-ABZ column with a solvent system of 30% MeOH at a flow rate of 1 mL/min., at 254 nm; sodium p-nitrosuccinanilate (C10H9N2NaO5) in a yield of 59%. Accurate mass measurement was observed by Fast Atom Bombardment on the double sodium ion at 283.0326 (calculated for C10H9N2Na2O5+, 283.03069 (Δ1.91 ppm)).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[N+]([O-])=O.P(Cl)(Cl)[Cl:16]>>[Cl:16][C:3]1[CH:2]=[CH:11][C:6]2[C:5](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:4]=1
Reactant: O=[N+]([O-])c1ncc2ccccc2c1O
Reactant: ClP(Cl)Cl
Product: Clc1ccc2ccccc2n1
Yield: 42.5 %

Procedure:
To 13.25 g (69.7 mmol) of 4-hydroxy-3-nitroisoquinoline was added 120 mL of phosphorous trichloride. After the mixture had been refluxed for 3 hours, 80 mL of POCl3 was distilled out. The remaining solution was poured onto approximately 150 g of crushed ice. The resulting solid was filtered and recrystallized from ethanol to give 6.2 g (42.5%) of the chioroquinoline as yellow needles: mp 103-104° C. (lit mp 108-109° C.); 1H-NMR (DMSO-d6, 200 MHz) δ 9.20 (s, 1H), 8.5 (d, 1H) 8.30 (d, 1H), 7.8 (m, 2H); IR (KBr) 1530 (s, NO2), 1344 (s, NO2) cm−1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([C:19]2[N:24]=[C:23]([C:25]([O:27]C)=[O:26])[CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.O>[C:1]([O:5][C:6](=[O:29])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([C:19]2[N:24]=[C:23]([C:25]([OH:27])=[O:26])[CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cccc(-c2cccc(OCCCCCC(=O)OC(C)(C)C)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)CCCCCOc1cccc(-c2cccc(C(=O)O)n2)c1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
To a solution of compound 8 (840 mg, 2.1 mmol, 1 eq.) in methanol (5 mL) was added NaOH (168 mg, 4.2 mmol, 2 eq.) dissolved in a minimum amount of water. The mixture was stirred at room temperature and monitored by TLC. After completion of the reaction volatiles were removed in vacuo and ethyl acetate added. The solution was washed with NaH2PO4 buffer (pH 5, 1M) and brine, dried over Na2SO4 and concentrated in vacuo to give 810 mg of crude compound 9, which was used directly in the next step. MS m/z 386 [M+H]+
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][N:6]2[CH:12]=1.[N:13]1([C:19]2[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[CH:21][CH:20]=2)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(CC)CC)C.C(O)CO>O>[CH3:11][C:9]1[CH:8]=[CH:7][N:6]2[CH:12]=[C:3]([CH2:2][N:16]3[CH2:15][CH2:14][N:13]([C:19]4[CH:20]=[CH:21][C:22]([C:23]([NH2:25])=[O:24])=[CH:26][CH:27]=4)[CH2:18][CH2:17]3)[N:4]=[C:5]2[CH:10]=1
Reactant: NC(=O)c1ccc(N2CCNCC2)cc1
Reactant: Cc1ccn2cc(CCl)nc2c1
Solvent: OCCO
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccn2cc(CN3CCN(c4ccc(C(N)=O)cc4)CC3)nc2c1
Temperature: 82.5 °C
Reaction time: 0.5 h
Yield: 36.4 %

Procedure:
A mixture of 2-(chloromethyl)-7-methylimidazo[1,2-α]pyridine (Example 6, Step 1; 0.300 g), 4-(piperazin-1-yl)benzamide (Example 3, Step 1; 0.357 g), triethylamine (Aldrich; 0.26 mL), and ethylene glycol (2 mL) is stirred for 30 min at 80-85° C. Additional ethylene glycol (1 mL) is added and the mixture is stirred for another 1.5 h. Water (8 mL) is added to the cooled mixture and the resulting solid is collected and dried. This material is adsorbed to silica gel and chromatographed on silica gel using methanol/dichloromethane/ammonium hydroxide (8/92/0.5). The appropriate fractions are combined and concentrated and the residue is crystallized from ethyl acetate/methanol to give 0.211 g of the title compound; mp 217-218° C.; ms m/z 349; IR (mineral oil) 1608, 1662, 1239, 3393, 1520 cm-1 ; 1H NMR (CDCl3) δ2.39, 2.74. 3.35. 3.75, 6.60. 6.88, 7.32, 7.46, 7.70 7.95.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)[CH:3]=1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CN1CCN(c2cc(Cl)ccc2[N+](=O)[O-])CC1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 4-chloro-2-fluoro-nitrobenzene (28.5 mmol), 1-methylpiperazine (28.5 mmol) and K2CO3 (37.0 mmol) in DMF is stirred at 100° C. for 16 h and diluted with water and EtOAc. The phases are separated and the aqueous phase is extracted with EtOAc. The organic phase and the extracts are combined, washed sequentially with water and brine, dried over Na2SO4 and dried in vacuo. The resultant residue is chromatographed (silica gel, 10% methanol in EtOAc as eluent) to afford the title product.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[F:26][C:27]([F:39])([F:38])[C:28]1[CH:29]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:34]([C:30]4[CH:31]=[CH:32][CH:33]=[C:28]([C:27]([F:26])([F:38])[F:39])[CH:29]=4)(=[O:36])=[O:35])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4cccc(C(F)(F)F)c4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 3-(trifluoromethyl)benzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[O:21])[C:10]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=3[O:36][CH:37]([CH3:39])[CH3:38])=[N:9]2)=[CH:4][CH:3]=1.[CH2:40]1[O:42][CH:41]1[CH2:43][OH:44]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:22]3[CH2:23][CH2:24][N:25]([CH2:40][CH:41]([OH:42])[CH2:43][OH:44])[CH2:26][CH2:27]3)=[O:21])[C:10]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=3[O:36][CH:37]([CH3:39])[CH3:38])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)N2CCNCC2)c(OC(C)C)c1
Reactant: OCC1CO1
Solvent: CO
Product: COc1ccc(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)N2CCN(CC(O)CO)CC2)c(OC(C)C)c1
Temperature: 40 °C
Yield: 44.3 %

Procedure:
[4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-piperazin-1-yl-methanone (50 mg, 0.088 mmol, example 10 g) was dissolved in anhydrous methanol (10 mL). Glycidol (0.15 mL, 2.26 mmol) was added and the reaction was heated at 40° C. for 20 h. The mixture was cooled to room temperature and concentrated in vacuo. Chromatography of the residue over silica gel using 1-6% methanol in methylene chloride gave [4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2,3-dihydroxy-propyl)-piperazin-1-yl]-methanone (25 mg, 44%). HR-MS (ES, m/z) calculated for C33H39N4O5Cl2[(M+H)+]641.2292, observed 641.2300.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9](O)=[O:10])=[CH:4][CH:3]=1.CN(C)C=O.C(Cl)(=O)C([Cl:21])=O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([Cl:21])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C(=O)O)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C(=O)Cl)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(4-Bromo-phenyl)-propionic acid (0.500 g, 2.18 mmol) in dichloromethane (20 mL) was treated with dimethylformamide (0.03 mL, 0.44 mmol), followed by oxalyl chloride (0.248 mL, 2.8 mmol) dropwise over 5 minutes, and the reaction was stirred at room temperature for 1 hour. The mixture was then concentrated and dried under vacuum to give the title compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.[N:8]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[CH:12]=[CH:11][CH:10]=[CH:9]1.[F:20][C:21]([F:34])([F:33])[C:22]([N:24]1[C@H:29]2[CH2:30][CH2:31][C@@H:25]1[CH2:26][C:27](=O)[CH2:28]2)=[O:23]>ClC(Cl)C>[F:34][C:21]([F:20])([F:33])[C:22]([N:24]1[CH:29]2[CH2:30][CH2:31][CH:25]1[CH2:26][C:27]1([O:19][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:8]3[CH:9]=[CH:10][CH:11]=[C:12]13)[CH2:28]2)=[O:23]
Reactant: O=C1C[C@H]2CC[C@@H](C1)N2C(=O)C(F)(F)F
Reactant: Oc1ccccc1-n1cccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: O=C(N1C2CCC1CC1(C2)Oc2ccccc2-n2cccc21)C(F)(F)F
Temperature: 70 °C
Yield: 51.4 %

Procedure:
A solution of TFA (387 μL, 5.02 mmol) in dichloroethane (18 mL) was added to 2-pyrrol-1-ylphenol (401 mg, 2.52 mmol) and (1R,5S)-8-(2,2,2-trifluoroacetyl)-8-azabicyclo[3.2.1]octan-3-one (620 mg, 2.80 mmol). The solution was heated at 70° C. overnight. The solvent was evaporated and the crude residue was purified by column chromatography (silica gel: 0-10% EtOAc in hexanes) to afford 2,2,2-trifluoro-1-(8′-azaspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,3′-bicyclo[3.2.1]octane]-8′-yl)ethanone as a clear oil (469 mg, 46%). 1H NMR (400 MHz, CDCl3) δ 7.27 (d, J=7.5 Hz, 1H), 7.07-6.94 (m, 4H), 6.23 (t, J=3.2 Hz, 1H), 5.87 (d, J=3.4 Hz, 1H), 4.74 (d, J=7.4 Hz, 1H), 4.42 (s, 1H), 2.50-2.34 (m, 2H), 2.34-2.16 (m, 3H), 2.16-1.89 (m, 3H). ESI-MS m/z calc. 362.4, found 363.3 (M+1)+; Retention time: 2.07 minutes (3 min run).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([CH3:10])[N:3]=1.[OH-].[NH4+:12].CO>O>[NH2:12][C:6]1[C:7]([F:8])=[C:2]([Cl:1])[N:3]=[C:4]([CH3:10])[N:5]=1
Reactant: Cc1nc(Cl)c(F)c(Cl)n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc(N)c(F)c(Cl)n1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
Part C: A mixture of 4,6-dichloro-5-fluoro-2-methylpyrimidine (1.55 g, 8.56 mmol), ammonium hydroxide (35%, 10.0 mL, 257 mmol), and MeOH (1.00 mL) was heated, in a sealed tube, at 70° C. for 2 h. The reaction mixture was cooled to RT, and a precipitate was formed. The reaction mixture was diluted with water (ca. 10 mL) and was stirred 30 min. The solids were collected by suction filtration, washed with water and air-dried to give 4-amino-6-chloro-5-fluoro-2-methylpyrimidine (845 mg, 61%) as a tan solid. LCMS (m/z): 162,164 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][Si](C)(C)C)=[CH:6][CH:5]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C#C[Si](C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C#Cc1ccc(C(=O)OC)cc1
Reaction time: 0.42 h
Yield: 79.9 %

Procedure:
To a solution of 4-trimethylsilanylethynyl-benzoic acid methyl ester (4.65 g, 20 mmol) (reference example 47) in THF (40 mL) is added (1M) tetrabutylammonium fluoride (3 mL, 30 mmol) and acetic acid (1.9 mL, 33 mmol). The resulting solution is stirred for 25 min, diluted with ethyl acetate, washed with water and brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (eluting with 10% ether, 10% dichloromethane in hexanes) to give 2.56 g of title compound as a pale yellow solid. 1H NMR (CDCl3) δ 3.23 (s, 1H), 3.92 (s, 3H), 7.55 (d, J=8 Hz, 2H), 8.00 (d, J=8 Hz, 2H). MS (EI) m/z 160 (M+).